[Effect of secretin and gabexate-mesilate (synthetic protease inhibitor) on serum amylase level after ERCP].
Complication rate of ERCP is about 2%, mortality rate 0,2%. In about 1% acute pancreatitis or recurrency of chronic pancreatitis occurs. In 20 to 73% a rise of serum amylase is noted without clinical symptoms. In a randomized trial the influence of secretin and gabexate-mesilate (synthetic protease inhibitor) on ERCP-correlated complications was analyzed. Gabexate-mesilate caused a significant decrease of ERCP-induced hyperamylasemias, whereas secretin showed no effect.


High production of poly(3-hydroxybutyrate) in Escherichia coli using crude glycerol.
Poly(3-hydroxybutyrate) (PHB) is a prominent bio-plastic and recognized as the potential replacement of petroleum-derived plastics. To make PHB cost-effective, the production scheme based on crude glycerol was developed using Escherichia coli. The heterogeneous synthesis pathway of PHB was introduced into the E. coli strain capable of efficiently utilizing glycerol. The central metabolism that links to the synthesis of acetyl-CoA and NADPH was further reprogrammed to improve the PHB production. Key genes were targeted for manipulation, involving those in glycolysis, the pentose phosphate pathway, and the tricarboxylic cycle. As a result, the engineered strain gained a 22-fold increase in the PHB titer. Finally, the fed-batch fermentation was conducted with the producer strain to give the PHB titer, content, and productivity reaching 36.3 ± 3.0 g/L, 66.5 ± 2.8%, and 1.2 ± 0.1 g/L/h, respectively. The PHB yield on crude glycerol accounts for 0.3 g/g. The result indicates that the technology platform as developed is promising for the production of bio-plastics.


Kinetoplast RNA of Leishmania tarentolae.
RNA has been isolated from highly purified kinetoplast-mitochondrial fractions of Leishmania tarentolae, and shown to consist of two major species that sediment at 9S and 12S in sucrose and also several additional low molecular weight species which were visualized by gel electrophoresis. The in vivo transcription of 9S and 12S RNAs was inhibited by ethidium bromide and rifampin, and was fairly insensitive to low actinomycin D and camptothecin. The 9S and 12S RNAs were isolated by acrylamide gel electrophoresis or by sedimentation in sucrose. Both RNAs contained approximately 80% A + U and did not contain long stretches of poly(A). The 9S and 12S RNAs were found to hybridize selectively to the maxicircle sequences of the kinetoplast DNA, implying that the maxicircle, and not the minicircle, represents the informational mitochondrial DNA in the kinetoplast.


Transcriptional regulation of the development of neurons and glia.
The past year has seen significant progress in the analysis of transcriptional regulation as it relates to neural development. Highlights include the identification and analysis of new homeobox genes that delimit developmental boundaries in the vertebrate forebrain, the study of upstream regulators of homeobox genes, the analysis of Pax genes that may contribute to specification of the vertebrate dorso-ventral neuraxis, and the functional analysis of transcription factors that are likely to specify particular neural cell types in both vertebrate and invertebrate nervous systems.


Hepatic expression of cannabinoid receptors CB1 and CB2 correlate with fibrogenesis in patients with chronic hepatitis B.
The endocannabinoid system is involved in the pathogenesis of liver fibrosis. However, most of the findings in this area have come from experimental studies in animal models or clinical trials on chronic hepatitis C. The roles of cannabinoid receptor 1 (CB1) and cannabinoid receptor 2 (CB2) in hepatofibrosis in patients with chronic hepatitis B (CHB) have not been studied fully. This study aimed to explore the relationship between liver fibrosis and the expression of CB1 and CB2 in patients with CHB. Eighty liver biopsy specimens from patients with CHB (52 male, 28 female) were analyzed in this study. Fibrosis was staged on a scale of 1 to 4 (F1 to F4, with F4 defining cirrhosis). There were 20 samples for each fibrosis stage. The expression of hepatic alpha-smooth muscle actin (α-SMA), CB1, and CB2 was detected by immunohistochemistry. Hepatic CB1 and CB2 were expressed in all patients with CHB. The degree of fibrosis was significantly associated with the increased expression of CB1 and CB2 in CHB. Furthermore a significant increase in cells positive for both CB1 and CB2 was detected in stage 3 and stage 4 disease compared to stage 1 and stage 2 disease. There was a strong positive association between CB1 expression and α-SMA expression. Moreover, double immunofluorescence staining for CB1 and α-SMA demonstrated that activated hepatic stellate cells (HSCs) express CB1. The hepatic expression of CB1 and CB2 plays an important role during the progression of fibrosis induced by CHB. Endogenous activation of CB1 receptors in patients with CHB enhances fibrogenesis by direct effect on activated HSCs.


Adverse events following percutaneous and surgical coronary revascularisation: Analysis of non-MACE outcomes in the Stent or Surgery (SoS) Trial.
To analyse adverse events requiring or prolonging hospitalisation in the Stent or Surgery (SoS) trial. Many adverse events following coronary revascularisation are non-major adverse cardiovascular events (non-MACE). Trials comparing percutaneous coronary intervention (PCI) and coronary artery bypass surgery (CABG) have reported rates of mortality and MACE only. Comparisons between PCI and CABG groups in the SOS trial were by intention to treat. For patients with non-fatal/non-MACE, number of events per 100 patient years follow-up and duration of hospital stay were assessed. Competing risk analysis was used to illustrate temporal pattern of adverse outcomes. During 2 y median follow up, 1 one or more adverse event occurred in 47.3% (231) of the PCI group and 53% (265) of the CABG group (p=0.086). Non-fatal/non-MACE occurred in 11.9% of the PCI group and 38.6% of the CABG group (p<0.001). Non-fatal/non-MACE per 100 patient years follow-up was 17.49 (PCI) and 35.04 (CABG), rate ratio 2.0, 95% CI 1.7 to 2.4, p<0.001. Cumulative non-fatal/non-MACE associated hospital stays were 1387 and 3287 days in PCI and CABG groups respectively. Median duration of hospitalisation per non-fatal/non-MACE was 5 days (interquartile range 2 to 11.75 days) in the PCI group and 6 days (interquartile range 2 to 12 days) in the CABG group, p=0.245. CABG had lower cumulative incidence of fatal or MACE outcomes, higher cumulative incidence of non-fatal/non-MACE outcomes, and longer cumulative hospitalisation periods compared to the PCI group.


Characterization of Oncology Clinical Trials Using Germline Genetic Data.
The recent successes of poly-ADP ribose polymerase (PARP) inhibitors and belzutifan support germline genetic data as an exciting, accessible source for biomarkers in cancer treatment. This study hypothesizes, however, that most oncology clinical trials using germline data largely prioritize BRCA1/2 as biomarkers and PARP inhibitors as therapy. To characterize past and ongoing oncology trials that use germline data. This retrospective cross-sectional study of oncology trials used the Informa Trialtrove database to evaluate trial attributes. Trials using germline information (including the terms germline, hereditary, or inherited in the title, treatment plan, interventions, end points, objectives, results, or notes) and conducted globally between December 1, 1990, and April 4, 2022 (data freeze date), were included. Trials by cancer type, phase, participants, sponsor type, end points, outcomes, and locations were described. Associated biomarkers and mechanisms of action for studied therapeutic interventions were counted. How germline data in trial inclusion and exclusion criteria are associated with end points, outcomes, and enrollment were also examined. A total of 887 of 84 297 (1.1%) oncology clinical trials in the Trialtrove database that use germline data were identified. Most trials were conducted in cancer types where PARP inhibitors are already approved. A total of 74.8% (672) of trials were performed in the phase 2 setting or above. Trials were primarily sponsored by industry (523 trials [59.0%]), academia (382 trials [43.1%]), and the government (274 trials [30.9%]), where trials may have multiple sponsor types. Among 343 trials using germline data with outcomes in Trialtrove, 180 (52.5%) reported meeting primary end points. Although BRCA1/2 are the most frequent biomarkers seen (BRCA1, 224 trials [25.3%]; BRCA2, 228 trials [25.7%]), trials also examine pharmacogenomic variants and germline mediators of somatic biomarkers. PARP inhibitors or immunotherapy were tested in 69.9% of trials; PARP inhibition was the most frequently studied mechanism (367 trials [41.4%]). An overwhelming number of trials using germline data were conducted in the US, Canada, and Europe vs other countries, mirroring disparities in cancer genetics data. Germline data in inclusion and exclusion criteria are associated with altered end point, outcomes, and enrollment compared with oncology trials with no germline data use. Examples of inclusion and exclusion criteria regarding germline data that may unintentionally exclude patients were identified. These findings suggest that for germline biomarkers to gain clinical relevance, trials must expand biomarkers, therapies, and populations under study.


Is it "every man's right to have babies if he wants them"? Male pregnancy and the limits of reproductive liberty.
Since the 1980s, a number of medical researchers have suggested that in the future it might be possible for men to become pregnant. Given the role played by the right to reproductive liberty in other debates about reproductive technologies, it will be extremely difficult to deny that this right extends to include male pregnancy. However, this constitutes a reductio ad absurdum of the idea of reproductive liberty. One therefore would be well advised to look again at the extent of this purported right in other contexts in which it is deployed.


Magic mushroom compound is a potential treatment for patients with major depression.
A hallucinogenic compound derived from magic mushrooms could provide a new route for antidepressant research.


Facilitating survival and recovery by removing autogenic pathology from the clinical picture.
For the most part, the clinical picture is the expression of autogenic pathology and, unless the anatomical insult represents a major structural compromise, it contributes little to the clinical picture. Autogenic pathology created by the processing of peripheral neurological impulses altered by the presence of anatomical insults is created independently of the gravity of the anatomical insults. Even in the presence of a survivable insult, autogenic pathology is often fatal. Each successful resuscitation effort identifies a patient with a survivable insult who almost died before autogenic pathology was removed by cerebral anoxia, and/or electric shock. Similar patients who suffer terminal brain damage cannot be identified. Cardinal receptors furnish the embryo with its first neural contact with its environment. On completion of embryological migration, they occupy a position in the skin overlying the root of their spinal nerve. Cardinal receptors are functionally segmented to the specific distribution of their spinal nerve and use the stable neurological impulses from the skin to furnish the cadence by which peripheral impulses are processed and valued. Selected cardinal receptors may be specifically stimulated by saline infiltration that produces intradermal blebs in the skin overlying their spinal nerve's root. An augmented burst of infiltration pain immediately followed by symptomatic relief identifies monitoring cardinal receptors. The identification of monitoring receptors confirms the presence of pathology found within the specific distribution of their spinal nerve. Peripheral impulses processed within the cadence of highly stimulated cardinal receptors are assigned an insignificant value. Assigning an insignificant value to peripheral impulses altered by the presence of an anatomical insult removes autogenic pathology from the clinical picture. The immediate onset of profound symptomatic relief heralds the removal of autogenic pathology. Visceral pathology is monitored by bilateral pairs of cardinal receptors so it produces discomfort perceived without specific location information. Therefore, the specific visceral distribution has been discounted and is virtually unknown. However, when visceral pathology is correlated with bilateral pairs of monitoring cardinal receptors there are no patient variations.


