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Studies in our laboratory have shown that developmental exposure to genistein causes deleterious effects on the reproductive system. Oral exposure to genistin (25mg/kg) increases uterine weight at 5 days of age similar to subcutaneous injection of genistein (20mg/kg) suggesting that subcutaneous injection of genistein is a suitable model for oral exposure to genistin. Mice treated neonatally by subcutaneous injection of genistein (0.5-50mg/kg) exhibit altered ovarian differentiation leading to multi-oocyte follicles (MOFs). Ovarian function and estrous cyclicity were disrupted in genistein treated mice with increasing severity over time. Reduced fertility was observed in mice treated with genistein (0.5, 5, or 25mg/kg) and infertility was observed at 50mg/kg. Females generated from genistein 25mg/kg females bred to control males have increased MOFs suggesting these effects can be transmitted to subsequent generations. Thus, neonatal treatment with genistein at environmentally relevant doses caused adverse consequences on reproduction in adulthood. | Phytoestrogens |
Prolonged luteal activity is one of the most formidable terminology challenges in mare reproductive biology. Prolonged luteal activity can be a result of persistence of an individual corpus luteum or the sequential development of luteal glands, each of which may have a normal life span. Luteal tissue can originate from an unovulated follicle or from an ovulation occurring during either follicular or luteal dominance. These complexities, together with ambiguous and inconsistent terminology, have resulted in confusion regarding those conditions which can be grouped broadly under the term prolonged luteal activity. Persistence of an individual corpus luteum can occur in association with severe damage to the endometrium resulting in loss of the uterine luteolytic mechanism. Spontaneous (no known uterine pathology) persistence of the corpus luteum from the follicular-phase ovulation has not been documented adequately as a clinical entity. The occurrence of ovulation towards the end of dioestrus may cause confusion about the origin of prolonged luteal activity. Such immature dioestrous corpora lutea may not respond to the release of uterine luteolysin, thereby leading to prolonged luteal activity even though the original corpus luteum regressed at the normal time. In the absence of critical monitoring of the corpus luteum (eg by ultrasound) the prolonged activity could be attributed erroneously to persistence of the corpus luteum from the follicular-phase ovulation. Pseudopregnancy is another confusing term that is sometimes used to describe persistence of the corpus luteum, especially when the luteal persistence is caused by embryonic loss after the embryo has blocked the uterine luteolytic mechanism.(ABSTRACT TRUNCATED AT 250 WORDS) | Luteinization |
cAMP-dependent protein kinases are reversibly complexed with any of the four isoforms of regulatory (R) subunits, which contain either a substrate or a pseudosubstrate autoinhibitory domain. The human protein kinase X (PrKX) is an exemption as it is inhibited only by pseudosubstrate inhibitors, i.e. RIalpha or RIbeta but not by substrate inhibitors RIIalpha or RIIbeta. Detailed examination of the capacity of five PrKX-like kinases ranging from human to protozoa (Trypanosoma brucei) to form holoenzymes with human R subunits in living cells shows that this preference for pseudosubstrate inhibitors is evolutionarily conserved. To elucidate the molecular basis of this inhibitory pattern, we applied bioluminescence resonance energy transfer and surface plasmon resonance in combination with site-directed mutagenesis. We observed that the conserved alphaH-alphaI loop residue Arg-283 in PrKX is crucial for its RI over RII preference, as a R283L mutant was able to form a holoenzyme complex with wild type RII subunits. Changing the corresponding alphaH-alphaI loop residue in PKA Calpha (L277R), significantly destabilized holoenzyme complexes in vitro, as cAMP-mediated holoenzyme activation was facilitated by a factor of 2-4, and lead to a decreased affinity of the mutant C subunit for R subunits, significantly affecting RII containing holoenzymes." | Cyclic AMP-Dependent Protein Kinases |
At present there is much excitement about drug-eluting stents, which hold promise for the treatment of coronary artery disease. This ingenious therapy involves coating the outside of a standard coronary stent with a thin polymer containing medication that can prevent scarring at the site of coronary intervention. Early trials with sirolimus coated stents showed that they might prevent coronary artery restenosis, but later studies, involving more complex coronary lesions, did not show a complete absence of restenosis. Recent studies have demonstrated the long term cost effectiveness of drug-eluting stents as they have reduced the need for revascularisation procedures. At present there are few data on the safety and effectiveness of stents over follow up periods exceeding two years, and data obtained from animal models of stenting might not be completely applicable to humans. There are concerns that drug-eluting stents might delay, rather than inhibit, restenosis. Also there is concern regarding the inflammation caused by the polymer substrate. This article reviews the present data on drug-eluting stents and their benefits, shortcomings, and concerns. | Drug Implants |
BACKGROUND: Thlaspi caerulescens is a natural selected heavy metal hyperaccumulator that can not only tolerate but also accumulate extremely high levels of heavy metals in the shoots. Thus, to identify the transportors involved in metal long-distance transportation is very important for understanding the mechanism of heavy metal accumulation in this hyperaccumulator. METHODOLOGY/PRINCIPAL FINDINGS: We cloned and characterized a novel gene TcOPT3 of OPT family from T. caerulescens. TcOPT3 was pronouncedly expressed in aerial parts, including stem and leaf. Moreover, in situ hybridization analyses showed that TcOPT3 expressed in the plant vascular systems, especially in the pericycle cells that may be involved in the long-distance transportation. The expression of TcOPT3 was highly induced by iron (Fe) and zinc (Zn) deficiency, especially in the stem and leaf. Sub-cellular localization showed that TcOPT3 was a plasma membrane-localized protein. Furthermore, heterogonous expression of TcOPT3 by mutant yeast (Saccharomyces cerevisiae) complementation experiments demonstrated that TcOPT3 could transport Fe(2+) and Zn(2+). Moreover, expression of TcOPT3 in yeast increased metal (Fe, Zn, Cu and Cd) accumulation and resulted in an increased sensitivity to cadmium (Cd) and copper (Cu). CONCLUSIONS: Our data demonstrated that TcOPT3 might encode an Fe/Zn/Cd/Cu influx transporter with broad-substrate. This is the first report showing that TcOPT3 may be involved in metal long-distance transportation and contribute to the heavy metal hyperaccumulation. | Thlaspi |
Young animals appear much less vulnerable to ischemic insults. In present study, we compared neuronal damage and changes in the immunoreactivities and levels of inflammatory cytokine, interleukin (IL-) 2 as a pro-inflammatory cytokine and its receptor (IL-2Rbeta), IL-4 and IL-13 as anti-inflammatory cytokines, in the hippocampal CA1 region between adult and young gerbils after 5 min of transient cerebral ischemia. Most (about 89%) of hippocampal CA1 pyramidal neurons showed neuronal damage only in the adult gerbil at 4 days post-ischemia; in the young ischemia-group, about 61% of CA1 pyramidal neurons showed neuronal damage at 7 days post-ischemia. Thereafter, the neuronal damage in the CA1 pyramidal neurons was not significantly changed in both the groups. IL-2 and IL-2Rbeta immunoreactivity in the stratum pyramidale (SP) of the CA1 region was similar in both the sham groups. At 4 days post-ischemia, IL-2 and IL-2Rbeta immunoreactivity in the adult SP was dramatically decreased; however, in the young SP, they were not changed, and they were decreased at 7 days post-ischemia. IL-4 and IL-13 immunoreactivity in the SP of the young sham-group were much lower than those in the adult group. Four days after ischemia-reperfusion, they were dramatically decreased in the adult ischemia-group; however, at this time, they were markedly increased in the young ischemia-group. In brief, our findings indicate that IL-2, 2Rbeta, IL-4 and IL-13 immunoreactivity in young gerbils was similar or low compared to those in the adult, and they were decreased at 4 days post-ischemia in the adult; however, at this time, they were distinctively increased in the young. | CA1 Region, Hippocampal |
Florida legislation implemented in the fall of 1992, unique in the nation, mandated that practice guidelines regarding cesarean section deliveries be disseminated to obstetric physicians. The law also required that peer review boards at hospitals be established to review cesarean deliveries and that the exact dates of implementation of the guidelines be reported to a state agency. To determine the impact of the legislation, we conducted a retrospective analysis of 366,246 total live births occurring in Florida hospitals during 1992 and 1993, before and after formal hospital certification of the implementation of the guidelines. Changes in primary and repeat cesarean rates were analyzed for 108 independent groups of births, controlling for the mother's age, race, payment source, and the timing of the implementation of the guidelines at hospitals. The guideline certification program did not accelerate the consistent but gradual downward trend in cesarean births which had already been evident in the three prior years. The data do suggest that the guideline program may have affected repeat cesareans more than primary cesareans, especially in the first quarter of 1993, immediately after the hospital certification period. Reductions in repeat cesareans involved both Medicaid and commercially insured births, whereas reductions in primary cesareans were found almost exclusively within commercially insured mothers, where the existing rates are highest. Although births with a prior cesarean represent only 12.5% of all births, significant decreases in repeat cesareans were found in groups representing 72.6% of this population. By comparison, significant decreases in primary cesareans were found in groups representing only 36.5% of the births without a prior cesarean. The date of guideline implementation reported by hospitals was not related to any systematic change in observed cesarean section rates. We concluded that the mere dissemination of practice guidelines by a state agency may not achieve either the magnitude or the specificity of the results desired without an explicit and thorough guideline implementation program. Blunt legislative mandates may be ineffective when multiple initiatives are already achieving desired outcomes. | Peer Review, Health Care |
BACKGROUND: We conducted a single-arm, dose-escalation, phase 1 clinical trial in order to define the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of bexarotene in combination with docetaxel. METHODS: Patients with solid tumors and no other curative treatment options were eligible. Oral bexarotene was taken daily in combination with docetaxel 25 mg/m(2) administered intravenously on days 1, 8, and 15 of a 28-day cycle. The dose of bexarotene started at 200 mg/m(2) and increased by 100 mg/m(2)/dose level, until either a MTD or the final dose of 400 mg/m(2) was reached. RESULTS: Fifteen patients were enrolled in the study. Median age was 58 years. The majority had non-small-cell lung cancer. The study went to completion without reaching an MTD. Hematological toxicities were mild. Three patients developed grade 3 hypertriglyceridemia, all occurring during the first cycle of treatment. No objective responses were noted. Four patients had stable disease as a best response, 3 with non-small-cell lung cancer and 1 with angiosarcoma. CONCLUSIONS: Treatment was well tolerated and no DLT was seen at docetaxel 25 mg/m(2) and bexarotene 400 mg/m(2). Given that stable disease was durable in 4 patients, future studies with this combination may be warranted. | Bexarotene |
Reported herein is a new entry in the growing arsenal of arylmethyl ether protecting groups. The para-siletanylbenzyl (PSB) ether is electronically similar to the benzyl ether. Cleavage of the PSB ether is accomplished under mild conditions--involving alkaline hydrogen peroxide--that are unique among cleavage protocols for arylmethyl ethers. Furthermore, the PSB group affords the user new flexibility in the implementation of protecting group strategies that revolve around multiple arylmethyl ether protecting groups. In addition to hydrogen peroxide-based cleavage protocols, conversion of a PSB ether into a para-methoxybenzyl (PMB) ether and assembly of a PSB ether from a pre-existing para-bromobenzyl (PBB) ether are described. Finally, a new reagent for installing PSB ethers under neutral mix and heat" conditions is reported." | Ethers |
BACKGROUND: Abnormal auditory processing of deviant stimuli, as reflected by mismatch negativity (MMN), is often reported in schizophrenia (SCZ). At present, it is still under debate whether this dysfunctional response is specific to the full-blown SCZ diagnosis or rather a marker of psychosis in general. The present study tested MMN in patients with SCZ, bipolar disorder (BD), first episode of psychosis (FEP), and in people at clinical high risk for psychosis (CHR). METHODS: Source-based MEG activity evoked during a passive auditory oddball task was recorded from 135 patients grouped according to diagnosis (SCZ, BD, FEP, and CHR) and 135 healthy controls also divided into four subgroups, age- and gender-matched with diagnostic subgroups. The magnetic MMN (mMMN) was analyzed as event-related field (ERF), Theta power, and Theta inter-trial phase coherence (ITPC). RESULTS: The clinical group as a whole showed reduced mMMN ERF amplitude, Theta power, and Theta ITPC, without any statistically significant interaction between diagnosis and mMMN reductions. The mMMN subgroup contrasts showed lower ERF amplitude in all the diagnostic subgroups. In the analysis of Theta frequency, SCZ showed significant power and ITPC reductions, while only indications of diminished ITPC were observed in CHR, but no significant decreases characterized BD and FEP. CONCLUSIONS: Significant mMMN alterations in people experiencing psychosis, also for diagnoses other than SCZ, suggest that this neurophysiological response may be a feature shared across psychotic disorders. Additionally, reduced Theta ITPC may be associated with risk for psychosis. | Evoked Potentials, Auditory |
The metabolism and toxicity of bromobenzene has been investigated for well over one hundred years. The urinary excretion of mercapturic acids was first reported in 1879, in animals treated with bromobenzene. Bromobenzene has since proven to be a valuable tool in efforts to unravel the complexities involved in chemical- induced toxicities. For example, the importance of metabolic activation via the cytochrome(s) P-450; the role of glutathione in the detoxification of reactive metabolites; and the toxicological significance of covalent binding, enzyme inactivation and lipid peroxidation have all been illustrated in studies with bromobenzene. Thus, many of the principles involved in chemical-induced toxicity have been exemplified in studies with bromobenzene. These studies have provided substantial insight into the role of chemically reactive metabolites in the genesis of xenobiotic-mediated cytotoxicity. | Bromobenzenes |
