Expectations of a new opt-out system of consent for deceased organ donation in England: A qualitative interview study.
In 2020 England moved to an opt-out deceased donation law. We aimed to investigate the views of a mixed stakeholder group comprising people with kidney disease, family members and healthcare practitioners towards the change in legislation. We investigated the expected impacts of the new legislation on deceased-donor and living-donor transplantation, and views on media campaigns regarding the law change. We undertook in-depth qualitative interviews with people with kidney disease (n = 13), their family members (n = 4) and healthcare practitioners (n = 15). Purposive sampling was used to ensure diversity for patients and healthcare practitioners. Family members were recruited through snowball sampling and posters. Interviews were audio-recorded and transcribed verbatim. Transcripts were analysed using thematic analysis. Three themes with six subthemes were identified: (i) Expectations of impact (Hopeful patients; Cautious healthcare professionals), (ii) Living-donor transplantation (Divergent views; Unchanged clinical recommendations), (iii) Media campaigns (Single message; Highlighting recipient benefits). Patients expected the law change would result in more deceased-donor transplant opportunities. Clinicians should ensure patients and families are aware of the current evidence regarding the impact of opt-out consent: expectations of an increased likelihood of receiving a deceased-donor transplant are not currently supported by the evidence. This may help to prevent a decline in living-donor transplantation seen in other countries with similar legislation. Media campaigns should include a focus on the impact of organ receipt. Two patient representatives from the Kidney Disease Health Integration Team, Primrose Granville and Soumeya Bouacida, contributed to the content and design of the study documents.


Psychophysiological response patterns in vascular and muscle-contraction headaches.
The psychophysiological response patterns of 43 headache subjects were compared to the response patterns of 11 nonheadache control subjects. The headache group was composed of subjects diagnosed as suffering from either muscle-contraction (N = 11), classic migraine (N = 11), common migraine (N = 11), or mixed (N = 10) headache. Discriminant analyses indicated that (1) the headache groups could be perfectly differentiated from the nonheadache control group after a period of relaxation and during a period of psychological stress and (2) the stress condition differentiated among the various headache groups. In general, the headache groups showed a higher level of arousal and were more responsive to stress. Also, the response pattern profiles differed among the headache groups in the stress condition. Muscle-contraction subjects tended to respond with higher frontal EMG, and classic migraine and mixed headache groups tended to respond with larger cardiovascular responses.


Measurement and distribution of vasopressin-converting aminopeptidase activity in rat brain.
The aminopeptidase activity in the brain which converts vasopressin into centrally active metabolites, was quantitated on basis of the release of 3H-Phe from the substate [3H-Phe3]vasopressin and separation by hydrophobic interaction chromatography on mini-columns. After subcellular fractionation of whole rat brain homogenates the highest specific activity of the peptidase was recovered in membrane fractions, in particular microsomes and the P3 fraction, and the cytosol. The peptidase activity was present in all brain areas. Highest activity was measured in membranes of the bulbus olfactorius, preoptical area and cerebellum. Lowest activity was found in the medulla oblongata and striatum. The peptidase activity is not restricted to the vasopressin system per se, but may have a more general role in neuropeptide metabolism.


Isolated Crohn's disease of the stomach.
Crohn's disease can involve any portion of the digestive tract, but isolated gastric Crohn's disease is a rare entity. In the few previously reported cases, the inflammatory disorder has involved only a portion of the stomach. Herein we describe a patient with diffuse involvement of the entire stomach and an associated gastrosplenic fistula but no evidence of involvement elsewhere in the gastrointestinal tract. Usually, a patient with isolated Crohn's disease of the stomach will have the clinical symptoms of nausea, vomiting, and epigastric pain and radiographic evidence of a small contracted stomach (or, occasionally, a huge dilated stomach). Because the condition may suggest the presence of a malignant lesion and biopsy specimens often reveal nonspecific inflammation, surgical resection is usually necessary for diagnosis of isolated Crohn's disease of the stomach.


Therapeutic Opportunities for Immunoreceptor-Engineered T Cell Therapy for Modulation of Alloimmunity.
Achieving immunosuppression-free immune tolerance to an allograft is one of the central goals of transplantation. In this article, we review recent developments in the fields of T cell-based therapies and T cell engineering using chimeric Ag receptors and their potential for effective and targeted immune modulation of T and B cell activity in an effort to eliminate pre-existing alloantibodies (desensitization) and achieve long-term tolerance. Approaches that span preclinical to early clinical studies in transplantation will be reviewed, with specific emphasis on advances in T cell immunotherapy that have shown promise. Lastly, we conclude with a forward-looking discussion of how T cell-based therapies in other fields of medicine can be potentially applied to solid organ transplantation.