Salicylic acid restrains nickel toxicity, improves antioxidant defence system and enhances the production of anticancer alkaloids in Catharanthus roseus (L.).
Salicylic acid (SA) has been reported to ameliorate various stresses in plants. In order to explore the role of SA under nickel (Ni) stress, thirty-days old plants of periwinkle (Catharanthus roseus L.) were supplied with eight treatments comprising basal application of Ni (0, 50, 100 and 150 mg kg(-1)) and foliar application of SA (0 and 10(-5)M) under net house conditions. Ni application significantly reduced the growth attributes including plant height, leaf-area index and fresh and dry weights of shoot and root. Increasing Ni concentration led to a gradual decrease in photosynthetic parameters and activities of nitrate reductase and carbonic anhydrase. The plants, undergoing Ni stress, exhibited a significant increase in the activity of superoxide dismutase, catalase and peroxidase together with an increase in electrolyte leakage and proline content. Total alkaloid content was also declined in Ni-treated plants. Foliar application of SA (10(-5)M) reduced the deleterious effects of Ni on plant growth, accelerating the restoration of growth processes. SA also improved the total alkaloid content under normal as well as adverse conditions. Foliar spray of SA significantly improved the content of anticancer alkaloids vincristine (by 22.2%) and vinblastine (by 50.0%) in plants treated with 150 mg kg(-1) of Ni.


Performance analysis of English hospitals during the first and second waves of the coronavirus pandemic.
The coronavirus infection COVID-19 killed millions of people around the world in 2019-2022. Hospitals were in the forefront in the battle against the pandemic. This paper proposes a novel approach to assess the effectiveness of hospitals in saving lives. We empirically estimate the production function of COVID-19 deaths among hospital inpatients, applying Heckman's two-stage approach to correct for the bias caused by a large number of zero-valued observations. We subsequently assess performance of hospitals based on regression residuals, incorporating contextual variables to convex quantile regression. Data of 187 hospitals in England over a 35-week period from April to December 2020 is divided in two sub-periods to compare the structural differences between the first and second waves of the pandemic. The results indicate significant performance improvement during the first wave, however, learning by doing was offset by the new mutated virus straits during the second wave. While the elderly patients were at significantly higher risk during the first wave, their expected mortality rate did not significantly differ from that of the general population during the second wave. Our most important empirical finding concerns large and systematic performance differences between individual hospitals: larger units proved more effective in saving lives, and hospitals in London had a lower mortality rate than the national average.


Recovery of polyphenols onto porous carbons developed from exhausted grape pomace: A sustainable approach for the treatment of wine wastewaters.
Removal of total polyphenols (TPP) is not only necessary as a pretreatment stepfor anaerobic digestion of wine wastewaters (WWW) but also the recovered polyphenols can be used as a dietary supplement. With a view to make the process sustainable, eco-efficient and cost effective, exhausted grape pomace (EGP) after the extraction of polyphenols was impregnated with ZnCl2 (1:1.5) and further activated at 450 °C for 1 h under inert atmosphere. The GPAC (grape pomace activated carbon) thus developed exhibited well-developed porosity with a predominance of micropores, high surface area and selective surface binding sites. Batch adsorption conducted on diluted WWW revealed the better performance of GPAC (84.3% removal) as compared to EGP (48.5% removal) under similar conditions; with maximum adsorption taking place at pH 3.8. While pH studies indicated a possible electron-donor-acceptor mechanism in the binding of TPP, kinetic studies indicated that diffusion was mediated by the porosity in GPAC. Isotherm studies conducted on GPAC and commercial carbon (CAC) revealed multilayer binding under WWW while Langmuir model was operative under simulated conditions. Contrary to the better performance of CAC, the same for GPAC was comparable at higher dosage where >80%TPP was removed from undiluted WWW. The phenol adsorption capacity of GPAC from real (28.4 mg/g) and from simulated wastewater (142.6 mg/g) was higher as compared to other reported adsorbents. Desorption of TPP from loaded GPAC was maximum (∼91%) with 1:1 ethanol-water solvent. The results reveal a sustainable eco-friendly solution for valorisation of exhausted grape pomace for recovery of polyphenols from wine wastewater.


Centrality of Social Interaction in Human Brain Function.
People are embedded in social interaction that shapes their brains throughout lifetime. Instead of emerging from lower-level cognitive functions, social interaction could be the default mode via which humans communicate with their environment. Should this hypothesis be true, it would have profound implications on how we think about brain functions and how we dissect and simulate them. We suggest that the research on the brain basis of social cognition and interaction should move from passive spectator science to studies including engaged participants and simultaneous recordings from the brains of the interacting persons.


Ovine coccidiosis: studies on the pathogenicity of Eimeria ovinoidalis and E. crandallis in conventionally-reared lambs, including possible effects of passive immunity.
No pathogenic effect was detected in lambs when 10(4) oocyts of each species were inoculated before 72 h of age. At 4 weeks of age the combined inoculum caused diarrhoea and weight loss, the severity being roughly proportional to the size of the inoculum. Even 1000 oocysts of each species caused diarrhoea; the pathogenic effect was attributable mainly to E. ovinoidalis. Hyperimmunization of ewes during pregnancy (by repeated inoculation of massive doses of oocysts) reduced the effects of oocyst inoculation in their progeny. Levamisole administration during pregnancy increased the birthweight of lambs.


Interaction of plasma apolipoproteins with lipid monolayers.
The monolayer technique has been used to study the interaction of lipids with plasma apolipoproteins. Apolipoprotein C-II and C-III from human very low density lipoproteins, apolipoprotein A-I from human high density lipoproteins and arginine-rich protein from swine very low density lipoproteins were studied. The injection of each apoprotein underneath a monolayer of egg phosphatidy[14C]choline at 20 mN/m caused an increase in surface pressure to approximately 30 mN/m. With apolipoprotein C-II and apolipoprotein C-III there was a decrease in surface radioactivity indicating that the apoproteins were removing phospholipid from the interface; the removal of phospholipid was specific for apolipoprotein C-II and apolipoprotein C-III. Although there was a removal of phospholipid from the monolayer, the surface pressure remained constant and was due to the accumulation of apoprotein at the interface. The rate of surface radioactivity decrease was a function of protein concentration, required lipid in a fluid state and, of the lipids tested, was specific for phosphatidylcholine. Cholesterol and phosphatidylinositol were not removed from the interface. The addition of 33 mol% cholesterol to the phosphatidylcholine monolayer did not affect the removal of phospholipids by apolipoprotein C-III. The addition of phospholipid liposomes to the subphase greatly facilitated the apolipoprotein C-II-mediated removal of phospholipid from the interface. Although apolipoprotein A-I and arginine-rich protein gave surface pressure increases, phospholipid was only slightly removed fromthe interface by the addition of liposomes. Based on these findings, we conclude that the apolipoproteins C interact specifically with phosphatidylcholine at the interface. This interaction is important as it relates to the transfer of the apolipoproteins C and phospholipids from very low density lipoproteins to other plasma lipoproteins. The addition of human plasma high density lipoproteins or very low density lipoproteins to the subphase increased the apolipoprotein C-mediated removal of phosphatidyl[14C]choline from the interface 3--4 fold. Low density lipoproteins did not affect the rate of decrease. During lipolysis of very low density lipoproteins to the subphase increased the apolipoprotein C-mediated removal of with the lipid monolayer. Lipolysis experiments were performed in a monolayer trough containing a surface film of egg phosphatidyl[14C]choline and a subphase of very low density lipoproteins and bovine serum albumin. Lipolysis was initiated by the addition of purified milk lipoprotein lipase to the subphase. As a result of lipolysis, there was a decrease in surface radioactivity of phosphatidylcholine. The pre-addition of high density lipoproteins decreased the rate of decrease in surface radioactivity...


Androgen-induced vitellogenin gene expression in primary cultures of rainbow trout hepatocytes.
The hormone induction of vitellogenin (Vg) gene expression was investigated in primary cultures of immature male rainbow trout hepatocytes. Vg cDNA was cloned from the liver of a female rainbow trout injected with estradiol-17beta (E2). A Vg mRNA of about 6.6 kb was detected in the hepatocytes after stimulation with 2 x 10(-9) M E2 for 24 h. The intensity of this signal increased with E2 concentration. Several other hormones including progesterone and androgens (testosterone, androsterone, methyltestosterone) also induced Vg mRNA not only at high (2 x 10(-5) M) but also at low (2 x 10(-9) M), physiologically relevant steroid concentrations. Only cortisol failed to do so at any tested concentration but, surprisingly, like progesterone, it induced an additive effect in the presence of E2. On the other hand, tamoxifen drastically reduced the expression of Vg gene whether stimulated by E2 or any other tested steroid. In conclusion, our studies have highlighted the unusual specificity of Vg mRNA induction in fish.


Sclerosing mucoepidermoid tumour of the parotid gland: report of a case.
A case of a low-grade mucoepidermoid tumour showing an unusual pattern of extensive central keloid-like sclerosis is reported. The sparsity of tumour islands renders recognition of its neoplastic nature difficult. It is postulated that the sclerosis results from exaggerated post-inflammatory scarring due to extravasation of mucin from the tumour into the stroma.


[Viability of autologous fat grafts harvested with the Coleman technique and the tissu trans system (shippert method): a comparative study].
Various methods for harvesting and refining autologous fat grafts have been described. One of the standard procedures, the Coleman technique, is based on manual aspiration to reduce the negative presssure and the centrifugation of the grafts. The Shippert technique uses automatic liposuction with reduced negative pressure and abstains from centifugation in order not to reduce viability of the graft by exposing it to centrifugal forces. This study intends to compare the viability of fat grafts processed with the above-mentioned methods.Fat grafts were obtained in 9 patients by using both the Tissu Trans system (Shippert technique) and the Coleman technique. To evaluate the impact of centrifugation forces, the grafts harvested with the Coleman technique were treated with standard adjustment of the centrifuge and also with doubled g-force. Viability of fat grafts was analysed with the WST-8 test and with annexin V/PI assay FACS analysis.The viability of fat grafts processed by the Coleman technique was significantly higher compared to the Shippert technique on applying the WST-8 test. Applying the annexin V/PI analysis, the viability of fat grafts was almost equal with both techniques. Whereas the fat grafts processed with the Tissu Trans system are injected without condensation, the grafts refined with the Coleman technique were concentrated 3 times by centrifugation compared to the primary liposuctioned graft volumes.The Coleman technique allows the preparation of a fat graft containing more viable cells than the Shippert technique. This is in part due to the condensation of the graft by centrifugation using the Coleman technique. The factor of condensation of the grafts harvested and refined with the Coleman technique exceeds the factor of increased fat graft viability in comparison to the Shippert technique. The Tissu Trans system is more than twice as fast and easier to use with a preferential use for large volume grafts like in breast augmentation, whereas the Coleman technique produces a more condensed graft, favouring it for fat grafting to the face where less volume is needed.