Plumage damage (PD) resulting from severe feather pecking (SFP) is a significant problem for animal welfare, performance, and economics in commercial laying hen farms. Genetics, nutrition, and housing conditions are central complexes that contribute to the multifactorial cause of SFP. Practical experience suggests that infestation by the poultry red mite (PRM), which is the most severe ectoparasite of laying hens in cage-free housing systems, may be a risk factor for the occurrence of PD, although evidence-based findings are lacking. The objective of this longitudinal observational field study was to investigate the effects of PRM infestation of commercial laying flocks on the occurrence of PD. Integument scoring (plumage damage and skin lesions) and the quantification of PRM infestation using mite traps were conducted during the laying period of 28 laying flocks, with an average flock size of 12,357 birds in barn (n = 21) or free-range (n = 7) systems. Across all flocks and survey times, the median PRM mass per trap was 0.7 mg (1.-3. quartile: 0.0-19.3 mg/trap), corresponding to a median count of 65.2 mites/trap (1.-3. quartile: 0.0-246.8 mites/trap). Binary logistic regression models revealed an association between PD and skin lesions with hen age, housing system, and hybrid type (p<0.001). The PRM load also affected the plumage condition, where PD increased with increasing PRM infestation (p<0.001). In addition, the PRM load tended to have an effect on skin injuries (p = 0.097). In conclusion, this longitudinal study identified the PRM load in laying hen flocks as a risk factor for PD. | Mite Infestations |
In a group of pedigree cats (nâ¯=â¯17) in poor health condition housed in an animal shelter in Vienna, Austria, with a history of persistent diarrhea, Tritrichomonas foetus infection was detected by PCR. Despite pre-existing clinical conditions all cats were treated with ronidazole (30â¯mg/kg PO q24h for 14â¯days) under close observation. After treatment, 11 of 14 initially positive animals remained negative for T. foetus during the observation period (six to eight weeks post treatment) and no diarrhea was observed. During treatment, nine cats showed mild to moderate neurological disorders (incoordination, mild tremor) at least once; six of these had already shown similar signs before treatment. Ronidazole treatment of multimorbid animals is acceptable if the benefit (here: clinical resolution and release from quarantine for adoption) is high. It is hypothesized that a high degree of inbreeding is a significant risk factor for the development of tritrichomonosis in cats. | Tritrichomonas |
The main objectives of this study were to evaluate the short-term effects of resisted sprint and plyometric training on sprint performance together with lower limb physiological and functional performance in collegiate football players. Ninety collegiate football players participated in this three-arm, parallel group randomized controlled trial study. Participants were randomly divided into a control group and two experimental groups: resisted sprint training (RST) (n = 30), plyometric training (PT) (n = 30), and a control group (n = 30). Participants received their respective training program for six weeks on alternate days. The primary outcome measures were a knee extensor strength test (measured by an ISOMOVE dynamometer), a sprint test and a single leg triple hop test. Measurements were taken at baseline and after 6 weeks post-training. Participants, caregivers, and those assigning the outcomes were blinded to the group assignment. A mixed design analysis of variance was used to compare between groups, within-group and the interaction between time and group. A within-group analysis revealed a significant difference (p < 0.05) when compared to the baseline with the 6 weeks post-intervention scores for all the outcomes including STN (RST: d = 1.63; PT: d = 2.38; Control: d = 2.26), ST (RST: d = 1.21; PT: d = 1.36; Control: d = 0.38), and SLTHT (RST: d = 0.76; PT: d = 0.61; Control: d = 0.18). A sub-group analysis demonstrated an increase in strength in the plyometric training group (95% CI 14.73 to 15.09, p = 0.00), an increase in the single leg triple hop test in the resisted sprint training group (95% CI 516.41 to 538.4, p = 0.05), and the sprint test was also improved in both experimental groups (95% CI 8.54 to 8.82, p = 0.00). Our findings suggest that, during a short-term training period, RST or PT training are equally capable of enhancing the neuromechanical capacities of collegiate football players. No adverse events were reported by the participants. | Plyometric Exercise |
Malingering is relatively common in criminal forensic evaluations as base rates of malingering have ranged from 20% to 30%. Given that the most prevalent criminal forensic evaluation is the assessment of competency to stand trial, the assessment of feigning during competency evaluations is necessary for accurate findings. Most of the response style literature focuses on feigning mental health symptoms, but in competency evaluations, individuals may attempt to feign legal knowledge deficits in order to be found incompetent to stand trial. The current investigation includes two studies: 195 students instructed to simulate feigned mental illness or incompetence to stand trial and one using a sample of 130 state psychiatric hospital residents who had been adjudicated incompetent to stand trial. The purpose of the study was to evaluate the Inventory of Legal Knowledge's (ILK; Musick & Otto, 2010) ability to detect individuals who are feigning legal knowledge deficits. Classification utility statistics, including sensitivity, specificity, positive predictive power, and negative predictive power are provided for each cut-score on the ILK beginning with a cut-score of 24 (which is the lower end of the range of chance) are provided. The current cut-score of 47 provided in the professional manual of the ILK was shown to create a large number of false positives and suggests that modifications to this cut-score are required. | Malingering |
OBJECTIVES: This study aims to mechanically compare five different extra-focal bi-cortical pin configurations (using two and three pins) employed for fixation of a simulated unstable extra-articular distal radius fracture with dorsal comminution using a sawbone model. MATERIALS AND METHODS: This in vitro mechanical study was conducted between June 2019 and July 2019. A standard fracture model (Arbeitsgemeinschaft fur Osteosynthesefragen [AO] type 23-A3.3) was created using a fourth generation composite artificial radius bone. Five groups with two- and three-pin configurations were tested under axial, volar, and dorsal loading with a universal test device. Mean stiffness values were compared statistically. RESULTS: Comparison of stiffness values from axial and volar loading tests between groups in paired comparison showed no statistically significant difference (p=0.194 and p=0.086, respectively). Dorsal loading tests showed statistically significant difference between the groups in pairwise comparison (p=0.002). Three-pin groups (Groups 3, 4, and 5) had higher stiffness values compared to two-pin groups (Groups 1 and 2) in dorsal loading tests (p=0.001). Three-pin configuration test groups with two divergent or convergent pins from the radial styloid performed better compared to both two-pin groups (p=0.01, p=0.002) in dorsal loading tests. CONCLUSION: Our data demonstrated that the three-pin configuration with two divergent or convergent Kirschner wires from the styloid and a third wire from the dorsal/ulnar cortex had higher stiffness values compared to two-pin configurations in dorsal loading tests. When indicated, we suggest the use of a three-pin construct. Particularly in cases with a risk of volar angulation, we recommend a three-pin configuration with two divergent or convergent bi-cortical Kirschner wires. | Bone Nails |
A 24-year-old woman was admitted to our hospital due to abdominal pain and a high fever. She was diagnosed with ileocolonic Crohn's disease (CD), complicated with a gastro-colic fistula and splenomegaly. After initial treatment with an infliximab-biosimilar, all blood cell line counts markedly decreased. Three-dimensional reconstructed computed tomography revealed splenic vein narrowing. Thus, her pancytopenia was deemed to have likely been caused by hypersplenism. Surgery was performed, and clinical remission was maintained without pancytopenia. This is the first report of a CD patient with pancytopenia caused by hypersplenism that was triggered by gastro-colic fistula-associated splenic vein obstruction. | Hypersplenism |
AIM: Langendorff-perfused murine hearts are increasingly used in cardiovascular research, but coronary cardiovascular haemodynamics vary considerably from one research group to another. The aim of this study was to establish an isolated, retrogradely perfused mouse heart preparation for the simultaneous measurement of left ventricular haemodynamics and of coronary flow (CF). METHODS: Heart rate was controlled by right atrial pacing (480 beats min(-1)) and heart temperature was kept constant. Accurate flow values of <0.5 mL min(-1) could be determined, and this methodology was then used to study the stability of this preparation, as well as coronary response to vasoactive drugs and to short-term ischaemia. RESULTS: The CF and maximum systolic pressure were well maintained over a 2-h perfusion period, both showing a 10% decline per hour. Sodium-nitroprusside (endothelium-independent) and adenosine (endothelium-dependent) increased CF relatively modest (30-50% above baseline values). Short-term no-flow ischaemia caused a transient 40-50% increase in CF on reperfusion. Peak reflow occurred approximately 15 s after start of reperfusion and flow returned to baseline during the following 1-2 min. Increased coronary blood flow following infusion of vasoactive drugs (nitroprusside or adenosine) or short-term ischaemia were associated with minor changes in ventricular pressure development. CONCLUSIONS: Blood flow and haemodynamics can readily be determined in this isolated perfused mouse heart model, but CF reserve is relatively small, compared with blood-perfused organs. | Coronary Circulation |
Tropomyosin (TM), a myofibrillar protein, is a major allergen in shrimp. The aim of this study was to evaluate the effect of transglutaminase (TGase)-catalyzed glycosylation on the potential allergenicity and conformational structure of TM in Metapenaeus ensis. Results showed that glycosylation of TM induced unfolding of the primary protein structure followed by loss of the secondary structure. Cleavage of certain free amino groups was observed during TGase-catalyzed glycosylation. The glycosylation rate correlated with reaction temperature. Western blotting and indirect ELISA with TM-specific polyclonal antibodies from rabbit and sera from patients allergic to shrimp demonstrated that antigenicity and potential allergenicity of TM decreased, which correlated well with the conformational changes in its structure. Considering TGase is widely utilized in the food industry, these results indicate that TGase-catalyzed glycosylation has the potential to serve as a mild method for reducing the allergenicity of shrimp products. | Shellfish Hypersensitivity |
Notch is a critical signaling pathway that controls cell fate and tissue homeostasis, but the functional characterization of Notch ligand domains that activate Notch receptors remains incomplete. Here, we established a method for immobilizing Notch ligand proteins onto beads to measure time-dependent Notch activity after the addition of Notch ligand-coated beads. A comparison between activities by the Notch ligand found on the cell surface to that of the ligand immobilized on beads showed that immobilized Notch ligand protein produces comparable signal activity during the first 10 h. Follow-up truncation studies showed that the N-terminal epidermal growth factor (EGF) repeat three region of delta like canonical Notch ligand 4 (DLL4) or jagged 1 (JAG1) is the minimum region for activating Notch signaling, and the DLL4 EGF repeat three domain may have a role in activation through a mechanism other than by increasing binding affinity. In addition, we found that reconstruction of the DLL4 delta and OSM-11 (DOS) motif (N257P) resulted in an increase in both binding affinity and signaling activity, which suggests that the role of the DOS motif is conserved among Notch ligands. Furthermore, active DLL4 protein on beads promoted T cell differentiation or inhibited B cell differentiation in vitro, whereas JAG1 proteins on beads did not have any effect. Taken together, our findings provide unambiguous evidence for the role of different Notch ligands and their domains in Notch signal activation, and may be potential tools for controlling Notch signaling activation. J. Cell. Biochem. 118: 785-796, 2017. (c) 2016 Wiley Periodicals, Inc. | Jagged-1 Protein |
BACKGROUND: The collectin surfactant protein D (SP-D) confers protection against pulmonary infection and inflammation. Recent data suggest a role for SP-D in the modulation of allergic inflammation. OBJECTIVE: The aim of this study is to characterize the immune responses of SP-D-deficient (SP-D(-/-)) mice in a kinetic model of allergic inflammation. We determined whether allergic parameters were enhanced in SP-D(-/-) mice in vivo. Further, we examined whether functional immune responses in vitro such as lymphocyte proliferation (LP) and cytokine production were modulated in the absence of SP-D. METHODS: In vivo, wild-type (WT) and SP-D(-/-) mice were sensitized and challenged with the allergen ovalbumin (OVA) and assessed for allergic parameters (bronchoalveolar lavage (BAL) eosinophils, IL-13 production, pulmonary IFN-gamma, IL-10 expression) at early time points (1 and 3 days of challenge) in comparison with late time points (7 days of challenge). In vitro, spleen cells from WT and SP-D(-/-) mice were stimulated with the mitogen concanavalin A (ConA) and lipid A (LpA) and analysed for LP, IL-13 and IFN-gamma production. Toll-like receptor 4 (TLR4), ligand for LpA, was assessed by mRNA expression and immunohistochemistry in vivo. RESULTS: Following allergen exposure in vivo, SP-D(-/-) mice expressed higher BAL eosinophils and IL-13 concentrations and lower IFN-gamma expression at early time points compared with WT mice. IL-10 expression was increased at early time points in SP-D(-/-) compared with WT mice. Allergen-induced TLR4 expression was increased in WT, but not in SP-D(-/-) mice. After stimulation with LpA and ConA in vitro LP was increased and IFN-gamma concentration was decreased in SP-D(-/-) mice. CONCLUSION: SP-D may be critical for the modulation of early stages of allergic inflammation in vivo." | Pulmonary Surfactant-Associated Protein D |
With the use of a rabbit surgical model, the ability of 1%, 2%, and 3% solutions of sodium carboxymethylcellulose to reduce postoperative uterine adhesions was determined. At all concentrations sodium carboxymethylcellulose was more effective than either 32% dextran 70 or heparinized lactated Ringer's solution. Neither the dextran nor Ringer's solution had a significant (p less than or equal to 0.05) effect. The beneficial effects of sodium carboxymethylcellulose were closely dose-dependent (correlation coefficient 0.97). Sodium carboxymethylcellulose is highly effective in reducing postoperative adhesions in laboratory animals, and additional studies are warranted to further define its efficacy and safety. | Carboxymethylcellulose Sodium |
We present a case of large pneumopericardium resulting from an esophageal pericardial fistula following ablation for atrial fibrillation (AF). The presentation, evaluation, and management of this specific patient, along with a review of present techniques to diagnose esophageal injury, provide a unique insight into the pathophysiology of left atrial-esophageal fistula formation. | Pneumopericardium |