Pharmacokinetic study of an injectable long-acting parenteral formulation of doxycycline hyclate in calves.
Doxycycline hyclate (DOX-h) can be regarded as a time-dependant antibacterial. Hence, a parenteral long-acting formulation may be regarded as more pharmacologically sound. A poloxamer-based matrix was used to produce a long-acting injectable preparation (DOX-h-LA) and its serum concentrations vs. time profile investigated after its s.c. injection to calves. Serum concentrations profiles for such a prepartion were compared to the corresponding profiles obtained with an aqueous formulation of DOX-h injected either i.m. or i.v. in 10 calves in a crossover study at dose of 10mg/kg, with washout periods. DOX-h-LA showed the greatest values for bioavailability (602%); maximum serum concentration (C(max)) value was 1.99microg/mL with a time to reach C(max) (T(max)) of 25h and an elimination half-life of 40.81h. Considering minimum effective serum concentration of 0.5microg/mL a dose-interval of 80h can be achieved for DOX-h-LA, and only 9.7h and 17h after the i.v. or i.m. administration of DOX-h, respectively.


Oral tolerance attenuates airway inflammation and remodeling in a model of chronic pulmonary allergic inflammation.
We investigated the effects of oral tolerance (OT) in controlling inflammatory response, hyperresponsiveness and airway remodeling in guinea pigs (GP) with chronic allergic inflammation. Animals received seven inhalations of ovalbumin (1-5mg/mL-OVA group) or normal saline (NS group). OT was induced by offering ad libitum ovalbumin 2% in sterile drinking water starting with the 1st ovalbumin inhalation (OT1 group) or after the 4th (OT2 group). The induction of OT in sensitized animals decreased the elastance of respiratory system (Ers) response after both antigen and methacholine challenges, peribronchial edema formation, eosinophilic airway infiltration, eosinophilopoiesis, and airways collagen and elastic fiber content compared to OVA group (P<0.05). The number of mononuclear cells and resistance of respiratory system (Rrs) responses after antigen and methacholine challenges were decreased only in OT2 group compared to OVA group (P<0.05). Concluding, our results show that inducing OT attenuates airway remodeling as well as eosinophilic inflammation and respiratory system mechanics.


Treatment of Iron Deficiency in Heart Failure.
Heart failure (HF) is commonly associated with iron deficiency (ID), defined as insufficient levels of iron to meet physiological demands. ID's association with anaemia is well understood but it is increasingly recognised as an important comorbidity in HF, even in the absence of anaemia. This review summarises contemporary evidence for the measurement and treatment of ID, in both HFrEF and HFpEF, and specific HF aetiologies, and highlights important gaps in the evidence-base. ID is common among patients with HF and associated with increased morbidity and mortality. Correcting ID in patients with HF can impact upon functional status, exercise tolerance, symptoms, and overall quality of life, irrespective of anaemia status. ID is a modifiable comorbidity in HF. Therefore, recognising and treating ID has emerging therapeutic potential and is important for all clinicians who care for patients with HF to understand the rationale and approach to treatment.


Molecular evolution of paclitaxel biosynthetic genes TS and DBAT of Taxus species.
Evolutionary patterns of sequence divergence were analyzed in genes from the conifer genus Taxus (yew), encoding paclitaxel biosynthetic enzymes taxadiene synthase (TS) and 10-deacetylbaccatin III-10 beta-O-acetyltransferase (DBAT). N-terminal fragments of TS, full-length DBAT and internal transcribed spacer (ITS) were amplified from 15 closely related Taxus species and sequenced. Premature stop codons were not found in TS and DBAT sequences. Codon usage bias was not found, suggesting that synonymous mutations are selectively neutral. TS and DBAT gene trees are not consistent with the ITS tree, where species formed monophyletic clades. In fact, for both genes, alleles were sometimes shared across species and parallel amino acid substitutions were identified. While both TS and DBAT are, overall, under purifying selection, we identified a number of amino acids of TS under positive selection based on inference using maximum likelihood models. Positively selected amino acids in the N-terminal region of TS suggest that this region might be more important for enzyme function than previously thought. Moreover, we identify lineages with significantly elevated rates of amino acid substitution using a genetic algorithm. These findings demonstrate that the pattern of adaptive paclitaxel biosynthetic enzyme evolution can be documented between closely related Taxus species, where species-specific taxane metabolism has evolved recently.