High success rate with exchange nailing to treat a tibial shaft aseptic nonunion.
To investigate the effects of tibial exchange nailing in treating a tibial shaft aseptic nonunion and to establish optimal indications for using this technique. Prospective, consecutive. University hospital. Twenty-five consecutive tibial shaft aseptic nonunions were prospectively treated with the exchange nailing technique. Indications for this procedure were a tibial shaft aseptic nonunion that had previously been treated with an inserted nonreamed or reamed intramedullary nail, displayed less than one centimeter of shortening, was with or without rotational or angular deformity, exhibited no segmental bony defects, and was anatomically suited for conventional or locked reamed intramedullary nail stabilization. The marrow cavity was reamed as extensively as possible, and a rigid intramedullary nail with stable fixation was inserted. During a follow-up period of two to four years (median thirty-two months), twenty-four nonunions healed, on average, in four months (range three to six months). The one remaining nonunion healed four months after a cancellous bone grafting procedure. No wound infection or malunion was noted. Because of its high union rate, low complication rate, and simplicity of method, we believe that the exchange nailing technique should be considered preferentially for all indicated cases.


Regeneration of enteric ganglia in mechanically lengthened jejunum after restoration into intestinal continuity.
We previously demonstrated that it is feasible to lengthen intestinal segments with mechanical force and to restore them back into intestinal continuity. The changes in the enteric ganglia in the lengthened intestinal segments have not been described. A 1-cm segment of rodent jejunum was isolated from intestinal continuity and was lengthened using a spring. After lengthening, jejunal segments were either retrieved (n=4) or restored into intestinal continuity (n=4). Rats with restored segments were euthanized 2 to 3 weeks later. Ganglia were identified and quantified by immunostaining of histological sections. The normal jejunum had 51 ± 5 myenteric and 31 ± 2 submucosal ganglia per circumferential tissue section. Lengthened segments had 21 ± 7 myenteric and 2 ± 2 submucosal ganglia. Restored segments had 46 ± 14 myenteric and 10 ± 10 submucosal ganglia. Circumferential density of ganglia followed a similar pattern. Mechanical lengthening led to a paucity of submucosal and myenteric ganglia. After restoration into continuity, the number increased toward normal, indicating regeneration of the enteric ganglia. The function of regenerated ganglia needs to be assessed in the future.


Paleoceanography of the northwestern Pacific across the Early-Middle Pleistocene boundary (Marine Isotope Stages 20-18).
The fluctuating position of the boundary between the Kuroshio (warm) and Oyashio (cold) currents in the mid-latitude western North Pacific affects both heat transport and air-ocean interactions and has significant consequences for the East Asian climate. We reconstruct the paleoceanography of Marine Isotope Stages (MIS) 20-18, MIS 19 being one of the closest astronomical analogues to the present interglacial, through multiple proxies including microfossil assemblage data, planktonic foraminiferal isotopes (δ18O and δ13C), and foraminiferal Mg/Ca-based temperature records, from the Chiba composite section (CbCS) exposed on the Boso Peninsula, east-central Japan. Principal component analysis (PCA) is used to capture dominant patterns of the temporal variation in these marine records, and shows that the relative abundances of calcareous nannofossil and radiolarian taxa are consistent with the water mass types inferred from geochemical proxies. The leading mode (36.3% of total variance) mirrors variation in the terrestrial East Asian winter monsoon (EAWM), reflecting seasonal trends dominated by the winter monsoon system. In the CbCS, this mode is interpreted as reflecting the interplay between the warm Kuroshio and cold Oyashio waters, which is likely related to the latitudinal shift of the subtropical-subarctic gyre boundary in the North Pacific. The second mode (15.4% of total variance) is closely related to subsurface conditions. The leading mode indicates that MIS 19b and 19a are represented by millennial-scale stadial/interstadial oscillations. Northerly positions for the gyre boundary during late MIS 19c, the interstadials of MIS 19a, and early MIS 18 are inferred from the leading mode, which is consistent with a weak EAWM and consequent mild winter climate in East Asia. Nonetheless, the northerly positions for the gyre boundary during late MIS 19c and early MIS 19a were not associated with subsurface warming presumably due to the suppressed gyre circulation itself caused by the weak Aleutian Low. Intermittent southerly positions for the gyre boundary are inferred for the stadials of MIS 19b and 19a. Regional sea surface temperature (SST) comparisons in the western North Pacific reveal that the moderate SSTs during MIS 19a through early MIS 18 were restricted to the mid- to high latitudes, influenced by the weak EAWM. Comparison between MIS 20-18 and MIS 2-1 suggests that glacial MIS 20 and 18 had significantly milder winters than MIS 2, likely related to the relatively weak EAWM. The online version contains supplementary material available at 10.1186/s40645-020-00395-3.


Cost-effectiveness and epidemiological impact of gender-neutral HPV vaccination in Spain.
All EU countries have introduced Human papilloma virus (HPV) vaccination for adolescent girls and many countries are expanding the strategy to include adolescent boys. There is uncertainty about the cost-effectiveness and epidemiological impact of a gender-neutral HPV vaccination strategy. Here we present the results of an economic model adapted for Spain. Five vaccination strategies were compared from the Spanish healthcare system perspective, combining two vaccines (4-valent and 9-valent) in a gender-neutral or girls-only programme in a dynamic population-based model with a discrete-time Markov approach. Costs and benefits were discounted at 3%. The benefits of immunization were measured with quality-adjusted life years (QALYs), which are achieved by reducing the incidence of diseases attributable to HPV. Incremental cost-effectiveness ratio (ICER) was compared with the willingness-to-pay threshold in Spain. The two most effective strategies were compared: gender-neutral 9-valent vaccination vs. girls-only 9-valent vaccination, resulting in an ICER of € 34,040/QALY, and an important number of prevented cases of invasive cancers and anogenital warts. The sensitivity analysis revealed that gender-neutral 9-valent vaccination would become cost-effective if protection against oropharyngeal and penile cancers was included or if the price per dose decreased from €45 to €28. The gender-neutral 9-valent HPV vaccination in Spain offers more benefits than any other modeled strategy, although in the conservative base case it is not cost-effective. However, certain plausible assumptions would turn it into an efficient strategy, which should be borne in mind by the decision makers together with equity and justice arguments.


Tolerability and Effectiveness of Exenatide Once Weekly Relative to Basal Insulin Among Type 2 Diabetes Patients of Different Races in Routine Care.
Analyses of efficacy and tolerability of pharmacologic interventions are based on clinical trials that often include predominately white populations, in part because of challenges associated with recruitment and retention of racial/ethnically diverse study populations. Using real-world electronic health record (EHR) data, we sought to evaluate the tolerability and effectiveness of exenatide once weekly (EQW), overall and relative to basal insulin (BI), according to race. Patients with type 2 diabetes initiating EQW or BI between 2012 and 2015 were selected from the Optum EHR Research Database, a system pooling data from dozens of hospitals throughout the US. Measures of HbA1c, weight, and body mass index (BMI) were summarized at initiation and quarterly in the first year afterwards. Occurrences of gastrointestinal (GI) symptoms and hypoglycemia were identified by diagnostic codes and clinical notes, and incidence rates (IR) and relative rates (RR) were calculated. Overall, 4907 white patients (mean age = 57 years) and 454 African American patients (mean age = 53 years) were included. The percent change in HbA1c from initiation through 9-12 months was similar for white and African American patients [EQW-White: -6.89 (95% CI: -8.29, -5.50), EQW-African American: -5.99 (95% CI: -10.33, -1.65), BI-White: -4.68 (95% CI: -5.51, -3.86), BI-African American: -3.11 (95% CI: -5.37, -0.85)]. For EQW, percent change in weight was -1.73 (95% CI: -2.45, -1.02) for white patients and -1.11 (95% CI: -3.02, -0.81) for African American patients. No weight loss was observed among BI initiators. Relative to BI initiators, EQW initiators had lower rates of hypoglycemia [White RR: 0.82 (95% CI: 0.66, 1.01), African American RR: 0.59 (95% CI: 0.26, 1.34)]. GI symptoms were increased in white EQW initiators. Treatment with EQW, relative to BI, was associated with larger reductions in HbA1c and weight and reduced risk of hypoglycemia, effects that were not different for white and African American patients. AstraZeneca, Gothenburg, Sweden.


Persistent Pseudomonas aeruginosa infection associated with non-invasive ventilation in a child with spinal muscular atrophy type 1.
Current standards of care suggest the use of non-invasive positive pressure ventilation (NIV) in children with spinal muscular atrophy and symptomatic respiratory failure. Theoretical concerns exist regarding NIV equipment as a source of infection in restrictive lung disease due to the possibility of prolonged NIV device use, greater risk in acquiring infections, and difficulties in managing and clearing infections. NIV devices may draw pathogens through the air inlet port that may contaminate the internal surfaces. These pathogens may then infect children with spinal muscular atrophy. We present a case of 2 genetically identical Pseudomonas aeruginosa cultures from both the patient's NIV device and from nasopharyngeal samples. This infection persisted both in nasopharyngeal aspirate cultures and from NIV equipment cultures despite the use of an eradication program involving both the child and the NIV device.


Beta-turn secondary structure and melanocortin ligands.
The melanocortin pathway has emerged during this past decade as an important target area for the discovery and development of therapeutic agents related to obesity and type 2 diabetes. This peptide-G-protein coupled receptor (GPCR) pathway has evolved from peptide-based ligands to small molecules possessing a variety of different molecular scaffolds. Herein, we summarize the originating hypothesis of the importance of the reverse beta-turn secondary structure for agonist ligand potency at the melanocortin receptors and how that information was utilized for the discovery of small molecules based upon this type of turn structure.