Treatment of venous thromboembolism (VTE) usually starts with concomitant administration of heparin or low-molecular-weight heparin (LMWH) and a vitamin K antagonist. The parenteral anticoagulant, which is given for at least 5 days, is stopped once the vitamin K antagonist produces a therapeutic level of anticoagulation. Although the introduction of LMWH has simplified the initial treatment of VTE, problems remain. LMWH must be given by daily subcutaneous (SC) injection and vitamin K antagonists require routine coagulation monitoring, which is inconvenient for patients and physicians. Recently, 3 new anticoagulants have been introduced in an attempt to overcome these limitations. These include fondaparinux and idraparinux, synthetic analogs of the pentasaccharide sequence that mediates the interaction of heparin and LMWH with antithrombin, and ximelagatran, an orally active inhibitor of thrombin. These agents produce a predictable anticoagulant response; thus, routine coagulation monitoring is unnecessary. Because they do not bind to platelets or platelet factor 4, fondaparinux and idraparinux do not cause heparin-induced thrombocytopenia (HIT). Unlike vitamin K antagonists, ximelagatran has a rapid onset of action, thereby obviating the need for concomitant administration of a parenteral anticoagulant when starting treatment. The lack of an antidote for these new agents is a drawback, particularly for idraparinux, which has a long half-life. | Azetidines |
Non-enveloped icosahedral double-stranded RNA (dsRNA) viruses possess multifunctional capsids required for their proliferation. Whereas protozoan/fungal dsRNA viruses have a relatively simple capsid structure, which suffices for the intracellular phase in their life cycle, metazoan dsRNA viruses have acquired additional structural features as an adaptation for extracellular cell-to-cell transmission in multicellular hosts. Here, we present the first atomic model of a metazoan dsRNA totivirus-like virus and the structure reveals three unique structural traits: a C-terminal interlocking arm, surface projecting loops, and an obstruction at the pore on the 5-fold symmetry axis. These traits are keys to understanding the capsid functions of metazoan dsRNA viruses, such as particle stability and formation, cell entry, and endogenous intraparticle transcription of mRNA. On the basis of molecular dynamics simulations of the obstructed pore, we propose a possible mechanism of intraparticle transcription in totivirus-like viruses, which dynamically switches between open and closed states of the pore(s). | Totivirus |
Fine control over the mechanical properties of thin sheets underpins transcytosis, cell shape, and morphogenesis. Applying these principles to artificial, liquid-based systems has led to reconfigurable materials for soft robotics, actuation, and chemical synthesis. However, progress is limited by a lack of synthetic two-dimensional membranes that exhibit tunable mechanical properties over a comparable range to that seen in nature. Here, we show that the bending modulus, B, of thin assemblies of nanoparticle surfactants (NPSs) at the oil-water interface can be varied continuously from sub-k(B)T to 10(6)k(B)T, by varying the ligands and particles that comprise the NPS. We find extensive departure from continuum behavior, including enormous mechanical anisotropy and a power law relation between B and the buckling spectrum width. Our findings provide a platform for shape-changing liquid devices and motivate new theories for the description of thin-film wrinkling. | Anisotropy |
This study evaluated the effectiveness of normal saline versus normal saline containing 10 U per 1 mL heparin for preventing loss of an intermittent intravenous site (heparin lock). The sample consisted of 260 surgical patients from a general surgery and a cardiovascular surgery nursing unit at a tertiary care hospital. Results indicated that heparinized saline is not needed to maintain the patency of an intermittent intravenous site, and the use of saline solution alone is less irritating, causes less phlebitis, is less expensive to patients, and saves nursing time. | Injections, Intravenous |
The application of new biotechnology to the study of the biochemistry of rickettsiae was a prominent feature of the presentations at the 3rd International Symposium on Rickettsiae and Rickettsial Diseases, held in Smolenice near Bratislava in September 1984. This review is an attempt to summarize recent advances leading up to these presentations as well as the studies that have been reported in the two years since the meeting. Since rickettsiae are intracellular parasites, most reviews deal with the interaction of rickettsiae with host cells. It is useful, however, to focus also--as we have done--on the properties of rickettsiae that can be demonstrated in the absence of their hosts, although, undoubtedly, many of these properties reflect adaptation to an intracellular microenvironment. | Rickettsiaceae |
The urachal ligament is an embryologic remnant connecting the dome of the bladder to the umbilicus via the ligamentum commune. Autopsy series suggest that in approximately a third of subjects, the urachal remnant may persist with tubular or cystic structures. However, tumors of this site are extremely rare. Patients usually present with hematuria and upon imaging, have evidence of a cystic or solid structure in the bladder dome or in the bladder midline. If a biopsy confirms adenocarcinoma, these tumors should be considered an urachal cancer until proven otherwise. Although there are no prospective clinical trials reported to date, large single-institution reports suggest surgical resection with a partial cystectomy and en bloc resection of the urachal ligament with umbilicus as the treatment of choice in the setting of localized disease. Although there is currently no definitive role for neoadjuvant or adjuvant chemotherapy in this tumor, risk factors predicting progression may allow for the selection of patients at higher relapse risk for prospective studies. Unfortunately, there are many patients who present with metastatic disease that currently is not likely to be curable. There is no standard chemotherapy regimen for these patients; however, there is new-found hope with a currently accruing clinical trial exploring a 5-fluorouracil-based chemotherapy combination in this patient population. | Urachal Cyst |
Two rare cases of villous adenoma of the duodenum are described. Obstructive jaundice was the presenting clinical feature. Histologically the tumour was benign in both cases. Local excision was performed. One year later both patients were free from recurrence, but one was treated for gastric adenocarcinoma after 2 years. The literature is reviewed. | Duodenal Neoplasms |
CONTEXT: Carbonic anhydrase III (CA III) is a cytosolic enzyme which is known to be highly expressed in the skeletal muscle and has been recently linked to important roles in several physiological processes. OBJECTIVE: This review is focused on properties of CA III, including its distribution, function, structure and modulation of enzymatic activity by activators or inhibitors. We also provide some novel data on its expression in murine tissues. METHODS: In this article, the most relevant literature on CA III has been covered. New information on the distribution has been obtained by immunohistochemical staining and western blotting. RESULTS AND CONCLUSION: CA III shows the highest expression in the skeletal muscle and liver. Several other tissues contain lower levels of the enzyme. Activation or inhibition of CA III may offer a novel opportunity to treat some of the diseases linked to the defective expression or function of this enzyme. | Isoenzymes |
OBJECTIVE: To explore the effects of electroacupuncture (EA) combined with motor imagery therapy on motor function and activity of daily living in patients with hemiplegic cerebral infarction. METHODS: Ninety patients with hemiplegic cerebral infarction were randomly divided into a rehabilitation group, an EA group and a comprehensive group, 30 patients in each one. The patients in the rehabilitation group were treated with regular care, medication and rehabilitation training; based on the rehabilitation group, the patients in the EA group were treated mainly with electroacupuncture at Baihui (GV 20), Dingnieqianxiexian (MS 6), Dingniehouxiexian (MS 7), Jianyu (LI 15), Waiguan (TE 5), Fengshi (GB 31) and Sanyinjiao (SP 6); with the arrival of qi. EA device was connected for 30 min. The patients in the comprehensive group were treated with EA as the EA group and motor imagery therapy, 20 min per treatment. The treatment was given once a day, five treatments per week, and totally 4-week treatment was performed. The Barthel index and Brunnstrom score before and after treatment were observed in the three groups. RESULTS: Three cases did not finish the trial and finally 87 cases were included into analysis, including 30 cases in the rehabilitation group, 29 cases in the EA group and 28 cases in the comprehensive group. Compared before treatment, the Barthel index and Brunnstrom score were significantly improved after treatment in the three groups (all P<0.01); after treatment, the Barthel index in the EA group and comprehensive group was significantly higher than that in the rehabilitation group (both P<0.01); the lower extremity score of Brunnstrom score in the comprehensive group was better than those in the EA group and rehabilitation group (both P<0.05). CONCLUSION: EA combined with motor imagery therapy and rehabilitation can significantly improve the motor function and activity of daily living in patients with hemiplegic cerebral infarction, which is superior to rehabilitation alone or EA alone. | Electroacupuncture |
The narrow absorption and emission bands, long fluorescence lifetime, and excellent stability of rare earth nanoparticles (referred to as RE NPs) make them very attractive for multimodal imaging and therapy of cancer. Their narrow absorption requires the careful selection of laser wavelength to achieve the best performance, particularly for RE NPs simultaneously having photothermal and photoluminescent properties (e.g., Nd-based nanoparticles), which has not been investigated. Herein, we prepared a series of different-sized NaNdF(4) nanoparticles (referred to as NNF NPs) (i.e., 4.7, 5.9, 12.8, and 15.6 nm) from ultrasmall nanoclusters and investigated their in vitro and in vivo size-dependent photothermal conversion and photoluminescence under irradiation by a 793 nm laser and an 808 nm laser, respectively. We find that all nanoparticles exhibited the better photothermal conversion performance under the irradiation of the 808 nm laser than under the 793 nm laser, of which 12.8 nm NNF NPs showed the best performance, and the temperature of their solution can be quickly increased from 30 degrees C to around 60 degrees C within 10 min under the irradiation of the 808 nm laser with a power intensity of 0.75 W/cm(2). When we used the 793 nm laser to excite these NNF NPs, we found that all nanoparticles exhibited the stronger photoluminescence in the second near-infrared window (NIR-II) than under the excitation by the 808 nm laser, of which 15.6 nm NNF NPs possessed the strongest NIR-II luminescence. We then modified 12.8 nm NNF NPs with phospholipid carboxyl PEG and functionalized with RGD for actively targeted imaging of cancer. The NaNdF(4)@PEG@RGD nanoparticles (referred to as NNF-P-R NPs) have good biocompatibility, stability, and excellent targeting capability. The in vivo result show that 12.8 nm NNF NPs exhibited better photothermal conversion performance under the irradiation of the 808 nm laser, and stronger NIR-II fluorescence under irradiation of the 793 nm laser, which are consistent with the in vitro result. This work demonstrates the significance of selection of the proper laser wavelength for maximally taking advantage of RE nanoparticles for the diagnosis and treatment of cancer. | Sodium Fluoride |
Depleted uranium used as ammunition corrodes in the environment forming mineral phases and then dissolved uranium species like uranium carbonates (Schimmack et al., in Radiat Environ Biophys 46:221-227, 2007) and hydroxides. These hydroxide species were contacted with plant cells (canola). After 24 h contact time the cells were fractionated and the uranium speciation in the fraction was determined by time resolved laser-induced fluorescence spectroscopy at room temperature as well at 150 K. It could be shown that the uranium speciation in the fractions is different to that in the nutrient solution. Comparison of the emission bands with literature data allows assignment of the uranium binding forms. | Uranium Compounds |
We report on a patient in whom a giant thrombus in the left atrium was detected by transthoracic echocardiography. Anticoagulant theraphy was started. After two months of therapy, repeat echocardiography showed complete resolution of the thrombus. This case indicates that large and presumably organised thrombi may be treated with anticoagulant therapy. | Systolic Murmurs |
Male germ cells undergo two consecutive processes - pre-spermatogenesis and spermatogenesis - to generate mature sperm. In eutherian mammals, epigenetic information such as DNA methylation is dynamically reprogrammed during pre-spermatogenesis, before and during mitotic arrest. In mice, by the time germ cells resume mitosis, the majority of DNA methylation is reprogrammed. The tammar wallaby has a similar pattern of germ cell global DNA methylation reprogramming to that of the mouse during early pre-spermatogenesis. However, early male germline development in the tammar or in any marsupial has not been described previously, so it is unknown whether this is a general feature regulating male germline development or a more recent phenomenon in mammalian evolutionary history. To answer this, we examined germ cell nuclear morphology and mitotic arrest during male germline development in the tammar wallaby (Macropus eugenii), a marsupial that diverged from mice and humans around 160 million years ago. Tammar pro-spermatogonia proliferated after birth and entered mitotic arrest after day 30 postpartum (pp). At this time, they began moving towards the periphery of the testis cords and their nuclear size increased. Germ cells increased in number after day 100 pp which is the time that DNA methylation is known to be re-established in the tammar. This is similar to the pattern observed in the mouse, suggesting that resumption of germ cell mitosis and the timing of DNA methylation reprogramming are correlated and conserved across mammals and over long evolutionary timescales. | Macropodidae |
Part of the life cycle of several fish species includes important salinity changes, as is the case for the sea bass (Dicentrarchus labrax) or the Atlantic salmon (Salmo salar). Salmo salar juveniles migrate downstream from their spawning sites to reach seawater, where they grow and become sexually mature. The process of preparation enabling juveniles to migrate downstream and physiologically adapt to seawater is called smoltification. Daily and seasonal variations of photoperiod and temperature play a role in defining the timing of smoltification, which may take weeks to months, depending on the river length and latitude. Smoltification is characterised by a series of biochemical, physiological and behavioural changes within the neuroendocrine axis. This review discusses the current knowledge and gaps related to the neuroendocrine mechanisms that mediate the effects of light and temperature on smoltification. Studies performed in S. salar and other salmonids, as well as in other species undergoing important salinity changes, are reviewed, and a particular emphasis is given to the pineal hormone melatonin and its possible role in osmoregulation. The daily and annual variations of plasma melatonin levels reflect corresponding changes in external photoperiod and temperature, which suggests that the hormonal time-keeper melatonin might contribute to controlling smoltification. Here, we review studies on (i) the impact of pinealectomy and/or melatonin administration on smoltification; (ii) melatonin interactions with hormones involved in osmoregulation (e.g., prolactin, growth hormone and cortisol); (iii) the presence of melatonin receptors in tissues involved in osmoregulation; and (iv) the impacts of salinity changes on melatonin receptors and circulating melatonin levels. Altogether, these studies show evidence indicating that melatonin interacts with the neuroendocrine pathways controlling smoltification, although more information is needed to clearly decipher its mechanisms of action. | Osmoregulation |