Characterization of bitiscetin-2, a second form of bitiscetin from the venom of Bitis arietans : comparison of its binding site with the collagen-binding site on the von Willebrand factor A3-domain.
Bitiscetin, a heterodimeric snake venom protein purified from Bitis arietans, binds to the A1 domain of von Willebrand factor (VWF) and induces binding of this domain to platelet glycoprotein (GP) Ib. We previously purified a distinct form of dimeric bitiscetin (herein called bitiscetin-2) that also induces the VWF A1 domain-GPIb interaction, but does not bind to the A1 domain. Instead, it interacts with the collagen-binding A3 domain of VWF. In the current study we identify the amino terminal sequence of the bitiscetin-2 as DEGCLPDDSSRT, showing conclusively that the protein is distinct form the originally described bitiscetin. We further studied the interaction of bitiscetin-2 and VWF using DeltaA3 VWF and a series of 33 VWF point mutants previously prepared to map the collagen-binding site. Our results confirm that DeltaA3 VWF, even though containing the A1-domain, is unable to interact with bitiscetin-2. Mutation of VWF-A3 residues Ile975, Asp979, Pro981, Ser1020 and His1023 reduces binding by 80% while mutation of residues Val980, Glu1001 and Arg1021 reduces binding by 30-60%. A 2- to 6-fold increase of binding is caused by mutation of residues Val985, Glu987, and Arg1016. Nearly all of these mutations also affect collagen binding showing that the binding sites for bitiscetin-2 and collagen type III in the VWF-A3 domain closely overlap.


Multistage targeted "Photoactive neutrophil" for enhancing synergistic photo-chemotherapy.
Cell-based drug delivery system holds a great promise in anticancer treatment, due to its potential of maximizing therapeutic efficacy while minimizing adverse effects. However, current cell system can only deliver drugs in tumor lesions, but lack an ability to target subcellular locus of therapeutic actions, thereby compromising anticancer efficacy. Herein, we bioengineered living neutrophils as a novel type of "Photoactive neutrophil" (PAN) with capabilities of self-amplified multistage targeting and inflammation response for enhancing mitochondria-specific photo-chemotherapy. PAN encapsulated multifunctional nanocomplex (RA/Ce6) of RGD-apoptotic peptide conjugate (RA) decorated liposomal photosensitizer Ce6, and could overcome tumor barriers to selectively release RA/Ce6 within tumor. Consequently, RA/Ce6 actively entered cancer cells and accumulated in mitochondria to trigger combined photodynamic therapy (PDT) and RA-induced mitochondrial membrane disruption, resulting in enhanced therapeutic effects. Importantly, PAN exhibited inflammation amplified tumor targeting after PDT, and initiated combined photo-chemotherapy to suppress tumor growth without adverse effects, leading to prolonged mice survival. Therefore, PAN represents the first multistage targeted cell therapy, and brings new insights into cancer treatment.


Efficient display of scFv antibodies on bacteriophage lambda.
In the present work we demonstrate the efficient display of functional scFv antibodies on the bacteriophage lambda capsid. A single-chain (scFv) anti-CEA antibody gene was cloned in two different vectors to obtain fusion of the scFv antibody to the N- or C-terminus of the bacteriophage lambda capsid protein D (gpD). Lambda bacteriophage assembly occurs in the reducing environment of the cytoplasm; despite this the lambda-displayed anti-CEA antibody fragments retain the capacity to recognize the antigen, indicating correct single-chain antibody folding. Efficient production of functional scFv exposed on lambda capsid with viable antigen binding specificity allowed us to study and compare the capacity of display, the stability of recombinant antibody expression and the assembly efficiency of bacteriophage particles decorated with recombinant antibody fused to the amino- or carboxy-terminus of lambda D protein.