Nitrogen from agriculture and temperature as the major drivers of deoxygenation in the central Bohai Sea.
Agricultural N losses strongly dominate the N delivery (average 72 % of total N delivery to rivers in the period 1980-2010) in the rivers discharging into the Bohai Sea, a semi-enclosed marginal sea, which has been suffering from eutrophication and deoxygenation since the 1980s. In this paper we investigate the relationship between N loading and deoxygenation in the Bohai Sea, and consequences of future N loading scenarios. Using modeling for the period 1980-2010, the contributions of different oxygen consumption processes were quantified and the main controlling mechanisms of summer bottom dissolved oxygen (DO) evolution in the central Bohai Sea were determined. Model results show that the water column stratification during summer impeded the DO exchange between oxygenated surface water and oxygen-poor bottom water. Water column oxygen consumption (60 % of total oxygen consumption) was strongly correlated with elevated nutrient loading, while nutrient imbalances (increasing N:P ratios) enhanced harmful algal bloom proliferation. Future scenarios show that deoxygenation may be reduced in all scenarios owing to increasing agricultural efficiency, manure recycling and wastewater treatment. However, even in the sustainable development scenario SSP1, nutrient discharges in 2050 will still exceed the 1980 levels, and with further enhancement of water stratification due to climate warming, the risk of summer hypoxia in bottom waters may persist in the coming decades.


Adventitial macrophage accumulation impairs perivascular nerve function in mesenteric arteries with inflammatory bowel disease.
Introduction: Inflammatory bowel disease involves aberrant immune responses and is associated with both cardiovascular disease risk and altered intestinal blood flow. However, little is known about how inflammatory bowel disease affects regulation of perivascular nerves that mediate blood flow. Previous work found perivascular nerve function is impaired in mesenteric arteries with Inflammatory bowel disease. The purpose of this study was to determine the mechanism of impaired perivascular nerve function. Methods: RNA sequencing was performed on mesenteric arteries from IL10-/- mice treated with H. hepaticus to induce disease (inflammatory bowel disease) or left non-gavaged (Control). For all other studies, Control and Inflammatory bowel disease mice received either saline or clodronate liposome injections to study the effect of macrophage depletion. Perivascular nerve function was assessed using pressure myography and electrical field stimulation. Leukocyte populations, and perivascular nerves, and adventitial neurotransmitter receptors were labeled using fluorescent immunolabeling. Results: Inflammatory bowel disease was associated with increases in macrophage-associated gene expression, and immunolabeling showed accumulation of adventitial macrophages. Clodronate liposome injection eliminated adventitial macrophages, which reversed significant attenuation of sensory vasodilation, sympathetic vasoconstriction and sensory inhibition of sympathetic constriction in inflammatory bowel disease. Acetylcholine-mediated dilation was impaired in inflammatory bowel disease and restored after macrophage depletion, but sensory dilation remained nitric oxide independent regardless of disease and/or macrophage presence. Conclusion: Altered neuro-immune signaling between macrophages and perivascular nerves in the arterial adventitia contributes to impaired vasodilation, particularly via dilatory sensory nerves. Targeting the adventitial macrophage population may help preserve intestinal blood flow in Inflammatory bowel disease patients.


Chemical characterization of the persistent fraction of hydroxyethyl starch in rat serum and spleen.
Hydroxyethyl starch (HES) found in rat serum and spleen after single and daily administrations of 0.9 g/kg for 1 week was characterized by gas-liquid chromatography. There was very little difference in the degree of substitution (D.S.) and molar substitution (M.S.) of HES in serum samples obtained at 1 hour and 57 days after multiple doses and of HES in spleen samples obtained at 1 hour and 168 days after a single dose of HES. The small increase in D.S. and M.S. was due to a decrease in the glucose content and not due to a change in the ratio of mono- to poly-substituted glucoses.


Relation of perimenstrual asthma with disease severity and other allergic co-morbidities--the first report of perimenstrual asthma prevalence in Saudi Arabia.
Perimenstrual asthma (PMA) has been documented in 30-40% of asthmatic women; however, there have been few epidemiological investigations of PMA in practice. Determination of the prevalence of perimenstrual asthma in a sample of female Saudi asthmatic patients, and to study the relation of PMA to asthma severity, aspirin-induced asthma and to other allergic co-morbidities. Data were analysed from all female asthmatic patients followed up in the unit from January 2008 to May 2009 who were not pregnant, not on oral contraceptive pills, not menopausal, nor had had a hysterectomy. They were asked about exacerbation of their asthma state regarding worsening of symptoms, need for more rescue medications and even visits to emergency room just before or in the first days of menstruation, or both. Moreover, relation with aspirin-induced asthma and other associated allergic co-morbidities recorded in their medical files with prevalence of PMA was reported. The prevalence was found to be 8.2%. Asthma severity was found to be significantly related to PMA (p<0.0001). Aspirin-induced asthma and allergic co-morbidities were more prone to occur in cases with PMA than other studied asthmatics. We have found a low prevalence of PMA in Saudi women of fertile age compared to other studies published. Study findings support the hypothesis that PMA is related to asthma severity.


Multi-residue analysis of 126 pesticides in chicken muscle by ultra-high-performance liquid chromatography coupled to quadrupole time-of-flight mass spectrometry.
Ensuring food safety requires effective methods for the simultaneous analysis of pesticide residues in animal-origin foods. A sensitive and reliable method for the multi-residue analysis of 126 pesticides in chicken muscle was developed using a modified QuEChERS technique and ultra-high-performance liquid chromatography coupled to quadrupole time-of-flight mass spectrometry. A new enhanced matrix removal-lipid material was used as the QuEChERS dispersive purification adsorbent. Method validation revealed satisfactory linearities with correlation coefficients higher than 0.994 for all pesticides. All limits of quantification were below 10 µg/kg, except in the cases of oxadiazon, clomazone, and lactofen. The matrix effects were nearly negligible, ranging from 73.09% to 125.22%. The recoveries at three spiked levels (50, 100, and 200 μg/kg) were 71.38-120.43% and the intra-day and inter-day precisions were lower than 10%, indicating the good accuracy and precision of the established method.


Proliferation and migration of hepatocellular carcinoma are accelerated by LINC01287 via the miR-559/TCF12 axis.
To uncover the role of LINC01287 in the progression of hepatocellular carcinoma (HCC) and the indicated molecular mechanism. Relative levels of LINC01287 and miR-559 in 32 pairs of HCC tissues and normal ones, as well as HCC cell lines were detected by quantitative real-time polymerase chain reaction (qRT-PCR). Receiver operating characteristic (ROC) curves and Kaplan-Meier curves were depicted for assessing the diagnostic and prognostic potentials of LINC01287 in HCC, respectively. Proliferative and migratory capacities in HCC cells influenced by LINC01287 were assessed by cell counting kit-8 (CCK-8) and transwell assay, respectively. The regulatory loop LINC01287/miR-559/TCF12 was ascertained by Dual-Luciferase reporter assay. The involvement of the regulatory loop in the progression of HCC was examined via rescue experiments. LINC01287 was upregulated in HCC tissues and cell lines, whereas miR-559 was downregulated. LINC01287 displayed certain diagnostic and prognostic potentials in HCC. Knockdown of LINC01287 could inhibit proliferative and migratory capacities in HCC cells. The regulatory loop LINC01287/miR-559/TCF12 was responsible for the aggravation of HCC. LINC01287 drives proliferative and migratory capacities in HCC via targeting the miR-559/TCF12 axis.


Turkish validity and reliability study of Paternal Antenatal Attachment Scale.
The aim of this study was to adapt the validity and reliability of the Paternal Antenatal Attachment Scale (PAAS) for Turkish fathers. The sample of the methodological study consisted of 580 father candidates. In the study, as a result of the exploratory factor analysis, it was determined that the PAAS consisted of 16 items, eight items in the "quality of attachment" subdimension and eight items in the "time spent in attachment mode" subdimension. It supported the 2-factor scale structure the confirmatory factor analysis. Cronbach's α was found to be .82 in the total scale. In addition, item-total correlation and test-retest analysis of the scale had a high correlation. Based on the study results, the Turkish language version of the PAAS is valid and reliable.


Solid chip-based detection of trace morphine in solutions via portable surface-enhanced Raman spectroscopy.
The accurate, sensitive and portable detection of morphine is important to handle judicial cases, but remains to be a great challenge. In this work, a flexible route is presented for the accurate identification and efficient detection of trace morphine in solutions based on surface-enhanced Raman spectroscopy (SERS) and a solid substrate/chip. A gold-coated jagged silicon nanoarray (Au-JSiNA) is designed and prepared via Si-based polystyrene colloidal template-reactive ion etching and sputtering deposition of Au. Such Au-JSiNA has three-dimensional nanostructure with good structural uniformity, high SERS activity and hydrophobic surface. Adopting this Au-JSiNA as SERS chip, trace morphine in solutions could be detected and identified in both dropping and soaking ways, and the limit of detection is below 10-4 mg/mL. Importantly, such chip is especially suitable for the detection of trace morphine in aqueous solutions and even domestic sewage. The good SERS performance is attributed to the high-density nanotips and nanogaps on this chip as well as its hydrophobic surface. Additionally, the appropriate surface modification of this Au-JSiNA chip with 3-mercapto-1-propanol or 3-mercaptopropionic acid/1-(3-dimethylaminopropyl)-3-ethylcarbodiimide can further increase its SERS performances to morphine. This work provides a facile route and practical solid chip for SERS detection of trace morphine in solutions, which is significant to develop the portable and reliable instruments for on-site analysis of drugs in solutions.


Production of immunoglobulin A in different reactor configurations.
A murine hybridoma line (Zac3), secreting an IgA monoclonal antibody, was cultivated in different systems: a BALB/c mouse, a T-flask, a stirred-tank bioreactor and a hollow fiber reactor. These systems were characterized in terms of cell metabolism and performances for IgA production. Cultures in T-flask and batch bioreactor were found to be glutamine-limited. Ammonia and lactate were produced in significant amounts. IgA productivity was found to be constant and growth associated. Final IgA concentration was similar in both systems. In fed-batch cultures, supplemented with glutamine and glucose, maximum viable cell concentration was increased by 60% and final IgA concentration by 155%. The hollow fiber reactor was able to produce very large amounts of IgA at very high concentrations, similar to the value found in ascites fluid. The productivity ofZac3 is similar to the values reported for IgG-producing cell lines.


Gut microbiota contributes towards immunomodulation against cancer: New frontiers in precision cancer therapeutics.
The microbiota influences human health and the development of diverse diseases, including cancer. Microbes can influence tumor initiation and development in either a positive or negative manner. In addition, the composition of the gut microbiota affects the efficacy and toxicity of cancer therapeutics as well as therapeutic resistance. The striking impact of microbiota on oncogenesis and cancer therapy provides compelling evidence to support the notion that manipulating microbial networks represents a promising strategy for treating and preventing cancer. Specific microbes or the microbial ecosystem can be modified via a multiplicity of processes, and therapeutic methods and approaches have been evolving. Microbial manipulation can be applied as an adjunct to traditional cancer therapies such as chemotherapy and immunotherapy. Furthermore, this approach displays great promise as a stand-alone therapy following the failure of standard therapy. Moreover, such strategies may also benefit patients by avoiding the emergence of toxic side effects that result in treatment discontinuation. A better understanding of the host-microbial ecosystem in patients with cancer, together with the development of methodologies for manipulating the microbiome, will help expand the frontiers of precision cancer therapeutics, thereby improving patient care. This review discusses the roles of the microbiota in oncogenesis and cancer therapy, with a focus on efforts to harness the microbiota to fight cancer.