Parathyroid hormone (PTH) is an important peptide hormone regulator of bone formation and osteoblast activity. However, its mechanism of action in bone cells is largely unknown. This study examined the effect of PTH on mouse osteocalcin gene expression in MC3T3-E1 preosteoblastic cells and primary cultures of bone marrow stromal cells. PTH increased the levels of osteocalcin mRNA 4-5-fold in both cell types. PTH also stimulated transcriptional activity of a 1.3-kb fragment of the mouse osteocalcin gene 2 (mOG2) promoter. Inhibitor studies revealed a requirement for protein kinase A, protein kinase C, and mitogen-activated protein kinase pathways in the PTH response. Deletion of the mOG2 promoter sequence from -1316 to -116 caused no loss in PTH responsiveness whereas deletion from -116 to -34 completely prevented PTH stimulation. Interestingly, this promoter region does not contain the RUNX2 binding site shown to be necessary for PTH responsiveness in other systems. Nuclear extracts from PTH-treated MC3T3-E1 cells exhibited increased binding to OSE1, a previously described osteoblast-specific enhancer in the mOG2 promoter. Furthermore, mutation of OSE1 in DNA transfection assays established the requirement for this element in the PTH response. Collectively, these studies establish that actions of PTH on the osteocalcin gene are mediated by multiple signaling pathways and require OSE1 and associated nuclear proteins. | Osteocalcin |
Dynamic behavioral analysis of carbon dioxide ([Formula: see text]) emissions to moderate the climate change helps to upgrade the developing measures utilized throughout the energy system decarbonization and mitigate global warming. Therefore, this research aims to analyze the role of the shale gas technology in behavioral characteristics of the US energy-related [Formula: see text] emissions. To this end, first, the Markov regime-switching methodology is used to assess the scale- and technology effects of the shale revolution on the switching-regimes for source-/sector-based [Formula: see text] emissions cycles of the US economy. Then, the dynamic network connectedness measures are utilized to determine the changes in the spillover effects between [Formula: see text] emissions cycle series by source/sector pre- and post-shale revolution. The findings indicate asymmetric and time-varying behavior of [Formula: see text] emissions cycles pre- and post-revolution. Particularly, the greater total spillover effect of the US source- and sector-based [Formula: see text] emissions network is accompanied with the higher speed of downward" regime following the revolution that lowers environmental degradation of the US economy. Hence, utilization of the US economies of scale in the shale technology develops the coordinating mechanism, which can support the cooperative relationship between sources/sectors of the energy system in response to the risks, time and cost change, caused by the shale revolution." | Climate Change |
Glutaric acidemia type 2 (GA2) is an autosomal recessive disorder resulting from a deficiency of electron transfer flavoprotein (ETF) or ETF dehydrogenase (ETFDH) that manifests from most severe neonatal to late-onset forms. However, the genetic defect responsible for the disease and clinical severity is not well-characterized. In order to understand the relationship between the phenotype and genetic defect, we investigated the clinical and molecular features of 15 Japanese patients, including 4 previously reported cases. Three patients had the neonatal form and 8 patients had the late-onset form, 1 of whom presented an extremely mild phenotype. Immunoblot analysis showed that either ETFalpha, ETFbeta, or ETFDH was significantly reduced or absent in all patients. However, no specific enzyme deficiency predominated, and there were no associations with the clinical severity. Genetic analyses identified 15 mutations including non-sense, missense, splice site mutations, and small deletions, in ETFA, ETFB and ETFDH genes. Although almost all mutations were unique to Japanese patients and no common mutations were found, some of them appeared to be associated with a specific phenotype. Our results suggest that clinical and mutational spectrums of Japanese GA2 patients are heterogeneous and that genetic diagnoses may help to predict a prognosis and provide more accurate diagnostic information for patients and families with GA2." | Multiple Acyl Coenzyme A Dehydrogenase Deficiency |
Radiocarbon dating of the carbonate binder of historical mortars is a strategic research topic not lacking in complexities. The critical step is the separation of anthropogenic CaCO(3)-binder from other carbonate sources that could severely affect the resulting dates. Here we present a complete procedure for the processing and characterization of difficult mortars and of the separated binder fractions in order to assess a priori the chances of positively dating the mortar, and produce a binder fraction yielding the most reliable radiocarbon dates possible. Two complex architectural case studies from Northern Italy are presented and discussed in detail: the churches of Santa Maria Maggiore (Lomello, Pavia) and Santa Maria (Torba, Varese). The results support that both the reliability assessment and the successful radiocarbon dating are possible through a multi-analytical approach encompassing mineralogical and petrographic characterization, X-ray powder diffraction, scanning electron microscopy, measurement of carbon and oxygen stable isotopes, and optical cathodoluminescence. | Radiometric Dating |
Plant seed knottins, mainly from the Cucurbitacea family, and sunflower seed trypsin inhibitor (SFTI 1) are the most low-molecular canonical peptide inhibitors of serine proteases. High efficiency of inhibition of various serine proteases, structure rigidity together with the possibility of limited variations of amino acid sequences, high chemical stability, lack of toxic properties, opportunity of production by either chemical synthesis or use of heterologous expression systems make these inhibitors attractive templates for design of new compounds for regulation of therapeutically significant serine protease activities. Hence the design of such compounds represents a prospective research field. The review considers structural characteristics of these inhibitors, their properties, methods of preparation and design of new analogs. Examples of successful employment of natural serine protease inhibitors belonging to knottin family and SFTI 1 as templates for the design of highly specific inhibitors of certain proteases are given. | Serine Proteinase Inhibitors |
Various saline solution formulae are frequently used in patients with rhinosinusitis. Osmolarity affects ciliary beat frequency (CBF); however, little is known about the effects of saline solutions on ciliary activity of nasal epithelial cells. The aim of this study was to assess whether CBF of normal turbinate mucosa is affected by hypertonic, isotonic, or hypotonic saline solution in vitro and whether histologic changes are associated with the alteration of ciliary movement. We assessed variations of CBF after exposure to 0.06%, 0.12%, 0.9%, 3.0%, or 7.0% saline solutions and histologic changes were examined by transmission electron microscopy. Isotonic and hypotonic solutions produced no ciliary slowing; however, ciliostasis was observed within a few minutes in 3.0% or 7.0% solution. The histologic changes demonstrated that the ciliary slowing might be attributed to epithelial damage by fluid transport toward the surrounding medium. In conclusion, hypertonic saline solutions decrease CBF and disrupt nasal epithelial cells in vitro. | Hypotonic Solutions |
Directing both innate and adaptive immune responses against foreign pathogens with correct timing, location and specificity is a fundamental objective for the immune system. Full activation of CD4+ T cells requires the binding of peptide-MHC complexes coupled with accessory signals provided by the antigen-presenting cell. However, aberrant activation of the T-cell receptor alone in mature T cells can produce a long-lived state of functional unresponsiveness, known as anergy. Recent studies probing both immune signalling pathways and the ubiquitin-proteasome system have helped to refine and elaborate current models for the molecular mechanisms underlying T-cell anergy. Controlling anergy induction and maintenance will be a key component in the future to mitigate unwanted T-cell activation that leads to autoimmune disease. | Clonal Anergy |
Adverse reaction reports for inhaled relatively beta 2-selective, adrenergic-agonist bronchodilators submitted to the Center for Drug Evaluation and Research of the Food and Drug Administration between 1974 and 1988 were reviewed. There were 126 reports associated with the use of these drugs by metered-dose inhaler, which were consistent with a diagnosis of paradoxical bronchospasm. In addition, 58 such reports were received for these drugs delivered as a solution for nebulization between 1983 and 1988. Increased reporting of reactions consistent with paradoxical bronchospasm generally correlated with increased availability of these products during the same time period, although there has not been a steady upward trend in such reports for metered-dose inhalers during the past 3 years, despite increasing distribution figures. Despite the apparent infrequency of inhaler-induced paradoxical bronchospasm, the potentially life-threatening nature of such reactions makes awareness of this possibility essential. Patients who report that an inhaled beta-adrenergic agonist makes their asthma worse, as well as the patients who fail to demonstrate expected improvement with this form of therapy, should be suspected of having developed paradoxical bronchospasm. | Adrenergic beta-Agonists |
Protein disulfide isomerase (PDI) is a multidomain enzyme, operating as an essential folding catalyst, in which the b' and a' domains provide substrate binding sites and undergo an open-closed domain rearrangement depending on the redox states of the a' domain. Despite the long research history of this enzyme, three-dimensional structural data remain unavailable for its ligand-binding mode. Here we characterize PDI substrate recognition using alpha-synuclein (alphaSN) as the model ligand. Our nuclear magnetic resonance (NMR) data revealed that the substrate-binding domains of PDI captured the alphaSN segment Val37-Val40 only in the oxidized form. Furthermore, we determined the crystal structure of an oxidized form of the b'-a' domains in complex with an undecapeptide corresponding to this segment. The peptide-binding mode observed in the crystal structure with NMR validation, was characterized by hydrophobic interactions on the b' domain in an open conformation. Comparison with the previously reported crystal structure indicates that the a' domain partially masks the binding surface of the b' domain, causing steric hindrance against the peptide in the reduced form of the b'-a' domains that exhibits a closed conformation. These findings provide a structural basis for the mechanism underlying the redox-dependent substrate binding of PDI. | Sulfur-Sulfur Bond Isomerases |
A new type of disposable external defibrillation electrode has been developed to reduce the skin irritation commonly associated with defibrillation and synchronised cardioversion. This design employs an impedance gradient to reduce the proportion of current delivered to the electrode periphery. The temperature distribution under the new electrode was compared with that of four other types of commercially available electrodes after repeated high-energy biphasic defibrillation discharges to domestic swine. Skin temperature distributions were acquired using non-invasive thermography. Measurements of the maximum temperature rise at each electrode site, taken 3.6s after the fifth defibrillation discharge, demonstrated that the new impedance-gradient electrode produced 50-60% less skin heating than two of the three uniform-impedance electrode designs. Histological examination of erythematous sites excised 24 h after defibrillation quantified the associated skin damage using a scoring protocol developed for this study. In contrast to previous studies, histological examinations demonstrated second-degree skin burns following defibrillation. The new electrode design, however, induced 44-46% less skin damage than two of the traditional uniform-impedance electrodes. | Burns, Electric |
This study investigated the effectiveness and safety of low-dose salvage craniospinal irradiation (CSI) for recurrent germinoma. We retrospectively reviewed long-term tumor control and late adverse effects in 15 recurrent germinoma patients treated at our hospital between 1983 and 2019. Following the first recurrence of germinoma, seven were treated with 24-30 Gy of salvage CSI, three underwent non-CSI, and five were treated with only chemotherapy. CSI achieved a significantly better recurrence-free survival rate after the first recurrence compared to other strategies (100% vs 33%, p < 0.001: log-rank test). To evaluate the safety of salvage CSI, we assessed the outcomes at the final follow-up of seven patients who received salvage CSI at first recurrence and three patients who received salvage CSI at second recurrence. The median follow-up period was 220 months after initial treatment. Five patients who received 40-50 Gy of radiation therapy or underwent multiple radiation therapy before salvage CSI were classified into Group A, whereas five patients treated with platinum-based chemotherapy and 24-32 Gy of radiation therapy to the primary site, whole ventricle, or whole brain were classified into Group B. In Group A, one had endocrine dysfunction and the other had visual dysfunction. None were socially independent. Meanwhile, in Group B, no endocrine or visual dysfunction was found, and three patients were socially independent. Salvage CSI achieved excellent tumor control in recurrent germinoma and was safe in patients initially treated with low-dose radiation therapy and chemotherapy. | Craniospinal Irradiation |
The effect of glucose on the formation of gas vesicles was investigated in Haloferax mediterranei and Hfx.volcanii transformants containing the mc-gvp gene cluster of Hfx. mediterranei (mc-vac transformants). Increasing amounts of glucose in the medium resulted in a successive decrease in the amount of gas vesicles in both species, with a complete inhibition of their formation at glucose concentrations of > 70 mM in mc-vac transformants, and 100 mM in Hfx. mediterranei. Maltose and sucrose imposed a similar inhibitory effect, whereas xylose, arabinose, lactose, pyruvate and 2-deoxy-glucose had no influence on the gas vesicle formation in mc-vac transformants. The activities of the two mc-vac promoters were strongly reduced in mc-vac transformants grown in the presence of > 50 mM glucose. The gas vesicle overproducing Delta D transformant (lacking the repressing protein GvpD) also showed a glucose-induced lack of gas vesicles, indicating that GvpD is not involved in the repression. The addition of glucose was useful to block gas vesicle formation at a certain stage during growth, and vice versa, gas vesicle synthesis could be induced when a glucose-grown culture was shifted to medium lacking glucose. Both procedures will enable the investigation of defined stages during gas vesicle formation. | Haloferax volcanii |