[Vacuum-assisted closure as a treatment modality for infrainguinal vascular prosthetic graft infection: our experience and take-home message].
Infection of the prosthetic graft represents one of the biggest challenges for practising vascular surgeons. The patient is jeopardized with possible future limb loss or, in the most serious cases, even death due to this complication. The incidence in the infrainguinal area amounts to a maximum of 6% of all arterial surgical procedures. Between January 2010 and December 2011, the authors performed a total of 689 vascular surgical reconstructions, of which 311 were performed in the infrainguinal area where 7 cases (2.25%) of graft infection occurred. None of the patients died or lost a limb due to this complication. Two patients with an infected infrainguinal prosthetic graft were successfully treated with vacuum-assisted closure (VAC) system. The prosthetic vascular graft infection is the most feared complication in vascular surgery. The generally recognized principles of the traditional surgical approach are well-known and widely accepted. However, in selected cases of infrainguinal vascular prosthetic infection, both the affected limb and the patent graft may be saved and successfully treated with the use of vacuum-assisted closure.


Left ventricular mass normalization for body size in children based on an allometrically adjusted ratio is as accurate as normalization based on the centile curves method.
Normalization for body size is required for reliable left ventricular mass (LVM) evaluation, especially in children due to the large variability of body size. In clinical practice, the allometrically adjusted ratio of LVM to height raised to the power of 2.7 is often used. However, studies presenting normative LVM data for children recommend centile curves as optimal for the development of normative data. This study aimed to assess whether the allometrically adjusted LVM-to-height ratio can reliably reproduce the results of LVM normalization for height based on the centile curves method. Left ventricular mass was computed for 464 boys and 327 girls, 5-18 years old, based on echocardiographic examination. Normalized data representing LVM for height were developed using the centile curves construction method and two variants of the allometrically adjusted ratio method: one variant with the allometric exponents specific to the study groups, and one variant with the universal exponent of 2.7. The agreement between the allometric methods and the centile curves method was analyzed using the concordance correlation coefficient, sensitivity, and specificity. For both the specific allometric variant and the universal variant, the analysis of concordance has indicated high reproducibility compared to the centile curves method. The respective coefficient values were 0.9917 and 0.9916 for girls, and 0.9886 and 0.9869 for boys. The sensitivity and specificity test has also shown high agreement. However, for girls, the sensitivity was higher for the specific variant (100% vs. 90.9%). The results of the study show that allometric scaling of LVM for height can very reliably reproduce the results of LVM normalization for height based on the centile curves method. However, the analysis of sensitivity and specificity indicates greater agreement for the allometric normalization with the group-specific allometric exponents.


Preventive health care among older women: missed opportunities and poor targeting.
Experts recommend that clinicians target mammography and colon cancer screening to individuals with at least 5 years life expectancy. Generally, immunizations and exercise counseling are recommended for all women aged > or =65 years, while Pap smears are generally not encouraged for these women. We used the 2005 National Health Interview Survey to examine receipt of several preventive health measures simultaneously among community dwelling US women aged > or =65 years by age and health status. We used functional status, significant diseases, and perceived health to categorize women into those most likely to be in above-average, average, or below-average health status. We used age and health status to estimate life expectancy. Of 4683 participants, 25.8% were > or =80 years; 81.8% were non-Hispanic white; 21% were in above-average and 20% were in below-average health status. Receipt of mammography and colon cancer screening decreased with age and was not associated with health status for women aged > or =80 years. Nearly half (49%) of women aged > or =80 years in below-average health received mammography screening, while 19% of women aged 65-79 years in above-average health did not report receiving mammography. Nearly half of women aged 65-79 years (49%) in above-average health did not report receiving colon cancer screening. Pap smear screening was common among older women. Few (34%) reported receiving exercise counseling. Many did not report receiving pneumococcal (43%) or flu vaccinations (40%). In our comprehensive review of preventive health measures for older women, we found evidence to suggest a need to improve delivery and targeting of preventive health services.