Ginsenoside Rg3 Protects Mouse Islet β-Cells Injured by High Glucose.
To investigate the effect of Ginsenoside Rg3 on insulin secretion in mouse MIN6 cells and the possible mechanism. The cultured mouse pancreatic islet MIN6 cells were divided into control group (NC), Rg3 group (Rg3, 50 μg/L), high glucose group (HG, 33 mmol/L), High glucose and Rg3 group (HG + Rg3), after 48 h of continuous culture, CCK-8 was used to detect cell viability; mouse insulin enzyme-linked immunoassay kit to detect insulin release; ATP content detection kit to detect ATP; DCFH-DA to detect intracellular reactive oxygen species (ROS) levels; total glutathione (T-GSH)/oxidized glutathione (GSSG) assay kit to detect the ratio of GSH/GSSG; Using the mitochondrial membrane channel pore (MPTP) fluorescence detection kit in MIN6 cells and collect the intensity of green fluorescence; Western blot to detect the expression of antioxidant proteins Glutathione reductase (GR). The results showed that compared with the NC group, the cell viability of the HG was decreased (P < 0.05), insulin release decreased (P < 0.001), ATP content decreased significantly (P < 0.001), and ROS content increased (P < 0.01), the GSH/GSSH ratio of pancreatic islet cells decreased (P < 0.05),the green fluorescence intensity decreased (P < 0.001), indicating that the permeability of mitochondria increased and the content of antioxidant protein in the cells decreased (P < 0.05). Compared with the HG group, the cell viability of the HG + Rg3 group was significantly increased (P < 0.05), the amount of insulin released was significantly increased (P < 0.001), ATP content was significantly increased (P < 0.01), and the ROS content was significantly decreased (P < 0.01), GSH/GSSH ratio increased significantly (P < 0.05), the green fluorescence intensity was increased (P < 0.001), indicating that the permeability of mitochondria decreased and antioxidant protein GR content increased significantly (P < 0.05). Taken together, our results suggest that Rg3 has an antioxidant protective effect on mouse pancreatic islet cells damaged by high glucose and maintains pancreatic islet cell function and promotes insulin secretion.


[Partial resection, inner thigh skin graft, and glans reconstruction for early-stage penile cancer: A report of 6 cases].
To explore the optimal methods for the reconstruction and preservation of the glans after partial penis resection in the treatment of early-stage penile cancer. Between January 2012 and June 2015, we treated 6 cases of early- stage penile cancer by partial penis resection, inner thigh skin graft, and glans reconstruction and followed them up for 0.5-3 years. The length of the penis before and after operation was ([6.5 ± 1.2] vs [4.5 ± 1.8] cm) in the flaccid state and ([12.8 ± 2.3] vs [9.1 ± 2.1] cm) in the erectile state. The sense of the reconstructed glans was completely recovered at 3 months after surgery. The glans skin was pale red and soft, nearly normal at 12 months, with no obvious graft contracture or scar formation. All the patients achieved normal erection and their partners were satisfied with their intercourse. No recurrence or metastasis was observed. The strategy of partial penis resection, inner thigh skin graft and glans reconstruction, simple, effective, and with few complications, is one of the best treatments of early-stage penile cancer, which not only ensures radical removal of the tumor but also maximally reserves the function of the organ.


Change in allodynia of patients with post-lingual nerve repair iatrogenic lingual nerve disorder.
Mandibular third molar extractions are common treatment in oral maxillofacial surgery, but risk disturbance of the lingual nerves causing anesthesia, eating difficulty and allodynia, which can seriously reduce patient quality of life. This study investigates the change in allodynia before and after repair in patients with lingual nerve disorder. This retrospective cohort study comprises the 52 patients with affected lingual nerve after third molar extraction at our hospital over a 7-year period. Pre- and postoperative (6 months and 12 months) neurosensory records were analyzed. Fifty-two patients underwent lingual nerve repair and returned for at least 1 year of follow-up. Mean age was 36.8 ± 11.9. Median interval between injury and surgery was 5 (4, 8) months. In 92.9% of those with pain before surgery, allodynia disappeared postoperatively. This study shows that microsurgical lingual reconstructions are effective in patients with preoperative allodynia, but a small number of patients may have remaining allodynia after surgery. Large-scale, more detailed analysis of such cases is required.


The properties of the actin-myosin interaction in the heart muscle depend on the isoforms of myosin but not of α-actin.
In myocardium of mammals there are two isoforms of myosin heavy chains, α and β. In ventricle, together with ventricular isoforms of light chains they form two isomyosins: V1 and V3, homodimers of α- and β-heavy chains, respectively. In atria, α- and β-heavy chains together with atrial light chains form A1 (αα) and A2 (ββ) isomyosins. Besides in myocardium two isoforms of α-actin, skeletal and cardiac, are expressed. We assume that the differences in the amino acid sequence of cardiac and skeletal actin may affect its interaction with myosin. To test this hypothesis, we investigated characteristics of actin-myosin interactions of cardiac and skeletal isoforms of α-actin with the isoforms of cardiac myosin using an optical trap technique and an in vitro motility assay. It was found that the mechanical and kinetic characteristics of the interactions of the isoforms of cardiac myosin with actin depend on the isoforms of myosin not α-actin.


Electrophoretic Deformation of Individual Transfer RNA Molecules Reveals Their Identity.
It has been hypothesized that the ribosome gains additional fidelity during protein translation by probing structural differences in tRNA species. We measure the translocation kinetics of different tRNA species through ∼3 nm diameter synthetic nanopores. Each tRNA species varies in the time scale with which it is deformed from equilibrium, as in the translocation step of protein translation. Using machine-learning algorithms, we can differentiate among five tRNA species, analyze the ratios of tRNA binary mixtures, and distinguish tRNA isoacceptors.


Bacterial-induced cell fusion is a danger signal triggering cGAS-STING pathway via micronuclei formation.
Burkholderia pseudomallei is the causative agent of melioidosis, an infectious disease in the tropics and subtropics with high morbidity and mortality. The facultative intracellular bacterium induces host cell fusion through its type VI secretion system 5 (T6SS5) as an important part of its pathogenesis in mammalian hosts. This allows it to spread intercellularly without encountering extracellular host defenses. We report that bacterial T6SS5-dependent cell fusion triggers type I IFN gene expression in the host and leads to activation of the cGAMP synthase-stimulator of IFN genes (cGAS-STING) pathway, independent of bacterial ligands. Aberrant and abortive mitotic events result in the formation of micronuclei colocalizing with cGAS, which is activated by double-stranded DNA. Surprisingly, cGAS-STING activation leads to type I IFN transcription but not its production. Instead, the activation of cGAS and STING results in autophagic cell death. We also observed type I IFN gene expression, micronuclei formation, and death of chemically induced cell fusions. Therefore, we propose that the cGAS-STING pathway senses unnatural cell fusion through micronuclei formation as a danger signal, and consequently limits aberrant cell division and potential cellular transformation through autophagic death induction.


[Isolation of bovine cell lines and susceptibility to foot-and-mouth disease virus].
Morphology and chromosomes of cell sublines derived from two new bovine kidney lines are reported. Cell susceptibility to the foot-and-mouth disease virus is discussed. One of the sublines showed epithelial-like cells, while the remainder, elonged fibroblastic-like cells. Most of them had a diploid number of chromosomes. From these sublines only one was sensible to the foot-and-mouth disease virus.


An efficient Bayesian platform trial design for borrowing adaptively from historical control data in lymphoma.
To reduce a clinical trial's cost and ethical risk to its enrollees, some oncology trial designers have suggested borrowing information from similar but already completed trials to reduce the number of patients needed for the current study. Motivated by competing drug therapies for lymphoma, we propose a Bayesian adaptive "platform" trial design that uses commensurate prior methods at interim analyses to borrow adaptively from the control group of an earlier-starting trial. The design adjusts the trial's randomization ratio in favor of the novel treatment when the interim posterior indicates commensurability of the two control groups. In this setting, our design can supplement a control arm with historical data, and randomize more new patients to the novel treatments. This design is both ethical and economical, since it shortens the process of introducing new treatments into the market, and any additional costs introduced by this design will be compensated by the savings in control arm sizes. Our approach performs well via simulation across settings with varying degrees of commensurability and true treatment effects, and compares favorably to an adaptive "all-or-nothing" approach in which the decision to pool or discard historical controls is based on a simple ad-hoc frequentist test at interim analysis. We also consider a three drug extension where a new imaginary intervention joins the platform, and show again that our procedure performs well via simulation.


Intrapulmonary potential of polyethylene glycol-modified glucagon-like peptide-1s as a type 2 anti-diabetic agent.
The pulmonary delivery of anti-diabetic peptide drugs can improve diabetic patient compliance. In this study, we tried to improve the pulmonary pharmacokinetic properties of glucagon-like peptide-1(7-36) (GLP-1) using a PEGylation approach. Initially, three types of site-specific (Lys(34)) PEGylated GLP-1 analogs were synthesized using PEGs of 2, 5, and 10 kDa, respectively. Their pharmacokinetic profiles were then examined in endotracheally cannulated rats. The results obtained show that all pharmacokinetic parameters (AUC(inf), C(max), t(1/2), V/F, and Cl/F etc.) of PEGylated GLP-1s were greatly improved by increasing PEG Mw. Specifically, the t(1/2) values of PEGylated GLP-1s (PEG Mw: 2, 5, 10 kDa) increased to 23.1+/-6.2, 41.6+/-12.3, and 81.7+/-11.7 min, respectively, vs. 8.9+/-2.9 min for intratracheally administered GLP-1. Also, PEGylated GLP-1s were found to have substantially greater C(max) values (7.4-7.8 ng/ml) than GLP-1 (4.0+/-2.4 ng/ml). Moreover, these PEGylated GLP-1s were found to have 10-20 fold more resistance to rat lung enzyme and plasma dipeptidyl peptidase IV (DPP IV). These findings indicate the dual-pharmacokinetic enhancements that PEGylated GLP-1s better survives proteolytic breakdown in the lungs than GLP-1s and better enters the systemic circulation, and that these analogs are more resistant to DPP IV-induced proteolysis and are much less rapidly removed from the systemic circulation. In conclusion, this study demonstrates the pharmaceutical usefulness of PEGylation in the context of the pulmonary delivery of GLP-1. These results show that PEGylated GLP-1s should be considered potential components of anti-diabetic inhalant preparations.