BACKGROUND: Transfer RNAs from an extreme thermophile, Thermus thermophilus, commonly possess 2'-O-methylguanosine at position 18 (Gm18) in the D-loop. This modification is post-transcriptionally introduced by tRNA (Gm18) methyltransferase. RESULTS: Partial amino acid sequence data were obtained from purified T. thermophilus tRNA (Gm18) methyltransferase by peptide sequencing and mass spectrometry. The sequence data were used to screen the T. thermophilus genome database currently in progress, resulting in the identification of the corresponding gene. Purified recombinant enzyme showed a strict specificity for methylation at the 2'-OH of G18 in tRNA. Sequence alignment with other known or putative methyltransferases elucidates that tRNA (Gm18) methyltransferases have specific conserved region as well as three consensus motifs found in RNA ribose 2'-O-methyltransferases. The enzyme truncated at its N and C termini by limited tryptic digestion still retained binding activity for S-adenosyl-l-homocysteine, but lost the catalytic activity. CONCLUSION: This is the first report describing the identification of a methyltransferase gene of the trmH family through the analysis of a purified protein. Further, our results indicate that a restricted region(s) in the terminal amino acid residues of T. thermophilus tRNA (Gm18) methyltransferase are responsible for tRNA recognition and a main part of the enzyme is allocated for a catalytic core. | tRNA Methyltransferases |
The membrane subunit (NarI) of Escherichia coli nitrate reductase A (NarGHI) contains two b-type hemes, both of which are the highly anisotropic low-spin type. Heme bD is distal to NarGH and constitutes part of the quinone binding and oxidation site (Q-site) through the axially coordinating histidine-66 residue and one of the heme bD propionate groups. Bound quinone participates in hydrogen bonds with both the imidazole of His66 and the heme propionate, rendering the EPR spectrum of the heme bD sensitive to Q-site occupancy. As such, we hypothesize that the heterogeneity in the heme bD EPR signal arises from the differential occupancy of the Q-site. In agreement with this, the heterogeneity is dependent upon growth conditions but is still apparent when NarGHI is expressed in a strain lacking cardiolipin. Furthermore, this heterogeneity is sensitive to Q-site variants, NarI-G65A and NarI-K86A, and is collapsible by the binding of inhibitors. We found that the two main gz components of heme bD exhibit differences in reduction potential and pH dependence, which we posit is due to differential Q-site occupancy. Specifically, in a quinone-bound state, heme bD exhibits an Em,8 of -35 mV and a pH dependence of -40 mV pH(-1). In the quinone-free state, however, heme bD titrates with an Em,8 of +25 mV and a pH dependence of -59 mV pH(-1). We hypothesize that quinone binding modulates the electrochemical properties of heme bD as well as its EPR properties. | Nitrate Reductase |
In aerobic reaction mixtures containing NADH, phenazine methosulfate, and nitroblue tetrazolium, O2- production is mediated by the tetrazolium, not the phenazine. Thus, superoxide dismutase inhibited reduction of the tetrazolium, but when ferricytochrome c was substituted for the tetrazolium its reduction was not affected by this enzyme. Furthermore, NADH plus the phenazine did not accelerate the oxidation of epinephrine to adrenochrome unless the tetrazolium was present, and under those circumstances superoxide dismutase did inhibit adrenochrome formation. When the tetrazolium and ferricytochrome c were present simultaneously, addition of superoxide dismutase was seen to accelerate the reduction of the cytochrome. This is explainable by the reduction of O2- by the reduced phenazine, which thus competes with cytochrome c for the available O2-. When the O2- was eliminated by superoxide dismutase, more of the reduced phenazine was available for the direct reduction of cytochrome c. | Tetrazolium Salts |
The identification of effective adjuvants is critical for tumor vaccine development. Towards this end, we examined whether the immunogenicity of a melanoma vaccine could be potentiated by DETOX, an adjuvant consisting of monophosphoryl lipid A (MPL) and purified mycobacterial cell-wall skeleton (CWS). Nineteen patients with resected stage III melanoma were immunized with a polyvalent melanoma antigen vaccine (40 micrograms) admixed with DETOX, q3 wks x 4. Seven patients received vaccine + low-dose DETOX (10 micrograms MPL + 100 micrograms CWS) and 12 received vaccine + high-dose DETOX (20 micrograms MPL + 200 micrograms CWS). A non-randomized control group of 35 patients was treated similarly with 40 micrograms vaccine + alum. One week after the fourth vaccine immunization, melanoma antibodies were increased over baseline in 7/7 (100%) patients treated with vaccine + low-dose DETOX, 8/12 (67%) patients treated with vaccine + high-dose DETOX, and in 4/19 (21%) of vaccine + alum patients. For the entire DETOX group, the antibody response rate was 15/19 (79%) compared 4/19 (21%) in the alum group (p < 0.001). In contrast, a strong delayed-type hypersensitivity (DTH) response (> or = 15 mm increase in DTH response over baseline) was induced in 50% of the entire DETOX group versus in 47% of the alum group. Median disease-free (DF) survival for the entire DETOX group was 17.8 months compared with 32.1 months in the alum group (p < 0.05). In conclusion, DETOX markedly potentiated antibody but had little effect on DTH responses to melanoma vaccine immunization. It did not appear to improve disease-free survival in comparison to alum in this non-randomized study. | Cell Wall Skeleton |
Dietary cholesterol regulation of cholesterol 7alpha-hydroxylase (Cyp7a1), the rate-limiting enzyme in the classical pathway of bile acid synthesis, has been implicated in plasma cholesterol responsiveness. In the current study, the effects of 0.0% and 0.5% cholesterol diets were examined in Cyp7a1 knockout (KO), heterozygous Cyp7a1 KO (Het), and human Cyp7a1 transgenic mice on the mouse Cyp7a1 KO background (Tg+KO). We confirmed previous findings that dietary cholesterol increased mouse Cyp7a1 activity in Het mice but decreased human Cyp7a1 activity in Tg+KO mice. However, in both Het and Tg+KO mice, dietary cholesterol increased bile acid pool size (36% and 72%, respectively) and fecal bile acid excretion (2.2- and 3.6-fold, respectively). The expression of cholesterol 27-hydroxylase (Cyp27), the major enzyme of the alternative pathway of bile acid synthesis, was not significantly different in cholesterol-fed KO, Het, or Tg+KO mice. Furthermore, dietary cholesterol had comparable effects on total plasma cholesterol and non-high-density lipoprotein cholesterol in KO, Het, and Tg+KO mice. Thus, in Tg+KO mice, dietary cholesterol regulates bile acid pool size, fecal bile acid excretion, and plasma cholesterol independently of Cyp7a1 activity. These results challenge the notion that dietary cholesterol regulation of Cyp7a1 is a major determinant of plasma cholesterol responsiveness." | Cholesterol 7-alpha-Hydroxylase |
The identification and purification of human cell proteins required for the production of form I DNA following DNA replication from the simian virus 40 (SV40) origin is described. Using these proteins, complete SV40 DNA replication was reconstituted with only purified DNA replication factors: SV40 large tumor antigen (TAg), replication protein A (RPA), DNA topoisomerases I and II, DNA polymerase alpha-primase, replication factor C (RFC), the proliferating cell nuclear antigen (PCNA), DNA polymerase delta, maturation factor 1 (MF1), and DNA ligase I. MF1, a 5' to 3' exonuclease and DNA ligase I were both identified as essential components for production of covalently closed circular relaxed (form I) DNA. MF1 is probably the same exonuclease previously shown by others to function during DNA synthesis on artificial DNA templates or in conjunction with DNA polymerase alpha from the SV40 origin. Combined with these previous studies, our results suggest that MF1 functions to remove an RNA primer attached to every Okazaki fragment during lagging strand DNA synthesis. Interestingly, whereas mammalian DNA ligase I functioned in the reconstituted replication system, mammalian DNA ligase III did not substitute and the phage T4 DNA ligase functioned inefficiently, suggesting that DNA ligase I has a specific role as a replicative DNA ligase in eukaryotic cells. | Replication Protein C |
PURPOSE: Multiple endocrine neoplasia type 1 is a rare tumor syndrome caused by germline mutations of MEN1 gene. Phenotype varies widely, and no definitive correlation with the genotype has been observed. Mutation-negative patients with MEN1-associated tumors represent phenocopies. By comparing mutation-positive and mutation-negative patients, we aimed to identify phenotype features predictive for a positive genetic test and to evaluate the role of MEN1 mutations in phenotype modulation. METHODS: Mutation screeening of MEN1 gene by Sanger sequencing and assessment of clinical data of 189 consecutively enrolled probands and relatives were performed at our national and European Reference Center. Multiple ligation probe amplification analysis of MEN1 gene and Sanger sequencing of CDKN1B were carried out in clinically suspicious but MEN1-negative cases. RESULTS: Twenty-seven probands and twenty family members carried MEN1 mutations. Five mutations have not been described earlier. Pronouncedly high number of phenocopies (>70%) was observed. Clinical suspicion of MEN1 syndrome emerged at significantly earlier age in MEN1-positive compared to MEN1-negative probands. Gastroenteropancreatic neuroendocrine tumors developed significantly earlier and more frequently in carriers compared to non-carriers. Probands with high-impact (frameshift, nonsense, large deletions) mutations, predicted to affect menin function significantly, developed GEP-NETs more frequently compared to low-impact (inframe and missense) mutation carriers. CONCLUSIONS: MEN1 phenocopy is common and represents a significant confounder for the genetic testing. GEP-NET under 30 years best predicted a MEN1 mutation. The present study thus confirmed a previous proposal and suggested that GEP-NET under 30 years should be considered as a part of the indication criteria for MEN1 mutational analysis." | Multiple Endocrine Neoplasia Type 1 |
Neurofibromatosis 1 (NF1) and neurofibromatosis 2 (NF2) are characterized by an autosomal dominant pattern of inheritance with irregular penetrance and a broad spectrum of different clinical phenotypes. There are large variations in the age of onset, progression and prognosis. Symptoms are often manifested early in childhood. Characteristics which the two main forms NF1 and NF2 have in common are a positive family history, characteristic skin alterations, such as cafe au lait macules, axillary or inguinal freckling and neural tumors such as neurofibroma and optic glioma (NF1) as well as (bilateral) vestibular schwannomas (NF2). An interdisciplinary cooperation is necessary for the diagnostics and therapy. | Neurofibromatoses |
OX40 belongs to the tumor necrosis factor receptor superfamily, and its expression is restricted to activated T-cells. Ligation of OX40 during T-cell-dendritic cell interaction is crucial for clonal expansion of antigen-specific T-cells and generation of T-cell memory. The ligand of OX40 (OX40L) is expressed not only on dendritic cells but also on other cell types, such as B-cells, vascular endothelial cells, natural killer cells, and mast cells. The pathophysiological relevance of this broad distribution needs further investigation. In particular, OX40L on vascular endothelial cells may play a role in inflammatory vasculitis as well as in atherosclerotic change. Recent studies with animal models have indicated the critical involvement of OX40 in the pathogenesis of a variety of immunologic abnormalities of inflammatory, autoimmune, infectious, allergic, and allotransplantation-related diseases. Blockade of OX40-OX40L interaction has been shown to prevent, cure, or ameliorate these diseases. In contrast, activation of OX40 is known to break an existing state of tolerance in malignancies, leading to a reactivation of antitumor immunity. These findings clearly suggest that the OX40/OX40L system is one of the most promising targets of immune intervention for treatment of these diseases. | Receptors, OX40 |
The opiate receptor was purified from a Triton-solubilized preparation of rat neural membranes by the use of affinity chromatography. The affinity gel was prepared by coupling 14-beta-bromoacetamidomorphine, a newly synthesized ligand, to omega-aminohexyl-Sepharose. After elution of the nonspecific proteins with 50 mM Tris (pH 7.5), the receptor proteins were eluted with 1 microM levorphanol or etorphine. NaDodSO4/polyacrylamide gel electrophoresis revealed three major proteins associated with the opiate receptor, having molecular weights of 43,000, 35,000, and 23,000. The purified receptor binds 10(-11) mol of dihydromorphine/per mg of protein, with a Kd of 3.8 X 10(-9) M. Other opiates, naloxone, and methionine-enkephalin, inhibit [3H]dihydromorphine binding in a manner similar to that observed with intact and solubilized neural membranes. | Dihydromorphine |
INTRODUCTION: Acute compartment syndrome is a serious complication of trauma and pathological disorders. Non-traumatic acute compartment syndrome is very rare and has no coherence with trauma. The case report demonstrates diagnostics difficulties and the treatment strategy. CASE REPORT: We present a 36-year-old man with acute onset of pain after manual labor with a shovel. He had been treated with anticoagulation therapy due to a heart valve replacement. Blood clotting test showed prolongation of prothrombin time of more than four times due to iatrogenic bleeding disorder. Symptoms were considered consistent with the diagnosis of tendovaginitis, however the worsening of the symptoms was underestimated. Four days after the onset of the first symptoms, the acute compartment syndrome developed and urgent fasciotomy of the forearm and hand was performed. The convalescence lasted 10 months with restoration of the function and range of motion of the hand. The patient was able to fully self-service and manually work with a light load. The permanent consequence remained a limitation of the hand grip strength and paresthesia and neuropathic pain due to median nerve impairment. CONCLUSION: Spontaneous compartment syndrome of the upper extremity is a rare but very dangerous entity requiring thorough understanding. It should be considered in the case of non-traumatic limb pain that does not respond to analgesics in patients receiving systemic anticoagulation. Only early diagnosis and immediate fasciotomy can prevent catastrophic permanent consequences. | Compartment Syndromes |
In this study, the effects of the immune stimulator Euglena gracilis (Euglena) in cyclophosphamide (CCP)-induced immunocompromised mice were assessed. The key component beta-1,3-glucan (paramylon) constitutes 50% of E. gracilis. Mice were orally administered Euglena powder (250 and 500 mg/kg body weight (B.W.)) or beta-glucan powder (250 mg/kg B.W.) for 19 days. In a preliminary immunology experiment, ICR mice were intraperitoneally injected with 80 mg of CCP/kg B.W. during the final 3 consecutive days. In the main experiment, BALB/c mice were treated with CCP for the final 5 days. To evaluate the enhancing effects of Euglena on the immune system, mouse B.W., the spleen index, natural killer (NK) cell activity and mRNA expression in splenocytes lungs and livers were determined. To detect cytokine and receptor expression, splenocytes were treated with 5 mug/ml concanavalin A or 1 mug/ml lipopolysaccharide. The B.W. and spleen index were significantly increased and NK cell activity was slightly enhanced in all the experimental groups compared to the CCP group. In splenocytes, the gene expression levels of tumor necrosis factor-alpha, interferon-gamma, interleukin (IL)-10, IL-6, and IL-12 receptor were increased in the E. gracilis and beta-glucan groups compared to the CCP group, but there was no significant difference. Treatment with 500mg of Euglena/kg B.W. significantly upregulated dectin-1 mRNA expression in the lung and liver compared to the CCP group. These results suggest that Euglena may enhance the immune system by strengthening innate immunity through immunosuppression. | beta-Glucans |