A new intravenous fat emulsion containing soybean oil, medium-chain triglycerides, olive oil, and fish oil: a single-center, double-blind randomized study on efficacy and safety in pediatric patients receiving home parenteral nutrition.
SMOFlipid 20% is an intravenous lipid emulsion (ILE) containing soybean oil, medium-chain triglycerides, olive oil, and fish oil developed to provide energy, essential fatty acids (FAs), and long-chain ω-3 FAs as a mixed emulsion containing α-tocopherol. The aim was to assess the efficacy and safety of this new ILE in pediatric patients receiving home parenteral nutrition (HPN) compared with soybean oil emulsion (SOE). This single-center, randomized, double-blind study included 28 children on HPN allocated to receive either SMOFlipid 20% (n = 15) or a standard SOE (Intralipid 20%, n = 13). ILE was administered 4 to 5 times per week (goal dose, 2.0 g/kg/d) within a parenteral nutrition regimen. Assessments, including safety and efficacy parameters, were performed on day 0 and after the last study infusion (day 29). Lipid peroxidation was determined by measurement of thiobarbituric acid reactive substances (TBARS). There were no significant differences in laboratory safety parameters, including liver enzymes, between the groups on day 29. The mean ± standard deviation changes in the total bilirubin concentration between the initial and final values (day 29 to day 0) were significantly different between groups: SMOFlipid group -1.5 ± 2.4 µmol/L vs SOE group 2.3 ± 3.5 µmol/L, P < .01; 95% confidence interval [CI], -6.2 to -1.4). In plasma and red blood cell (RBC) phospholipids, the ω-3 FAs C20:5ω-3 (eicosapentaenoic acid) and + C22:6ω-3 (docosahexaenoic acid) increased significantly in the SMOFlipid group on day 29. The ω-3:ω-6 FA ratio was significantly elevated with SMOFlipid 20% compared with SOE group (plasma, day 29: 0.15 ± 0.06 vs 0.07 ± 0.02, P < .01, 95% CI, 0.04-0.11; and RBC, day 29: 0.23 ± 0.07 vs 0.14 ± 0.04, P < .01, 95% CI, 0.04-0.13). Plasma α-tocopherol concentration increased significantly more with SMOFlipid 20% (15.7 ± 15.9 vs 5.4 ± 15.2 µmol/L, P < .05; 95% CI, -2.1 to 22.6). The low-density lipoprotein-TBARS concentrations were not significantly different between both groups, indicating that lipid peroxidation did not differ between groups. SMOFlipid 20%, which contains 15% fish oil, was safe and well tolerated, decreased plasma bilirubin, and increased ω-3 FA and α-tocopherol status without changing lipid peroxidation.


Vasopressin-dependent control of basolateral Na/H-exchange in highly differentiated A6-cell monolayers.
We have used a well-differentiated A6-cell preparation (A6-C1) to study cellular location and vasopressin control of Na/H-exchange activity. After cell acidification, cell pHi (measured by BCECF-fluorescence) only recovered by the addition of Na medium to the basolateral cell surface; this pHi recovery was inhibited by dimethylamiloride (2 microM) consistent with basolateral location of Na/H-exchange activity. Addition of vasopressin produced stimulation of Na/H-exchange activity and increased the affinity of the exchanger for Na+. Stimulation of Na/H exchange was mimicked by pharmacological activation of protein kinase A (forskolin, 8-Br-cAMP) and not by pharmacological activation of protein kinase C (TPA). It is concluded that basolaterally located Na/H-exchange in A6-C1 cells is activated by vasopressin.


Patience is a virtue: Individual differences in cue-evoked pupil responses under temporal certainty.
Attention control is often examined behaviorally by measuring task performance and self-reported mind wandering. However, recent studies have also used pupillometry to measure task engagement versus task disengagement/mind wandering. In the current study, we investigated participants' ability to engage versus relax attention control in anticipation of hard (antisaccade) versus easy (prosaccade) trials within a saccade task, creating a "Cue-Evoked" Pupillary Response (CEPR). Participants completed the Automated OSPAN as a measure of working memory capacity (WMC) followed by a saccade task with a constant 5,000 ms delay between cue and stimulus. Occasional thought probes were included to gauge on- versus off-task attentional state. Consistent with recent findings (Hutchison et al., 2020, Journal of Experimental Psychology: Learning, Memory, and Cognition, 46, 280-295; Wang et al., 2015, European Journal of Neuroscience, 41, 1102-1110), we found better performance and more Task-Unrelated Thoughts (TUTs) on prosaccade trials, larger pupil diameters when preparing for antisaccade trials, and larger pupil diameters when on-task. Further, lower WMC individuals showed pupil dilation throughout the fixation delay for both types of trials, whereas higher WMC individuals only showed dilation immediately before stimulus onset when expecting an antisaccade trial. Saccade accuracy was predicted by WMC, smaller early CEPR, larger late CEPR, and less CEPR variability, but not self-reported TUTs. These findings demonstrate that, under temporal certainty, higher WMC individuals may be more efficient in their exertion of attention control. Further, they indicate that physiological measures can not only validate self-report measures, but also help identify situations in which self-report may be inaccurate.