HLH-11 modulates lipid metabolism in response to nutrient availability.
The ability of organisms to sense nutrient availability and tailor their metabolic states to withstand nutrient deficiency is critical for survival. To identify previously unknown regulators that couple nutrient deficiency to body fat utilization, we performed a cherry-picked RNAi screen in C. elegans and found that the transcription factor HLH-11 regulates lipid metabolism in response to food availability. In well-fed worms, HLH-11 suppresses transcription of lipid catabolism genes. Upon fasting, the HLH-11 protein level is reduced through lysosome- and proteasome-mediated degradation, thus alleviating the inhibitory effect of HLH-11, activating the transcription of lipid catabolism genes, and utilizing fat. Additionally, lipid profiling revealed that reduction in the HLH-11 protein level remodels the lipid landscape in C. elegans. Moreover, TFAP4, the mammalian homolog of HLH-11, plays an evolutionarily conserved role in regulating lipid metabolism in response to starvation. Thus, TFAP4 may represent a potential therapeutic target for lipid storage disorders.


Organic photorefractive glass with infrared sensitivity and fast response.
Infrared imaging materials with high speed and dynamic range are required for a variety of imaging and diagnostic techniques. We present an organic photorefractive glass that shows high diffraction efficiencies of as great as 40% with 25-mum-thick samples and fast response times of 4.3 ms under irradiation at 790 nm. Furthermore, the intensity dependence and field dependence of the grating decay are investigated.


Malacoplakia: a case involving epididymis and a case involving a bladder complicated by calculi.
We report the sixth case of malacoplakia of the epididymis in the world literature and the first to occur in a patient who had undergone a vasectomy previously. The patient was treated successfully by epididymectomy. Another case of malacoplakia of the bladder is reported in which multiple adherent stones developed on the surface of the lesion. Long-term antibiotic therapy led to stabilization of bilateral obstruction at the ureterovesical junction.


Distress intolerance mediates attentional control on posttraumatic stress symptoms: Evidence from two clinical samples.
Theoretical models emphasize the importance of both affective and cognitive risk factors in the development of posttraumatic stress symptoms (PTSS). Two such factors predicting PTSS have been studied extensively: distress intolerance (DI) - an affective factor indicative of the ability to tolerate negative affective states - and attentional control (AC), a cognitive factor reflecting the ability to flexibly shift and maintain attention to goal-relevant tasks. Previous work primarily highlights the independent contributions of DI and AC and their interaction to predict PTSS. Some models, however, suggest a mediational pathway such that AC indirectly affects PTSS via diminished DI. The current paper addressed this gap by first attempting to replicate prior findings, while also exploring this mediation model. Results were examined in two clinical samples - a trauma-exposed sample of adults (study 1; N = 73) and trauma-exposed treatment-seeking adults (study 2; N = 204). Results partially supported our hypotheses; both studies failed to replicate prior moderation findings, but our mediational hypothesis was supported in both samples. Low AC appears to decrease an individual's tolerance for distressing situations, which in turn increases the severity of PTSS. Results suggest that PTSD treatments may benefit by incorporating components of AC, DI, or a combination of the two to mitigate PTSS. Taken together, this study provides a novel examination of how cognitive and affective risk factors, namely AC and DI, work in tandem to increase PTSS.


Physical intimate partner violence among women reporting prior fertility treatment: a survey of U.S. postpartum women.
To determine the prevalence of physical intimate partner violence (IPV) among postpartum women reporting preconception fertility treatment compared with those who conceived without the use of assisted reproduction. Retrospective cross-sectional population-based study. Not applicable. Postpartum respondents of the Centers for Disease Control Pregnancy Risk Assessment Monitoring System survey. Preconception fertility treatment utilization. Physical IPV. Of the 43,999 respondents included in this analytic sample, roughly 2% reported physical IPV. Respondents reporting preconception fertility treatment (12.6%) were less likely to endorse physical IPV than those who conceived without fertility treatment exposure (odds ratio, 0.5; 95% confidence interval, 0.4-0.7). In the multivariate regression model, the odds of physical IPV were similar among postpartum women regardless of the fertility treatment exposure (adjusted odds ratio, 1.2; 95% confidence interval, 0.8-2.0). Residing in a household with an income under the federal poverty level and increased preconception stressors were predictive of reported physical IPV. There was no difference in the type of fertility treatment and report of physical IPV. Among women exposed to fertility treatment, predictors of physical IPV included self-identification of Black or Hispanic race and ethnicity as well as report of 4 or more stressors in the 12 months before the most recent delivery. The use of fertility treatment did not confer greater risk of physical IPV within this postpartum population. However, there are many individuals with infertility who never present for an assessment, proceed with treatment, or are unsuccessful, thus the extent to which infertility and fertility treatment exposure is associated with physical IPV remains to be elucidated. Women reporting a greater number of stressors may be uniquely at risk despite the access and exposure to fertility treatment. The preconception period, inclusive of encounters with infertility specialists, represents a novel opportunity to screen and counsel all women for IPV.


Selective amyloid β oligomer assay based on abasic site-containing molecular beacon and enzyme-free amplification.
Amyloid-beta (Aβ) oligomers are highly toxic species in the process of Aβ aggregation and are regarded as potent therapeutic targets and diagnostic markers for Alzheimer's disease (AD). Herein, a label-free molecular beacon (MB) system integrated with enzyme-free amplification strategy was developed for simple and highly selective assay of Aβ oligomers. The MB system was constructed with abasic site (AP site)-containing stem-loop DNA and a fluorescent ligand 2-amino-5,6,7-trimethyl-1,8-naphyridine (ATMND), of which the fluorescence was quenched upon binding to the AP site in DNA stem. Enzyme-free amplification was realized by target-triggered continuous opening of two delicately designed MBs (MB1 and MB2). Target DNA hybridization with MB1 and then MB2 resulted in the release of two ATMND molecules in one binding event. Subsequent target recycling could greatly amplify the detection sensitivity due to the greatly enhanced turn-on emission of ATMND fluorescence. Combining with Aβ oligomers aptamers, the strategy was applied to analyze Aβ oligomers and the results showed that it could quantify Aβ oligomers with high selectivity and monitor the Aβ aggregation process. This novel method may be conducive to improve the diagnosis and pathogenic study of Alzheimer's disease.


Plasma testosterone levels and ovarian testosterone content in adult mice treated with diethylstilbestrol neonatally.
Neonatal female NMRI mice (n = 16) were treated with 5 micrograms diethylstilbestrol (DES) per day, for the first 5 days after birth and killed postpubertally. Control females (n = 52) were injected with vehicle only and killed in different stages of the estrous cycle. The plasma testosterone level was significantly lower in DES females than in control females in any of the estrous phases. Ovariectomy (n = 5), adrenalectomy (n = 5) or a combination of both ablations (n = 3) did not affect the plasma testosterone in DES treated females while it was significantly reduced in control females (ovariectomy n = 5; adrenalectomy n = 9); most effective was the combination ovariectomy-adrenalectomy (n = 7). Ovarian homogenates from DES treated females (n = 10) had a significantly lower testosterone content than homogenates from control females in any phase of the estrous cycle (6-10 females per phase), which held true on both a per ovary basis and when related to ovarian weight. After a 2 h incubation in vitro, the testosterone levels had increased significantly in DES homogenates (n = 6) and to a lower extent in homogenates from control females in estrus (n = 9). No similar effect was found in homogenates from diestrus (n = 10) or proestrus (n = 9) females. The results are discussed in relation to the special ovarian morphology of adult but neonatally DES treated females and also with respect to endocrine control mechanisms.


Quantification of tricuspid regurgitation by measuring the width of the vena contracta with Doppler color flow imaging: a clinical study.
We sought to evaluate the vena contracta width (VCW) measured using color Doppler as an index of severity of tricuspid regurgitation (TR). The VCW is a reliable measure of mitral and aortic regurgitation, but its value in measuring TR is uncertain. In 71 consecutive patients with TR, the VCW was prospectively measured using color Doppler and compared with the results of the flow convergence method and hepatic venous flow, and its diagnostic value for severe TR was assessed. The VCW was 6.1+/-3.4 mm and was significantly higher in patients with, than those without, severe TR (9.6+/-2.9 vs. 4.2 +/- 1.6 mm, p<0.0001). The VCW correlated well with the effective regurgitant orifice (ERO) by the flow convergence method (r = 0.90, SEE = 0.17 cm2, p<0.0001), even when restricted to patients with eccentric jets (r = 0.93, p < 0.0001). The VCW also showed significant correlations with hepatic venous flow (r = 0.79, p < 0.0001), regurgitant volume (r = 0.77, p<0.0001) and right atrial area (r = 0.46, p< 0.0001). A VCW > or =6.5 mm identified severe TR with 88.5% sensitivity and 93.3% specificity. In comparison with jet area or jet/right atrial area ratio, the VCW showed better correlations with ERO (both p<0.01) and a larger area under the receiver operating characteristic curve (0.98 vs. 0.88 and 0.85, both p<0.02) for the diagnosis of severe TR. The VCW measured by color Doppler correlates closely with severity of TR. This quantitative method is simple, provides a high diagnostic value (superior to that of jet size) for severe TR and represents a useful tool for comprehensive, noninvasive quantitation of TR.