The percentage of Neisseria meningitidis serogroup Y isolated from patients with invasive meningococcal disease (IMD) in Italy has increased from 1998 to 2006. In this study, phenotypic features and genetic relatedness have been investigated in all serogroup Y meningococci isolated during that period. Multilocus sequence typing (MLST) identified the ST-23 complex/Cluster A3 as the major clonal complex in 88.8% of the strains. That complex included all strains belonging to the sequence type (ST) 23 isolated from 1998 to 2004, whereas the ST-3171 was prevalent among strains in the years 2005 and 2006. The STs 23 and 3171 differ for only one nucleotide in the phosphoglucomutase (pgm) housekeeping gene. Over 80% of serogroup Y ST-23 complex/Cluster A3 strains showed phenotype Y:14:NST and 85% of the latter resulted indistinguishable by pulsed-field gel electrophoresis analysis. In 2005, serogroup Y meningococci with decreased susceptibility to penicillin were isolated for the first time in Italy. In the following year, three of the seven strains showed this phenotype. The results of this study allow us to draw a profile of the molecular characteristics of invasive serogroup Y in Italy and will be helpful to monitor the spread of this serogroup in the next years." | Neisseria meningitidis, Serogroup Y |
AIM: To evaluate the feasibility and therapeutic effects of para-aortic nodal dissection (PAND) for advanced gastric cancer. METHODS: Randomized controlled trials (RCTs) and non-randomized studies comparing D2 + PAND with D2 lymphadenectomy were identified using a pre-defined search strategy. Five-year overall survival rate, post-operative mortality, and wound degree of surgery between the two operations were compared by using the methods provided by the Cochrane Handbook for Systematic Reviews of Interventions. RESULTS: Four RCTs (1120 patients) and 4 non-randomized studies (901 patients) were identified. Meta-analysis showed that there was no significant difference between these two groups in 5-year overall survival rate [risk ratio (RR) 1.04 (95% CI: 0.93-1.16) for RCTs and 0.96 (95% CI: 0.83-1.10) for non-randomized studies] and post-operative mortality [RR 0.99 (95% CI: 0.44-2.24) for RCTs and 2.06 (95% CI: 0.69-6.15) for non-randomized studies]. There was a significant difference between these two groups in wound degree of surgery, operation time was significantly longer [weighted mean difference (WMD) 195.32 min (95% CI: 114.59-276.05) for RCTs and 126.07 min (95% CI: 22.09-230.04) for non-randomized studies] and blood loss was significantly greater [WMD 301 mL (95% CI: 151.55-450.45) for RCTs and 302.86 mL (95% CI: 127.89-477.84) for non-randomized studies] in D2 + PAND. CONCLUSION: D2 + PAND can be performed as safely as standard D2 resection without increasing post-operative mortality but fail to benefit overall survival in patients with advanced gastric cancer. | Lymph Node Excision |
A uniformly sized molecularly imprinted polymer (MIP) for atropine has been prepared. The MIP was prepared using 2-(trifluoromethyl) acrylic acid and ethylene glycol dimethacrylate as a functional monomer and cross-linker, respectively, by a multi-step swelling and thermal polymerization method. The selectivity factor, which is defined as the ratio of the retention factors (k) on the molecularly imprinted and non-imprinted polymers, k(imprinted)/k(non-imprinted), was 2.2 for atropine on the MIP. The obtained MIP was applied for the determination of tropane alkaloids (atropine and scopolamine) in a commercial gastrointestinal drug by a column-switching HPLC system, consisting of an MIP material as a pre-column, and a conventional cation-exchange analytical column. An interference peak was observed at the retention time of atropine derived from pre-column. However, since the peak area was less than 0.5% the peak area of atropine of a standard solution under the analytical conditions of this study (0.2 microg of atropine was loaded), this interference was negligible in the determination of atropine. On the other hand, no interference peak was observed at the retention time of scopolamine. Calibration curves of atropine and scopolamine showed good linearity in the range of 0.02-0.9 microg/ml (r=0.9999) and 0.003-0.09 microg/ml (r=0.9998), respectively. The mean recoveries of atropine and scopolamine from a placebo pharmaceutical preparation sample were 98.9 and 99.9%, respectively. The intra-day precision (measured by relative standard deviation, R.S.D. (%)) of both ingredients was less than 2.0%. The optimized column-switching system was applied successfully to the determination of atropine and scopolamine in a commercial gastrointestinal drug. | Scopolia |
Salmonella enterica serovar Typhimurium DT104 11601 was tested for its ability to maintain viability in minimal, chemically defined solutions. Periodic monitoring of growth and survival in microcosms of different ion concentrations, maintained at various temperatures, showed a gradual decline in culturable organisms ( approximately 235 days) at 5 degrees C. Organisms maintained at a higher temperature (21 degrees C) showed continuous, equivalent CFU per milliliter ( approximately 10(6)) up to 400 days after inoculation. Fluorescence microscopy with Baclight revealed that nonculturable cells were actually viable, while observations with scanning electron microscopy showed that the cells had retained their structural integrity. Temperature upshift (56 degrees C +/- 0.5, 15 s) of the nonculturable organisms (5 degrees C) in Trypticase soy broth followed by immediate inoculation onto Trypticase soy agar (TSA) gave evidence of resuscitation. Interestingly, S. enterica serovar Typhimurium DT104 from the microcosms at either 5 degrees C (1 to 200 days) or 21 degrees C (1 to 250 days) did not show enhanced growth after intermittent inoculation onto catalase-supplemented TSA. Furthermore, cells from 21 degrees C microcosms exposed to oxidative and osmotic stress showed greater resistance to stresses over increasing times of exposure than did recently grown cells. It is possible that the exceptional survivability and resilience of this particular strain may in part reflect the growing importance of this multidrug-resistant organism, in general, as a cause of intestinal disease in humans. The fact that S. enterica serovar Typhimurium DT104 11601 is capable of modifying its physiological characteristics, including entry into and recovery from the viable but nonculturable state, suggests the overall possibility that S. enterica serovar Typhimurium DT104 may be able to respond uniquely to various adverse environmental conditions. | Salmonella typhimurium |
INTRODUCTION: The APECS and AMARANTH trials showed that beta-secretase (BACE) inhibitors verubecestat and lanabecestat failed to slow cognitive and functional decline in individuals with prodromal or early Alzheimer's disease. Here, the performance on secondary and exploratory cognitive measures in both studies is reported. METHODS: APECS (verubecestat) and AMARANTH (lanabecestat) were randomized, double-blind, placebo-controlled, parallel-group, 104-week clinical trials conducted by different sponsors. Measures included the 3-Domain Composite Cognition Score (CCS-3D), Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), Letter/Category Fluency, and Digit Symbol Coding. RESULTS: Verubecestat showed worsening on the CCS-3D Total Score, Episodic Memory, and Attention/Processing Speed domains. Lanabecestat showed worsening on the RBANS Total Score, Immediate Memory, and Visuospatial/Constructional Indexes. Both BACE inhibitors showed worsening on Digit Symbol Coding and improvements on Letter/Category Fluency. DISCUSSION: In both studies, many measures showed treatment-associated cognitive worsening, whereas verbal fluency tasks showed improvement. | Cyclic S-Oxides |
The therapeutic effects of allogeneic bone marrow transplantation (BMT) in a canine model of mucopolysaccharidosis I (MPS I) were investigated. Long-term post-BMT pathologic and biochemical studies were performed on three groups of dogs: 1) MPS I-affected dogs that did not receive BMT, 2) MPS I-affected dogs that received total body irradiation followed by an allogeneic BMT, and 3) normal, unaffected dogs that served as BMT donors. All dogs were necropsied at approximately 20 months after BMT. The severity of MPS I-related lesions in the dogs receiving BMT was greatly diminished. These dogs had only slight cardiac valvular thickening, no meningeal thickening, no renal tubular epithelial vacuolation, decreased neuronal vacuolation, decreased corneal stromal vacuolation, and greatly diminished arterial medial thickening. The severity and incidence of degenerative arthropathy also were decreased in BMT dogs, however, vertebral lesions were similar to nontransplanted, affected dogs. Chondrocytes of both MPS I-BMT and MPS I-no BMT groups had similar marked cytoplasmic vacuolation, except for MPS I-BMT chondrocytes near the articular surface, which had more normal morphology. Ultrastructurally, the liver and kidney tissue in BMT recipients had no appreciable lysosomal accumulation of GAGs. These morphologic findings were supported by near normal levels and electrophoretic patterns of glycosaminoglycans (GAG) in most tissues of BMT recipient dogs. This study demonstrates that BMT is capable of substantially diminishing the severity of MPS I-related lesions in this canine model. | Mucopolysaccharidosis I |
Adenosine and ATP modulate cellular and tissue functions via specific P1 and P2 receptors, respectively. Although, in general, adenosine inhibits excitability and ATP functions as an excitatory transmitter in the central nervous system, little is known about the direct interaction between P1 and P2 receptors. We recently demonstrated that the G(i/o)-coupled adenosine A1 receptor (A1R) and G(q/11)-coupled P2Y1 receptor (P2Y1R) form a heteromeric complex with a unique pharmacology in cotransfected HEK293T cells using the coimmunoprecipitation of differentially epitope-tagged forms of the receptor [Yoshioka et al. (2001) Proc. Natl. Acad. Sci. USA 98, 7617-7622], although it remained to be determined whether this hetero-oligomerization occurs in vivo. In the present study, we first demonstrated a high degree of colocalization of A1R and P2Y1R by double immunofluorescence experiments with confocal laser microscopy in rat cortex, hippocampus and cerebellum in addition to primary cultures of cortical neurons. Then, a direct association of A1R with P2Y1R was shown in coimmunoprecipitation studies using membrane extracts from these regions of rat brain. Together, these results suggest the widespread colocalization of A1R and P2Y1R in rat brain, and both receptors can exist in the same neuron, and therefore associate as hetero-oligomeric complexes in the rat brain. | Receptors, Purinergic P2Y1 |
The learning curve of hip arthroscopy has been described as steep. A wide range, between 30 and 520 cases, has been gathered as the learning curve before complications are minimized. While the precise number of cases required for proficiency has remained elusive, the heterogeneity in surgeon profile and baseline training can serve as an explanation. Moreover, as caseload increases, case complexity, revision surgeries, and outside referrals may begin to consume the greater-volume surgeon. While the learning curve remains hard to define, innovations in surgical training hold the promise of improving proficiency. Regardless of career stage, hip arthroscopists can still expect improved patient outcomes with appropriate indications and a properly executed procedure. | Learning Curve |
In recently developed approaches for high-resolution imaging within intact tissue, molecular characterization over large volumes has been largely restricted to labeling of proteins. But volumetric nucleic acid labeling may represent a far greater scientific and clinical opportunity, enabling detection of not only diverse coding RNA variants but also non-coding RNAs. Moreover, scaling immunohistochemical detection to large tissue volumes has limitations due to high cost, limited renewability/availability, and restricted multiplexing capability of antibody labels. With the goal of versatile, high-content, and scalable molecular phenotyping of intact tissues, we developed a method using carbodiimide-based chemistry to stably retain RNAs in clarified tissue, coupled with amplification tools for multiplexed detection. The resulting technology enables robust measurement of activity-dependent transcriptional signatures, cell-identity markers, and diverse non-coding RNAs in rodent and human tissue volumes. The growing set of validated probes is deposited in an online resource for nucleating related developments from across the scientific community." | Ethyldimethylaminopropyl Carbodiimide |
Recent advances in mobile technology have shown that augmented unisensory feedback can be leveraged to improve gait using wearable systems, but less is known about the possible benefits and usability of multisensory (i.e., multimodal) feedback. This paper introduces the preliminary results of an innovative research project aiming to develop an mHealth system including Android smart glasses, and providing multisensory cues for gait rehabilitation of people affected by Parkinson's disease in and out of the medical context. In particular, the paper describes a preliminary pilot focusing on the design of visual, auditory, and haptic cues, and testing the design methodologies to be used in further developments of the project. Considered research questions were: Which kinds of images, sounds, and vibrations mostly influence gait speed, stride length, and cadence? Which are the ones stressing the user the least? Which ones induce the most immediate reaction? Thus, in this starting part of the research project, different typologies of sensory cues were designed, tested, and evaluated considering quantitative and qualitative parameters to properly answer the research questions. | Smart Glasses |
We describe the case history of a 13-year-old girl with chronic fatigue and prolonged microcytic anaemia. She received oral iron since the age of 11 but failed to respond to it. Laboratory studies revealed elevated C-reactive protein and hypergammaglobulinaemia. A large solitary mesenterial lymph node could be demonstrated by ultrasonography and CT. A diagnosis of Castleman disease was suspected and confirmed histologically. After surgical removal of the lymphoma the patient recovered completely. CONCLUSION: Castleman disease should be considered in cases of chronic fatigue, unexplained fever, microcytic anaemia and hypergammaglobulinaemia. | Castleman Disease |
Complex carbohydrates are essential for many biological processes, from protein quality control to cell recognition, energy storage, and cell wall formation. Many of these processes are performed in topologically extracellular compartments or on the cell surface; hence, diverse secretion systems evolved to transport the hydrophilic molecules to their sites of action. Polyprenyl lipids serve as ubiquitous anchors and facilitators of these transport processes. Here, we summarize and compare bacterial biosynthesis pathways relying on the recognition and transport of lipid-linked complex carbohydrates. In particular, we compare transporters implicated in O antigen and capsular polysaccharide biosyntheses with those facilitating teichoic acid and N-linked glycan transport. Further, we discuss recent insights into the generation, recognition, and recycling of polyprenyl lipids. | Polyprenols |