Fetal carotid blood flow during videofetoscopy.
Intracranial bleeding has been reported as one of the complications of both open and minimally invasive fetal surgery and putatively attributed to intraoperative fluctuations of carotid blood flow. The aim of this study was to look at fetal carotid blood flow and its relationship with umbilical blood flow, blood pressure, oxygen delivery, and acid-base status in the fetus at various intraamniotic pressures with both liquid and gas media during fetoscopic surgery. Six 115- to 130-day-gestation ewes underwent continuous invasive systemic blood pressure monitoring in the descending aorta. A hysterotomy was performed. A 6-mm ultrasonic blood flow probe was placed around the common umbilical artery at its origin from the fetal aorta. This was followed by placement of a double-lumen, 4F catheter in the fetal descending aorta through a femoral artery. A 4-mm ultrasonic blood flow probe was then placed around the fetal left common carotid artery. A pressure-monitoring, multiperforated catheter was placed inside the amniotic cavity. The fetus was repositioned inside the uterus, which was then closed. The abdominal wall was closed loosely. No further manipulation was performed for 1 hour. Intraamniotic pressure was raised from 0 to 30 mm Hg at 5-mm Hg intervals by infusing either warmed saline or medical air. Common umbilical artery and left carotid artery blood flows, blood pressure, blood gases, bicarbonate, sodium, and hematocrit were recorded in all fetuses at each 5-mm Hg interval. Maternal systemic blood pressure, O2 saturation, and temperature were kept constant. Carotid blood flow remained stable within the intra-amniotic pressure range studied (0 to 30 mm Hg), despite the significant drop in common umbilical artery blood flow uniformly observed above 20 mm Hg when saline was infused and above 15 mm Hg when air was infused. There was fetal hypoxemia and hypercarbia concomitant with decreased common umbilical artery blood flow (however, without fetal acidosis, because of compensatory elevation of bicarbonate). Within the intraamniotic pressure range studied, fetal aortic blood pressure, sodium, and hematocrit did not vary significantly, even when there was decreased umbilical blood flow. Fetal carotid blood flow is protected, possibly autoregulated, remaining stable even after umbilical blood flow decreases as a consequence of elevated intrauterine pressures up to 30 mm Hg during videofetoscopy. These data suggests that perioperative intracranial bleeding related to videofetoscopic surgery is caused by factors other than fluctuations of cerebral blood flow.


Follow-up skeletal surveys for suspected non-accidental trauma: can a more limited survey be performed without compromising diagnostic information?
Follow-up skeletal surveys have been shown to improve the rate of fracture detection in suspected cases of non-accidental trauma (NAT). As these studies are performed in a particularly radiosensitive population, it is important to evaluate if all of the (approximately 20) radiographs obtained at repeat skeletal survey are clinically useful. Our goal was to evaluate if certain radiographs can be excluded at follow-up skeletal survey without compromising the clinical efficacy. This retrospective study included 22 cases of suspected NAT (average age 3.8 months, range 0.7-15 months) in which patients received both initial and follow-up bone surveys. The follow-up survey was performed an average of 16.7 days (range 11-29 days) after the initial survey. Radiographs were reviewed by 2 pediatric radiologists, with discrepancies resolved by consensus. In addition, we combined our data with data from all known previously published reports of follow-up skeletal surveys for NAT for meta-analysis. A total of 36 fractures were found on the initial bone survey in 16/22 patients (73%). Six patients had no fractures detected at initial survey. Follow-up bone surveys demonstrated an additional 3 fractures (2 extremities and 1 rib) in 3/22 cases (14%); 1 was in a patient whose initial survey was negative. No additional fractures in the skull, spine, pelvis, feet, or hands were detected in any case. In combination with patients reported in the literature (194 patients total) no new fracture of the skull, spine, pelvis, or hands was detected at follow-up survey. The skull, spine and pelvis radiographs are the highest dose-exposure studies of the skeletal survey. If no injury is detected or suspected in the pelvis, spine, hands, or skull at initial bone survey for suspected NAT, a limited follow-up skeletal survey which excludes the pelvis, lateral spine, hands, and skull should be considered to limit radiation exposure without limiting diagnostic information.