Winter photosynthetic activity of twenty temperate semi-desert sand grassland species.
The winter photosynthetic activity (quantified by net CO(2) assimilation rates and chlorophyll (Chl) a fluorescence parameters) of 20 plant species (including two lichens and two mosses) of a Hungarian temperate semi-desert sand grassland was determined on one occasion per year in 1984, 1989 and 1994. Throughout winter, the overwintering green shoots, leaves or thalli were regularly exposed to below zero temperatures at night and daytime temperatures of 0-5 degrees C. In situ tissue temperature varied between -2.1 and +6.9 degrees C and the photosynthetic photon flux density (PPFD) between 137 and 351 micromol m(-2)s(-1). Under these conditions 18 of the grassland species exhibited photosynthetic CO(2) uptake (range: vascular plants ca. 0.2-3.8 micromol m(-2)s(-1), cryptogams 0.3-2.79 micromol kg(-1)s(-1)) and values of 0.9-5.1 of the Chl fluorescence decrease ratio R(Fd). In 1984, Festuca vaginata and Sedum sexangulare had net CO(2) assimilation at leaf temperatures of -0.85 to -1.2 degrees C. In 1989, all species except Cladonia furcata showed net CO(2) assimilation at tissue temperatures of 0 to +3.3 degrees C, with the highest rates observed in Poa bulbosa and F. vaginata. The latter showed a net CO(2) assimilation saturation at a PPFD of 600 micromol m(-2)s(-1) and a temperature optimum between +5 and +18 degrees C. At the 1994 measurements, the photosynthetic rates were higher at higher tissue water contents. The two mosses and lichens had a net photosynthesis (range: 1.1-2.79 micromol CO(2)kg(-1)s(-1)) at 2 degrees C tissue temperature and at 4-5 degrees C air temperature. Ca. 80% of the vascular grassland plant species maintained a positive C-balance during the coldest periods of winter, with photosynthetic rates of 1.5-3.8 micromol CO(2)m(-2)s(-1). In an extremely warm beginning March of the relatively warm winter of 2006/2007, the dicotyledonous plants had much higher CO(2) assimilation rates on a Chl (range 6-14.9 micromol g(-1)Chl s(-1)) and on a dry weight basis (9-48 micromol kg(-1)dw s(-1)) than in the cold winter of 1994. However, the assimilation rates of the three investigated cryptogams (Tortula and two Cladonia) and the two grasses Festuca and Poa were not affected by this increase. The results indicate that the photosynthetic activity of temperate semi-desert sand grassland species can help somewhat in slowing the general CO(2) rise in winter and function as a potential carbon sink of the investigated semi-desert Hungarian grassland species.


Height, body weight, skinfold thickness and endurance fitness of children attending national schools in Ireland.
Height, body weight, the thickness of triceps, biceps, subscapular and supra-iliac skinfolds and the six-minute run-walk test of aerobic endurance were measured on 1163 National school children between the ages of 7 and 13, who were attending rural or urban schools in counties Cork, Galway, Limerick, Mayo, Waterford and Wexford. Height, weight and the sum of triceps and subscapular skinfolds were compared with 11 to 13 year-olds from Northern Ireland, for whom the same data is available. Endurance scores were compared with international norms. Although of the same height as other European children, the subjects were heavier and had higher skinfold thicknesses. Aerobic endurance scores averaged about 80% of international norms.


The effects of political protests on youth human capital and well-being in Egypt.
Protests are one of the most common expressions of modern political conflict, and the wave of demonstrations that marked the onset of the Arab Spring contributed to a global increase in protest activity. Yet few studies have examined the effects of exposure to protests on population well-being even though such exposure may have profound and lasting effects, especially if experienced at critical stages of development over the life course. The aim of our study is to estimate the effects of exposure to political protests on the human capital accumulation and well-being of youth during the tumultuous political transition experienced in Egypt from 2011 to 2014. For a nationally representative panel of youth captured in the 2009 and 2013/2014 waves of the Survey of Young People in Egypt (SYPE), we exploit exogenous geospatial variation in the occurrence of political protests from the Armed Conflict Location & Event Data (ACLED) Project to estimate individual-level changes in social trust, uncertainty, education, and health outcomes for youth exposed to protests. In our panel, 31.1% of the sample lived in districts where riots or protests occurred. Exposure to protests increased overall perceptions of uncertainty about the future. Young men ever exposed to protests were slightly more likely to report good overall health, but experienced sizable worsening in mental health compared to young women ever exposed. Differences by own and family participation in protest events were found for perceptions of uncertainty and mental health. In the aftermath of the Arab Spring and other mass protest movements around the globe, these findings highlight the importance of examining the population-level impacts of different forms of political conflict, particularly as substantial numbers of youth in Middle East and North Africa and elsewhere progress to adulthood under conditions of political instability.


Surgical Trends in the Management of Duodenal Injury.
Surgical management of traumatic duodenal injury remains challenging. While various surgical techniques have been described in the attempt to reduce complications and mortality, recent data suggests that surgical approach using less invasive procedures might be associated with improved patient outcomes. The purpose of this study was to determine the recent trend of surgical procedures performed for patients with duodenal injury and their outcome. A retrospective analysis of the National Trauma Data Bank (NTDB) from 2002 to 2014 was performed. A total of 2163 patients who sustained a traumatic duodenal injury requiring surgical intervention were included. Patient characteristics, injury data, procedures, and outcomes were examined. Types of duodenal procedures and patient outcomes were compared between two study periods (2002-2006 vs. 2007-2014). The median age was 27 (IQR 20-39), 78.9% were male, and 63.8% sustained penetrating duodenal injury. The median injury severity score was 18 (IQR 13-26). In patients with isolated duodenal injury, the later study period (2007-2014) was significantly associated with the increased use of primary repair (OR 1.77; 95% CI 1.11-2.83, p = 0.017). Overall mortality was 11.7%. Patients in the later study group were significantly associated with lower odds of inhospital mortality (OR 0.47, 95% CI 0.22-0.95, p = 0.041). A progressive trend toward less invasive procedures for duodenal injury was noted in the current study. Inhospital mortality has improved in the late study period.


Nitrogen removal by Rhodococcus sp. SY24 under linear alkylbenzene sulphonate stress: Carbon source metabolism activity, kinetics, and optimum culture conditions.
Artificial intervention combined with stress acclimation was used to screen a heterotrophic nitrifying-aerobic denitrifying (HN-AD) bacterial, strain Rhodococcus SY24, resistant to linear alkylbenzenesulfonic acid (LAS) stress. When LAS was<15 mg/L, strain SY24 performed better cell growth and carbon source metabolism activity. The maximum nitrification and denitrification rates of SY24 under LAS stress could reach 1.18 mg/L/h and 1.05 mg/L/h, respectively, which were 13.80 % and 8.81 % higher than those of the original strain CPZ24. Higher LAS tolerance was seen in the functional genes (amoA, nxrA, napA, narG, nirK, nirS, norB, and nosZ). Response surface modeling revealed that 2 mg/L LAS, sodium succinate as a carbon source, 190 rams, and carbon/nitrogen 11 were the ideal culture conditions for SY24 to nitrogen removal under the LAS environment. This study offered a new screening strategy for the functional species, and strain SY24 showed significant LAS tolerance and HN-AD potential.


Conceptual models: an assessment framework.
What criteria would you use to assess the conceptual model you choose to guide your nursing department's practice? Whether you are assessing a model for your own use or critiquing someone else's, there are several considerations relating to the model's utility that should be kept in mind. To avoid choices based primarily on intuition or what "seems right," the author presents a framework for assessing the adequacy, completeness, and appropriateness of nursing models before their adoption for use in practice.


The beneficial effects of betaine on dysfunctional adipose tissue and N6-methyladenosine mRNA methylation requires the AMP-activated protein kinase α1 subunit.
The current study was conducted to determine whether betaine could improve fatty acid oxidation, mitochondrial function and N6-methyladenosine (m(6)A) mRNA methylation in adipose tissue in high-fat-induced mice and how AMP-activated protein kinase α1 subunit (AMPKα1) was involved. AMPKα1 knockout mice and wild-type mice were fed either a low-fat diet, high-fat diet or high-fat diet supplemented with betaine in the drinking water for 8weeks. Our results showed that mitochondrial genes (PGC1α) and β-oxidation-related genes (CPT1a) at protein level were increased in wild-type mice supplemented with betaine when compared with those in mice with high-fat diet. Betaine also decreased FTO expression and improved m(6)A methylation in adipose tissue of wild-type mice with high-fat diet. However, betaine failed to exert the abovementioned effects in AMPKα1 knockout mice. In adipocytes isolated from mice with high-fat diet, betaine treatment increased lipolysis and lipid oxidation. Moreover, betaine decreased FTO expression and increased m(6)A methylation. However, while AMPKα1 was knockdown, no remarkable changes in adipocytes were observed under betaine treatment. Our results indicated that betaine supplementation rectified mRNA hypomethylation and high FTO expression induced by high-fat diet, which may contribute to its beneficial effects on impaired adipose tissue function. Our results suggested that the AMPKα1 subunit is required for the beneficial effects of betaine on dysfunctional adipose tissue and m(6)A methylation. These results may provide the foundation for a mechanism that links m(6)A methylation status in RNA, AMPKα1 phosphorylation and dysfunctional adipose tissue induced by high-fat diet.


Discovery of novel analogs of KHS101 as transforming acidic coiled coil containing protein 3 (TACC3) inhibitors for the treatment of glioblastoma.
Transforming acidic coiled coil containing protein 3 (TACC3) is emerging as an attractive anticancer target in recent years, however, few TACC3 small-molecular inhibitors have been reported up to now. In this study, fifteen compounds were designed and synthesized based on the lead compound KHS101 to find more potent TACC3 inhibitors. Among them, the most potent compound 7g exhibited about 10-folds more potent antiproliferative activities than KHS101 in various cancer cell lines. Two different protein-drug binding assays including DARTS, and CETSA revealed TACC3 as a biologically relevant target of compound 7g. In addition, compound 7g induced cell cycle arrest at the G2/M phase and induced cell apoptosis. Furthermore, compound 7g depolarized the MMP and induced ROS generation in a dose-dependent manner in U87 cells. More importantly, 7g reduced tumor weight by 72.7% in U87 xenograft model at a dose of 20 mg/kg/day without obvious toxicity. Altogether, compound 7g deserved further investigations as a novel, safe and efficacious TACC3 inhibitor for the treatment of GBM.


A Structural Ensemble of a Tau-Microtubule Complex Reveals Regulatory Tau Phosphorylation and Acetylation Mechanisms.
Tau is a microtubule-associated protein that regulates the stability of microtubules. We use metainference cryoelectron microscopy, an integrative structural biology approach, to determine an ensemble of conformations representing the structure and dynamics of a tau-microtubule complex comprising the entire microtubule-binding region of tau (residues 202-395). We thus identify the ground state of the complex and a series of excited states of lower populations. A comparison of the interactions in these different states reveals positions along the tau sequence that are important to determine the overall stability of the tau-microtubule complex. This analysis leads to the identification of positions where phosphorylation and acetylation events have destabilizing effects, which we validate by using site-specific post-translationally modified tau variants obtained by chemical mutagenesis. Taken together, these results illustrate how the simultaneous determination of ground and excited states of macromolecular complexes reveals functional and regulatory mechanisms.