Traditional RNA sequencing (RNA-seq) allows the detection of gene expression variations between two or more cell populations through differentially expressed gene (DEG) analysis. However, genes that contribute to cell-to-cell differences are not discoverable with RNA-seq because RNA-seq samples are obtained from a mixture of cells. Single-cell RNA-seq (scRNA-seq) allows the detection of gene expression in each cell. With scRNA-seq, highly variable gene (HVG) discovery allows the detection of genes that contribute strongly to cell-to-cell variation within a homogeneous cell population, such as a population of embryonic stem cells. This analysis is implemented in many software packages. In this study, we compare seven HVG methods from six software packages, including BASiCS, Brennecke, scLVM, scran, scVEGs and Seurat. Our results demonstrate that reproducibility in HVG analysis requires a larger sample size than DEG analysis. Discrepancies between methods and potential issues in these tools are discussed and recommendations are made. | RNA-Seq |
Alteration of ryanodine receptor (RyR)-mediated calcium (Ca(2+)) signaling has been reported in Alzheimer disease (AD) models. However, the molecular mechanisms underlying altered RyR-mediated intracellular Ca(2+) release in AD remain to be fully elucidated. We report here that RyR2 undergoes post-translational modifications (phosphorylation, oxidation, and nitrosylation) in SH-SY5Y neuroblastoma cells expressing the beta-amyloid precursor protein (betaAPP) harboring the familial double Swedish mutations (APPswe). RyR2 macromolecular complex remodeling, characterized by depletion of the regulatory protein calstabin2, resulted in increased cytosolic Ca(2+) levels and mitochondrial oxidative stress. We also report a functional interplay between amyloid beta (Abeta), beta-adrenergic signaling, and altered Ca(2+) signaling via leaky RyR2 channels. Thus, post-translational modifications of RyR occur downstream of Abeta through a beta2-adrenergic signaling cascade that activates PKA. RyR2 remodeling in turn enhances betaAPP processing. Importantly, pharmacological stabilization of the binding of calstabin2 to RyR2 channels, which prevents Ca(2+) leakage, or blocking the beta2-adrenergic signaling cascade reduced betaAPP processing and the production of Abeta in APPswe-expressing SH-SY5Y cells. We conclude that targeting RyR-mediated Ca(2+) leakage may be a therapeutic approach to treat AD." | Adrenergic beta-2 Receptor Antagonists |
Riemerella anatipestifer is a major bacterial pathogen that causes septicemic and exudative diseases in domestic ducks. In our previous study, we found that deletion of the AS87_01735 gene significantly decreased the bacterial virulence of R. anatipestifer strain Yb2 (mutant RA625). The AS87_01735 gene was predicted to encode a nicotinamidase (PncA), a key enzyme that catalyzes the conversion of nicotinamide to nicotinic acid, which is an important reaction in the NAD(+) salvage pathway. In this study, the AS87_01735 gene was expressed and identified as the PncA-encoding gene, using an enzymatic assay. Western blot analysis demonstrated that R. anatipestifer PncA was localized to the cytoplasm. The mutant strain RA625 (named Yb2DeltapncA in this study) showed a similar growth rate but decreased NAD(+) quantities in both the exponential and stationary phases in tryptic soy broth culture, compared with the wild-type strain Yb2. In addition, Yb2DeltapncA-infected ducks showed much lower bacterial loads in their blood, and no visible histological changes were observed in the heart, liver, and spleen. Furthermore, Yb2DeltapncA immunization of ducks conferred effective protection against challenge with the virulent wild-type strain Yb2. Our results suggest that the R. anatipestifer AS87_01735 gene encodes PncA, which is an important virulence factor, and that the Yb2DeltapncA mutant can be used as a novel live vaccine candidate. IMPORTANCE: Riemerella anatipestifer is reported worldwide as a cause of septicemic and exudative diseases of domestic ducks. The pncA gene encodes a nicotinamidase (PncA), a key enzyme that catalyzes the conversion of nicotinamide to nicotinic acid, which is an important reaction in the NAD(+) salvage pathway. In this study, we identified and characterized the pncA-homologous gene AS87_01735 in R. anatipestifer strain Yb2. R. anatipestifer PncA is a cytoplasmic protein that possesses similar PncA activity, compared with other organisms. Generation of the pncA mutant Yb2DeltapncA led to a decrease in the NAD(+) content, which was associated with decreased capacity for invasion and attenuated virulence in ducks. Furthermore, Yb2DeltapncA immunization of ducks conferred effective protection against challenge with the virulent wild-type strain Yb2. Altogether, these results suggest that PncA contributes to the virulence of R. anatipestifer and that the Yb2DeltapncA mutant can be used as a novel live vaccine candidate. | Riemerella |
Miconazole has one chiral center, and consists of two enantiomers. In this study, a novel chiral liquid chromatography-tandem mass spectrometry method was developed for enantioselective separation and determination of miconazole in rat plasma. For the first time, the enantioselective pharmacokinetics of miconazole was investigated by the current method. Firstly, attempts were made to separate the enantiomers in reversed-phase mode with a mobile phase that was mass spectrometry compatible. Baseline separation was achieved on a Chiralpak IC column with a mobile phase composed of acetonitrile and aqueous ammonium hydrogen carbonate (5 mM; 80:20, v/v). Data were acquired in multiple reaction monitoring mode with positive electrospray ionization by triple-quadrupole mass spectrometry. Then, overall method validation regarding the linearity, accuracy, precision, extraction recovery, matrix effect, and stability of each enantiomer was performed, and acceptable results were obtained for all of these. Finally, the method developed was applied in an enantioselective pharmacokinetic study of miconazole enantiomers in rats after oral administration of racemic miconazole at doses of 5 and 10 mg/kg. The results demonstrated that (-)-(R)-miconazole had a higher concentration than (+)-(S)-miconazole in plasma, with a ratio of 1.3-1.7 for both doses. This is the first experimental evidence of enantioselective behavior of miconazole in vivo, and provides a reference for clinical practice and encourages further research into miconazole enantioselective metabolism and drug interactions. Graphical Abstract A stereoselective pharmacokinetic study of the miconazole enantiomers was investigated using a novel chiral liquid chromatography-tandem mass spectrometry method. Baseline separation was achieved on Chiralpak IC column, and Chiralcel OJ column was used to collect single enantiomer. A significant difference between the two enantiomers was observed in view of the plasma concentration. | Miconazole |
The toxicity of arsenic (As) in the environment is controlled by its concentration, availability and speciation. The aims of the study were to evaluate the accumulation and speciation of As in carrot, lettuce and spinach cultivated in soils with various As concentrations and to estimate the concomitant health risks associated with the consumption of the vegetables. Arsenic concentration and speciation in plant tissues and soils was analysed by HPLC, AAS and XANES spectroscopy. To estimate the plants influence in the rhizosphere, organic acids in lettuce root exudates were analysed by ion chromatography. The results showed that the As accumulation was higher in plants cultivated in soil with higher As extractability. Arsenate predominated in the soils, rhizosphere and root exudates of lettuce. Succinic acid was the major organic acid in lettuce root exudates. Ingestion of the tested vegetables may result in an intake of elevated levels of inorganic As. | Daucus carota |
BACKGROUND: Regular monitoring of anti-malarial drug efficacy is vital for establishing rational malaria treatment guidelines and ensuring adequate treatment outcomes. This study aimed to synthesize the available evidence on the efficacy of artemether-lumefantrine for the management of uncomplicated falciparum malaria in Ethiopia. METHODS: The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed. Relevant published studies were searched from the databases (PubMed, Google Scholar and Clinical trial registry) on published artemether-lumefantrine therapeutic efficacy studies conducted in Ethiopia from 2004 to 2020. The retrieved studies were assessed for quality using the modified Newcastle Ottawa Scale for observational studies and modified Jadad scale for interventional studies. Risk of bias was also assessed by using ROBINS-I tool. OpenMeta-Analyst software was used for the statistical analysis. The review protocol is registered in PROSPERO, number CRD42020201859. RESULTS: Fifteen studies (1523 participants) were included in the final analysis. The overall PCR-uncorrected pooled proportion of treatment success of artemether-lumefantrine therapy for uncomplicated falciparum malaria was 98.4% (95%CI 97.6-99.1). A random-effects model was used because of considerable heterogeneity [chi(2) = 20.48, df (14), P = 0.011 and I(2) = 31.65]. PCR-corrected pooled proportion of treatment success of artemether-lumefantrine therapy was 98.7% (95% CI 97.7-99.6). A random-effects model was used [chi(2) = 7.37, df(6), P = 0.287 and I(2) = 18.69]. Most studies included in the present review achieved a rapid reduction of fevers and parasitaemia between D0 and D3 of assessment. Adverse events were mostly mild and only two cases were reported as serious, but were not directly attributed to the drug. CONCLUSION: The present meta-analysis suggests that artemether-lumefantrine therapy is efficacious and safe in treating uncomplicated falciparum malaria in Ethiopia. However, owing to the high risk of bias in the included studies, strong conclusions cannot be drawn. Further high-quality RCTs assessing anti-malarial efficacy and safety should be performed to demonstrates strong evidence of changes in parasite sensitivity to artemether-lumefantrine in Ethiopia. | Lumefantrine |
Information on the immune response during the mpox virus (MPXV) infection is still scarce or limited to past studies when cross-reactive immunity from smallpox vaccination was predominant. Here, we describe the short-term kinetics of the antibody response in patients with acute MPXV infection during the 2022 multicountry outbreak. A total of 64 samples from 18 MPXV-positive patients were longitudinally collected from the day of symptom onset (DSO) up to 20 days after and tested for anti-MPXV immunoglobulin G (IgG), IgM, IgA, and neutralizing antibodies (nAb) using the whole-live virus isolated in May 2022. IgG, IgM, and IgA were detected as early as 4 DSO (median time of seroconversion 7.5 DSO for IgG, 8 DSO for IgM and IgA). Anti-MPXV nAb were detectable in samples collected as early as 1 week after symptoms, with stable levels up to 20 DSO. After 2 weeks, IgG and nAb reached high titers. No significant differences were observed regardless of status of smallpox vaccination, human immunodeficiency virus positivity, or disease severity. Significant lower levels of IgM and IgG were observed in the patients treated with antivirals. These results contribute to extending the knowledge of the MPXV infection and the antibody response in a population with no historic smallpox vaccination. | Globulins |
Hydrolysis of polyethylene terephthalate (PET) is an efficient strategy for the depolymerization of waste PET to terephthalic acid (TPA), which can be used as a fundamental building block for the repolymerization of PET or for the synthesis of biodegradable plastics and metal-organic frameworks. However, most of the reported hydrolysis catalysts are strong acids or bases, which are soluble in reaction media and difficult to separate after the reaction, leading to high production costs and a profound influence on the environment. Herein, we propose the use of TPA, the basic unit of PET, as an acid catalyst to promote the hydrolysis of PET. Under optimized conditions, i.e., 2.5 g of PET, a TPA concentration of 0.1 g/mL, mass ratio PET:H(2)O of 1:8, 220 degrees C of temperature, and 180 min of reaction time, a PET conversion of up to 100.0% and a TPA yield of 95.5% were achieved. Furthermore, the produced TPA exhibited a high purity of 99%, similar to that of fresh TPA, and was easily recoverable for PET hydrolysis without tedious workup and purification processes. More importantly, the hydrolysis efficiency was maintained over eight consecutive reaction cycles. Overall, this study provides a green, easy, and low-cost technology to recover and reuse TPA for waste PET hydrolysis. | Hydrolysis |
Six female olive baboons (Papio cynocephalus anubis) were treated with a single dose of 150 mg of Depo-Provera i.m. at day 30 of pregnancy, approximately three times the human dose equivalent on a body weight basis. Fetectomies were performed at day 100 of gestation. The body weights and measurements of the five live fetuses were comparable to age-matched controls and no gross or histologic abnormalities were seen. The dead fetus was in an advanced state of decomposition. This preliminary study suggests that, at levels up to three times that used for human contraception, Depo-Provera does not appear to have any adverse effects on fetal development. | Medroxyprogesterone |
Recently, we have reported new basic information on the ultrastructure of human metaphase chromosomes using both scanning and transmission electron microscopy. This includes the observation of a bipartite chromatid structure (BCS) for some metaphase chromatids, a zipper-like" configuration (ZC) between chromatids that likely resulted from chromatin coiling, and a "brush-like" border (BB) that was observed primarily on chromosomes that were not exposed to colcemid. Now we have examined the effects of colcemid and several metals on the occurrence of the BCS, the ZC, and the BB. Although we do not as yet know the function of the zipper-like and bipartite chromatid configurations, we have found that colcemid clearly caused a significant increase in the occurrence of chromosomes with a BCS or ZC. We also have confirmed our original observation of increased occurrence of the BB on chromosomes not exposed to colcemid and finally, have shown that aluminum and other metals had some effect on the frequencies of the BCS, the ZC, and the BB with and without exposure to colcemid." | Chromatids |
The patient presented with acute and constant abdominal pain. He had had a lobectomy of the left lung three months before. On the 4th day in hospital the pain increased and he went into temporary shock. The next day a hydropneumothorax and incarcerated stomach were revealed by chest X-ray and computed tomography. He was transferred to the University Hospital immediately and underwent an operation. The diagnosis was an incarcerated para-oesophageal hernia with hydropneumothorax and perforation of the stomach. As a para-oesophageal hernia may be fatal, it is important to diagnose and treat it early. | Hydropneumothorax |
PURPOSE OF REVIEW: Faecal microbiota transplantation (FMT) has undergone dramatic progression over the past year and continues to evolve as knowledge of the gastrointestinal microbiota (GiMb) develops. This review summarizes therapeutic advances in FMT, latest FMT therapies and presents the potential of FMT therapeutics in other gastrointestinal and extra-intestinal conditions. RECENT FINDINGS: The GiMb is now known to have a central role in the pathogenesis of many diseases. The success of FMT in curing Clostridium difficile infection (CDI) is well established and preliminary findings in other gastrointestinal conditions are promising. Published data from over 500 CDI cases suggest that FMT is generally well tolerated with minimal side effects. The commercial potential of FMT is being explored with several products under development, including frozen GiMb extract, which has been shown highly effective in treating relapsing CDI. Such products will likely become more available in coming years and revolutionize the availability and method of delivery of GiMb. SUMMARY: Recent literature unequivocally supports the use of FMT in treating relapsing CDI. Trials are underway to determine the therapeutic potential of FMT in other conditions, particularly inflammatory bowel disease. Therapeutic FMT is a dynamic field with new and emerging indications along with ongoing developments in optimal mode of administration. | Tissue Transplantation |
Although fungi produce highly structurally diverse metabolites, many of which have served as excellent sources of pharmaceuticals, no fungi-derived agent has been approved as a cancer drug so far. This is despite a tremendous amount of research being aimed at the identification of fungal metabolites with promising anticancer activities. This review discusses the results of clinical testing of fungal metabolites and their synthetic derivatives, with the goal to evaluate how far we are from an approved cancer drug of fungal origin. Also, because in vivo studies in animal models are predictive of the efficacy and toxicity of a given compound in a clinical situation, literature describing animal cancer testing of compounds of fungal origin is reviewed as well. Agents showing the potential to advance to clinical trials are also identified. Finally, the technological challenges involved in the exploitation of fungal biodiversity and procurement of sufficient quantities of clinical candidates are discussed, and potential solutions that could be pursued by researchers are highlighted. | Aphidicolin |
The aim of this study was to test the hypothesis that the addition of continuous or milled GdAlO3/Al2O3 fibers to a dental porcelain increases its mechanical properties. Porcelain bars without reinforcement (control) were compared to those reinforced with long fibers (30 vol%). Also, disk specimens reinforced with milled fibers were produced by adding 0 (control), 5 or 10 vol% of particles. The reinforcement with continuous fibers resulted in significant increase in the uniaxial flexural strength from 91.5 to 217.4 MPa. The addition of varied amounts of milled fibers to the porcelain did not significantly affect its biaxial flexural strength compared to the control group. SEM analysis showed that the interface between the continuous fiber and the porcelain was free of defects. On the other hand, it was possible to note the presence of cracks surrounding the milled fiber/porcelain interface. In conclusion, the reinforcement of the porcelain with continuous fibers resulted in an efficient mechanism to increase its mechanical properties; however the addition of milled fibers had no significant effect on the material because the porcelain was not able to wet the ceramic particles during the firing cycle. | Gadolinium |
A new monoterpenoid indole alkaloid, ochroborbone (1), along with five known alkaloids (2-6), were isolated from the stems and leaves of Ochrosia borbonica. Among them, ochroborbone (1) is a rare C17-nor monoterpenoid indole alkaloid, and the known compounds (2-6) were isolated from Ochrosia for the first time-These structures were established on the basis of extensive spectroscopic methods. All isolated compounds were evaluated for their cytotoxicities against five human cancer cell lines: HL-60, SMMC-7721, A-549, MCF-7 and SW480 in vitro. Compounds 1 and 2 exhibited inhibitory effects with IC(5)(0) values comparable with those of cisplatin. | Ochrosia |
The intracellular metabolism of selenium in the brain currently remains unknown, although the antioxidant activity of this element is widely acknowledged to be important in maintaining brain functions. In this study, a comprehensive method for identifying the selenium-binding proteins using PenSSeSPen as a model of the selenium metabolite, selenotrisulfide (RSSeSR, STS), was applied to a complex cell lysate generated from the rat brain. Most of the selenium from L-penicillamine selenotrisulfide (PenSSeSPen) was captured by the cytosolic protein thiols in the form of STS through the thiol-exchange reaction (R-SH+PenSSeSPen-->R-SSeSPen+PenSH). The cytosolic protein species, which reacted with the PenSSeSPen mainly had a molecular mass of less than 20 kDa. A thiol-containing protein at m/z 15155 in the brain cell lysate was identified as the cystatin-12 precursor (CST12) from a rat protein database search and a tryptic fragmentation experiment. CST12 belongs to the cysteine proteinase inhibitors of the cystatin superfamily that are of interest in mechanisms regulating the protein turnover and polypeptide production in the central nervous system and other tissues. Consequently, CST12 is suggested to be one of the cytosolic proteins responsible for the selenium metabolism in the brain. | Selenium-Binding Proteins |
X-linked adrenoleukodystrophy (X-ALD) is a neurodegenerative disorder resulting from mutations within the ABCD1 gene. Adrenomyeloneuropathy (AMN) and childhood cerebral ALD (CCALD) are most common phenotypes in the Western ALD patients. Here we performed mutation analysis of ABCD1 in 10 Chinese ALD families and identified 8 mutations, including one novel deletion (c.1477_1488+11del23) and 7 known mutations. Mutations c.1772G>A and c.1816T>C were first reported in the Chinese patients. Mutations c.1661G>A and c.1679C>T were demonstrated to be de novo mutations. The dinucleotide deletion 1415_16delAG, described as a mutational hotspot in different ethnic groups, was identified in two families. In addition, we performed a retrospective nation-wide mutation study of X-linked ALD in China based on a literature review. The retrospective study further confirmed the hypothesis that exon 6 is a potential mutation cluster region in the Asian populations. Furthermore, it suggested that CCALD is the most common phenotype in China." | ATP Binding Cassette Transporter, Subfamily D, Member 1 |
The toxic effects of the common organophosphorus pesticide dimethoate on freshwater zooplankton Brachionus calyciflorus (rotifer) were tested. Because of the advantages of behavioral response in environmental monitoring, swimming behavior was used as the endpoint in this research. After exposure 6 h at five dimethoate concentrations (0.18, 0.53, 0.88, 1.23 and 1.59 mg.L(-1)), the pesticide disrupted the balance in rotifer swimming direction and caused an obvious direction preference. It also inhibited significantly the swimming angular and linear speed. Our results showed that dimethoate has a sublethal toxic effect on this aquatic invertebrate. | Dimethoate |
Evidence indicates that the gut microbiota and/or interactions between the microbiota and the host immune system are involved in the pathogenesis of inflammatory bowel disease (IBD). Strategies that target the microbiota have emerged as potential therapies and, of these, probiotics have gained the greatest attention. Data derived from animal models of IBD have revealed the potential of several bacterial strains to modify the natural history of IBD. However, thought there is some evidence for efficacy in ulcerative colitis and in pouchitis, in particular, there has been little indication that probiotics exert any benefit in Crohn disease. More targeted approaches involving live bacteria, genetically modified bacteria, and bacterial products are now being evaluated. | Probiotics |
Artificial intelligence and machine learning (AI-ML) offer vast potential in optimal design, monitoring, and control of biopharmaceutical manufacturing. The driving forces for adoption of AI-ML techniques include the growing global demand for biotherapeutics and the shift toward Industry 4.0, spurring the rise of integrated process platforms and continuous processes that require intelligent, automated supervision. This review summarizes AI-ML applications in biopharmaceutical manufacturing, with a focus on the most used AI-ML algorithms, including multivariate data analysis, artificial neural networks, and reinforcement learning. Perspectives on the future growth of AI-ML applications in the area and the challenges of implementing these techniques at manufacturing scale are also presented. | Artificial Intelligence |
Biodiesel is an alkyl ester of long chain fatty acids and is considered to leave smaller footprint on the environment. It is produced by transesterification of a fat/oil with a short chain primary alcohol like methanol or ethanol. The three routes to its preparation are: alkali catalyzed, acid catalyzed and lipase-catalyzed transesterification. This review summarizes the key patents filed over the last few decades. The chemistry used in these patents is one of the three routes mentioned above. In few patents, heterogeneous catalysts have been used for catalyzing the transesterification process. The innovations mostly concern fine-tuning of the reaction conditions, plant design to improve logistics and use of glycerol produced as a by-product during biodiesel production. There is a concern that biofuels like biodiesel cut into resources like land meant for food crop production. Life cycle studies also create doubt about there being energy efficient fuels. Judicious choices that would differ with different regions are recommended. For the next few decades till better alternatives like hydrogen become viable, biodiesel would continue to be an important alternative fuel"." | Bioelectric Energy Sources |
BACKGROUND: A nomogram that integrates risk models and clinical characteristics can accurately predict the prognosis of individual patients. We aimed to identify the prognostic factors and establish nomograms for predicting overall survival (OS) and cause-specific survival (CSS) in patients with multi-organ metastatic colorectal cancer (CRC). METHODS: Demographic and clinical information on multi-organ metastases from 2010 to 2019 were extracted from the Surveillance, Epidemiology, and End Results (SEER) Program. Univariate and multivariate Cox analyses were used to identify independent prognostic factors that were used to develop nomograms to predict CSS and OS, and to assess the concordance index (C-index), area under the curve (AUC), and calibration curve. RESULTS: The patients were randomly assigned to the training and validation groups at a 7:3 ratio. A Cox proportional hazards model was conducted for CRC patients to identify independent prognostic factors, including age, sex, tumor size, metastases, degree of differentiation, stage T, stage N, primary and metastasis surgery. The competing risk models employed by Fine and Gray were used to identify the risk factors for CRC. Death from other causes was treated as a competing event, and Cox models were used to identify the factors for death to identify the independent factors of CSS. By incorporating the corresponding independent prognostic factors, we established prognostic nomograms for OS and CSS. Finally, we used the C-index, ROC curve, and calibration plots to assess the utility of the nomogram. CONCLUSIONS: Using the SEER database, we constructed a predictive model for CRC patients with multi-organ metastases. Nomograms provide clinicians with 1-, 3-, and 5-year OS and CSS predictions for CRC, allowing them to formulate appropriate treatment plans. | Prognosis |
Reduction in nursing staff injuries has occurred with the use of an evidence-based approach to safe patient handling and mobility. Parts of the evidence-based practice initiative include having the appropriate equipment, such as mechanical patient-lifting devices, a no-lift policy, and the use of peer coaches. The combination of the implementation of a culture of safety can sustain evidence-based, safe patient-handling practices that reduce patient-handling injuries. Patient-handling programs should include adaptations for an aging nursing workforce. The use of safety checklists in health care can improve communication and compliance with safe patient-handling and mobility policy and program components. | Moving and Lifting Patients |
AIMS: Diabetes-related dementia (DRD) is a new dementia subtype associated with type 2 diabetes mellitus, first described in 2013. This study investigated data from a local New Zealand memory service to identify patients that met the criteria for DRD. METHODS: Using routinely collected data from 2013-2021, we selected a sample of people with dementia, diabetes, and no CT evidence of Alzheimer's disease (AD), vascular dementia, or frontotemporal dementia. We compared their socio-demographic, clinical, and cognitive characteristics with a sample of patients with diabetes and Alzheimer's disease. RESULTS: Forty (16%) of 249 patients with diabetes and dementia had "normal" CT scans (DRD subgroup), and 38 (15%) had AD (AD subgroup). Compared to NZ Europeans, disproportionally more Maori and Pacific Islanders (70.2%) were in the DRD subgroup. In the Pacific subgroup (n=31), the DRD subgroup had higher memory subscores than the AD subgroup (p=0.047), and the Kaplan-Meier plot suggested poorer survival (p=0.13). Maori patients with diabetes and dementia were more likely to meet all four criteria for DRD. CONCLUSION: We have replicated the findings of the 2013 DRD research and have demonstrated a higher risk for the DRD subtype of dementia among the Maori and Pacific Islander patients in our sample." | Routinely Collected Health Data |
This study examined the effects of appraisal of sexual stimuli on sexual arousal in women with superficial dyspareunia (n = 50) and sexually functional women (n = 25). To elicit different appraisals of an erotic film fragment, participants received an instruction prior to viewing it, with a focus on genital pain or on sexual enjoyment. A neutral instruction served as a control condition. Assignment to instruction condition was randomized. Genital arousal (vaginal pulse amplitude) and self-report ratings of affect and genital sensations were obtained in response to the erotic stimulus. As predicted, appraisal of the erotic stimulus affected genital responding, albeit marginally significant. Follow-up tests indicated that women who received the genital pain instruction responded with marginally significant lower genital arousal levels than women who received the sexual enjoyment instruction (d = 0.67). A significant instruction effect for negative affect was found, signifying that negative affect ratings were highest after the genital pain instruction and lowest after the sexual enjoyment instruction (d = 0.80). A marginally significant group by instruction interaction effect was observed for positive affect, indicating that women with dyspareunia reported significantly less positive affect than controls after the sexual enjoyment instruction (d = 1.48). Whereas women with dyspareunia reported overall marginally significant more negative affect than controls (d = 0.48), there were no differences in genital responsiveness between groups. These results provided preliminary evidence for the modulatory effects of appraisal of sexual stimuli on subsequent genital responding and affect in women with and without sexual complaints. | Dyspareunia |
Nocturnal enuresis is a common problem that children may present with in a primary care setting. It is important to take a detailed history to rule out secondary causes; however, most cases are primary in nature. It is essential to demystify the problem and reassure parents by educating them that the episodes are nonvolitional and most children outgrow the problem over time. Behavioral interventions are considered first line and are most successful when the child is invested in succeeding. Interventions should be initiated with specific goals in mind. Medications are effective and should be used in conjunction with behavioral interventions. | Nocturnal Enuresis |
Recent data highlight how eukaryotic ribosomes connect polypeptide synthesis to translational regulation and targeting. Information contained in nascent polypeptides can be transmitted by surprisingly diverse routes." | Ribonucleoproteins, Small Cytoplasmic |
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