Perfluorocarbon liquids as postoperative short-term vitreous substitutes in complicated retinal detachment.
To avoid postoperative "compartmentalization" of the vitreous cavity, which can potentially accelerate the recurrence of proliferative vitreoretinopathy (PVR), 32 eyes of 32 selected patients with complicated retinal detachment were managed with lensectomy, vitrectomy, 5-day internal tamponade with perfluorocarbon liquids (PFCL) and postoperative supine positioning until PFCL removal. Intraoperatively, 19 eyes had grade C3 or greater PVR; 10 eyes exhibited ocular trauma and 6 displayed giant tears. All but 5 patients (PFCL/fluid exchange) underwent PFCL/silicone oil exchange 5 days after surgery. Anatomic attachment of the retina was achieved with one operation in 25 (78%) of the 32 eyes with a median follow-up of 8 months (mean 8.4 months). Of the 20 eyes that underwent silicone oil removal, none redetached. Nineteen eyes (61%) showed no or only mild reproliferation; a macular pucker developed in 50% of the 20 eyes successfully reattached after PFCL/silicone oil exchange and in none of the 5 eyes successfully reattached after PFCL/fluid exchange. Intraocular tolerance of PFCL for up to 5 days of internal tamponade appeared to be good as judged by static threshold perimetry in the two patients tested and by our functional outcomes, with 88% of the reattached eyes showing a final visual acuity of 5/200 or better.


Ghrelin is produced in taste cells and ghrelin receptor null mice show reduced taste responsivity to salty (NaCl) and sour (citric acid) tastants.
The gustatory system plays a critical role in determining food preferences, food intake and energy balance. The exact mechanisms that fine tune taste sensitivity are currently poorly defined, but it is clear that numerous factors such as efferent input and specific signal transduction cascades are involved. Using immunohistochemical analyses, we show that ghrelin, a hormone classically considered to be an appetite-regulating hormone, is present within the taste buds of the tongue. Prepro-ghrelin, prohormone convertase 1/3 (PC 1/3), ghrelin, its cognate receptor (GHSR), and ghrelin-O-acyltransferase (GOAT , the enzyme that activates ghrelin) are expressed in Type I, II, III and IV taste cells of mouse taste buds. In addition, ghrelin and GHSR co-localize in the same taste cells, suggesting that ghrelin works in an autocrine manner in taste cells. To determine a role for ghrelin in modifying taste perception, we performed taste behavioral tests using GHSR null mice. GHSR null mice exhibited significantly reduced taste responsivity to sour (citric acid) and salty (sodium chloride) tastants. These findings suggest that ghrelin plays a local modulatory role in determining taste bud signaling and function and could be a novel mechanism for the modulation of salty and sour taste responsivity.


Purification of alpha-toxin from Staphylococcus aureus and application to cell permeabilization.
Crude alpha-toxin was produced by Staphylococcus aureus, strain Wood 46. The amount of exotoxin was monitored during growth and all subsequent purification steps by determination of its hemolytic activity against rabbit erythrocytes. The culture supernatant was treated with ammonium sulfate (75% saturation). The resulting precipitate was dialyzed and subjected to cation-exchange chromatography. The fractions containing the hemolytic activity were further purified by gel chromatography. The final product was enriched by a factor of 8.5 compared to the crude toxin. In sodium dodecyl sulfate-polyacrylamide gel electrophoresis the purified toxin exhibited one major band. It caused the release of 86Rb+ and ATP from rat insulinoma (RIN A2) as well as pheochromocytoma cells (PC12) in culture, indicating efficient permeabilization of their plasma membranes for small molecules.


Diastolic wall motion abnormality after myocardial infarction: relation to neurohormonal activation and prognostic implications.
Systolic wall motion abnormality (WMA) after acute myocardial infarction (AMI) is a major determinant of outcome; the presence and importance of diastolic WMA after AMI are unknown. We therefore sought to detect diastolic WMA using color kinesis and to assess its relation to neurohormonal activation and its prognostic importance in a consecutive population with a first AMI. Complete color-encoded color kinesis and 2-dimensional and Doppler echocardiography were performed in 149 consecutive patients with documented first AMI within 24 hours of their admission. N-terminal pro-brain natriuretic peptide was measured 3 days after AMI. Study end point was cardiac death or readmission for heart failure. Diastolic area of WMA exceeded the systolic area in all but 5 patients (97%) and was significantly correlated with brain natriuretic peptide (unadjusted beta = .67, P < .0001; adjusted for systolic function, age, Killip class, and overall diastolic function beta = .27, P = .007). Diastolic WMA was also correlated with the number of diseased vessels on coronary angiography (beta = .59, P < .0001). During follow-up, 25 patients died and 11 were readmitted because of recurrent heart failure. On univariate analysis, the area of diastolic WMA was a predictor of the composite end point (hazard ratio 1.07 [95% CI 1.05-1.09], P < .0001) and remained a predictor on multivariate Cox analysis after adjustment of well-known risk factors, left ventricular systolic and overall diastolic functions (hazard ratio 1.09 [95% CI 1.06-1.15], P < .001). The extent of diastolic WMA can be assessed early after AMI using color kinesis. Diastolic WMA is associated with neurohormonal activation and angiographic severity of coronary artery disease and provides independent prognostic information.


Assessment of the relation between the initial viability and the attachment of freshly isolated rat hepatocytes used for the in vivo/in vitro DNA repair assay (UDS).
Crucial steps of the in vivo/in vitro DNA repair assay (UDS) are the hepatocyte isolation procedure and the establishment of the hepatocyte cultures. Since the attachment of the isolated hepatocytes on the surface of the culture vessel is an essential prerequisite for the in vitro part of this assay to yield scorable autoradiograms, we assessed the relation between the initial viabilities of hepatocyte preparations and the resulting attachment efficiencies from 286 rats. The initial viability was determined by means of the trypan blue dye exclusion assay. The actual cell number was corrected for the viability and a constant number of 2.5 x 10(5) viable cells were seeded into each well of gelatinized six-well dishes. The amount of adherent cells was determined after a 1.5-h attachment period using a recently described modification (Fautz et al., 1991) of the neutral red dye absorption assay. The attachment is described by the optical density at 540 nm obtained after the elution of neutral red from the adherent cells (OD540 value). To facilitate a comparison of the data we divided the 286 animals into eight arbitrary viability groups. The mean values of the viability groups were 53.1, 62.2, 66.3, 68.4, 70.9, 73.6, 76.9, and 84.0% living cells. Although there was a great interindividual variation, the resulting mean OD540 values were nearly uniform, about 0.5, in all eight groups, regardless of the initial viability of the hepatocytes. UDS data obtained from 46 animals treated with the positive control chemical 2-acetylaminofluorene demonstrated that there was no correlation between the in vitro DNA repair capacity and the initial viability or the attachment efficiency of the hepatocytes. Our results suggest that (i) great interindividual differences exist between the attachment of particular cell preparations with no regard to the initial viability, (ii) the correction of the cell number for viability leads to relatively uniform OD540 mean values and (iii) for an in vivo/in vitro UDS assay even cell suspensions with relatively low viabilities can be used since they will yield adherent cultures which are capable of DNA repair synthesis. The latter item often allows a reduction in the number of animals required for this in vivo assay because it is not necessary to perform repeated experiments because of low viability preparations.


A new, fast surgical knot for skin closures.
A modified surgeon's knot is proposed. Tying is based on twisting the throws instead of laying them down flat. The second (granny) throw is snugged against the first in a locking manner. The knot is tied rapidly by needleholder and is particularly useful for skin sutures with monofilament thread.


Radiation recall dermatitis during treatment of endometrial cancer with pembrolizumab plus lenvatinib: A case report.
Radiation Recall encompasses an array of inflammatory reactions, most commonly dermatitis, that occurs in response to a systemic medication with distribution in a previously irradiated field. While historically cytotoxic chemotherapy was a major culprit, this case report describes radiation recall dermatitis in response to pembrolizumab and lenvatinib in a 62-year old female with ongoing advanced endometrial cancer and history of breast cancer. Discontinuation of lenvatinib alone lead to complete resolution of the dermatitis, and she ultimately resumed her previous lenvatinib dose without recurrent symptoms. This case represents an important possible adverse effect of a commonly used targeted therapy, particularly in a population likely to have a history of prior radiation exposure.


Sympathetic axons and nerve terminals: the protein composition of small and large dense-core and of a third type of vesicles.
Homogenates of bovine splenic nerve and of vas deferens were subjected to differential and density gradient centrifugation to investigate their noradrenaline-storing organelles. The subcellular fractions obtained were analysed by immunoblotting in order to define the presence of various antigens in small dense-core and large dense-core vesicles. In both large granule and microsomal fractions from splenic nerve only one type of noradrenaline-storing vesicle was found, which represents the large dense-core vesicles. These organelles contained chromogranin A, chromogranin B, cytochrome b-561, carboxypeptidase H, glycoprotein II, glycoprotein III, dopamine beta-hydroxylase and the monoamine carrier which are also present in adrenal chromaffin granules. The subcellular distribution of synaptin/synatophysin was more complex since this protein was apparently present in two organelles: in a light vesicle which did not contain significant amounts of antigens found in large dense-core vesicles (dopamine beta-hydroxylase, cytochrome b-561 and the monoamine carrier) and in the dense fractions of the gradient, possibly within large dense-core vesicles. In the microsomal gradient from vas deferens several markers (catecholamines, synaptin/synaptophysin and dopamine beta-hydroxylase) were found in a bimodal distribution, which is consistent with their presence in small and large dense-core vesicles. When the larger granules were removed with higher centrifugation speed a microsomal fraction containing only light vesicles was obtained. After gradient centrifugation of this fraction several components (catecholamines, dopamine beta-hydroxylase, cytochrome b-561, the monoamine carrier and synaptin/synaptophysin) were concentrated in a peak at low density; apparently only small dense-core vesicles were now present.(ABSTRACT TRUNCATED AT 250 WORDS)


Chronic gouty nephropathy treated by long-term hemodialysis and allopurinol.
A patient with intractable tophaceous gout and advanced renal failure responded favorably to treatment by long-term hemodialysis and administration of allopurinol. Plasma uric acid levels returned to normal, tophi decreased in size, and the frequency of attacks of gout decreased markedly and permitted the patient to return to full-time employment.


[Thalassemia major (with a case report of a 6-month-old patient)].
This article describes recent views about patophysiology of thalassemia, and deals with a case of thalassemia major in a 6-month infant from the continental part of Croatia. Based on literature data, therapy included frequent transfusions of blood so as to correct anaemia to the level enabling the child to develop and interact with his environment as normally as possible. Administration of desferioxamine promoted excretion of iron in urine and decreased its concentration in serum.


Improved high-performance liquid chromatographic procedure for the determination of tetracyclines in plasma, urine and tissues.
An improved extraction procedure for the determination of oxytetracycline, tetracycline and chlortetracycline in urine, plasma and tissues by high-performance liquid chromatography is described. The addition of phenylbutazone (3,5-dioxo-1,2-diphenyl-4-n-butylpyrazolidine) to water, urine or plasma enhances the extraction of these compounds by ethyl acetate. The recovery of oxytetracycline from plasma is increased six fold and the need for two separate extractions of urine and plasma is eliminated. The formation of phenylbutazone-tetracycline ion pairs and their role in the extraction process is discussed.