Glycosylation with trichloroacetimidates in ionic liquids: influence of the reaction medium on the stereochemical outcome.
[reactions: see text] The glycosylation with trichloroacetimidates derived from different glycopyranoses bearing a nonparticipating group at C-2 was explored in different ionic liquids as solvents. The stereoselectivity of the reaction was significantly affected by the reaction media and by the anomeric configuration of the donor.


RelB sustains endocrine resistant malignancy: an insight of noncanonical NF-κB pathway into breast Cancer progression.
The activation of the NF-κB pathway plays a crucial role in the progression of breast cancer (BCa) and also involved in endocrine therapy resistance. On the contrary to the canonical NF-κB pathway, the effect of the noncanonical NF-κB pathway in BCa progression remains elusive. BCa tumor tissues and the corresponding cell lines were examined to determine the correlation between RelB and the aggressiveness of BCa. RelB was manipulated in BCa cells to examine whether RelB promotes cell proliferation and motility by quantitation of apoptosis, cell cycle, migration, and invasion. RNA-Seq was performed to identify the critical RelB-regulated genes involved in BCa metastasis. Particularly, RelB-regulated MMP1 transcription was verified using luciferase reporter and ChIP assay. Subsequently, the effect of RelB on BCa progression was further validated using BCa mice xenograft models. RelB uniquely expresses at a high level in aggressive BCa tissues, particularly in triple-negative breast cancer (TNBC). RelB promotes BCa cell proliferation through increasing G1/S transition and/or decreasing apoptosis by upregulation of Cyclin D1 and Bcl-2. Additionally, RelB enhances cell mobility by activating EMT. Importantly, RelB upregulates bone metastatic protein MMP1 expression through binding to an NF-κB enhancer element located at the 5'-flanking region. Accordingly, in vivo functional validation confirmed that RelB deficiency impairs tumor growth in nude mice and inhibits lung metastasis in SCID mice. Video abstract.


Expression of phoenixin-14 and nesfatin-1 in the hypothalamo-pituitary-gonadal axis in the phases of the estrous cycle.
Phoenixin-14 (PNX-14) and nucleobindin 2 (NUCB2)/nesfatin-1 are regulatory neuropeptides expressed in the hypothalamus. These neuropeptides can be effective in hormonal regulation of the hypothalamo-pituitary-gonadal (HPG) axis and reproductive functions. In the present study, the distribution of PNX-14 and NUCB2/nesfatin-1 in the hypothalamus, pituitary, ovary, and uterus tissues during the phases of the estrous cycle in female rats was investigated. Eighteen Wistar Albino rats determined among animals showing regular estrous cycle by vaginal smear method were divided into three groups: proestrus (Group I), estrus (Group II) and diestrus (Group III). Serum gonadotropin-releasing hormone (GnRH), plasma PNX-14, and NUCB2/nesfatin-1 concentrations were the highest, moderate, and lowest in estrus, diestrus, and proestrus phases, respectively. PNX-14 immunoreactivity in the supraoptic and arcuate nuclei of the hypothalamus and NUCB2/nesfatin-1 immunoreactivity in the paraventricular nuclei were particularly evident in the estrus phase. These neuropeptide immunoreactivities were decreased in different cells of anterior pituitary during proestrus compared with those during estrus and diestrus. PNX-14 immunoreactivity in the ovary, especially during the estrus phase, was diffuse and intense in the granulosa and luteal cells and oocytes, and it was few and weak in theca cells. In addition, NUCB2/nesfatin-1 immunoreactivity was abundant and strong in granulosa and luteal cells, theca and interstitial cells, and oocytes during estrus. In the estrus phase, PNX-14 immunoreactivity was strong in the glandular epithelial cells and stromal cells of the endometrium, also NUCB2/nesfatin-1 immunoreactivity was strong in the epithelial and glandular epithelial cells. As a result, when the estrous cycle was evaluated, it was concluded that the changes in the distribution of PNX-14 and NUCB2/nesfatin-1 at all phases were related to GnRH and that these neuropeptides showed the highest immunoreactivity especially in the HPG axis and uterus tissues of estrus rats.


Effects of dexmedetomidine on smooth emergence from anaesthesia in elderly patients undergoing orthopaedic surgery.
Intraoperative dexmedetomidine may decrease postoperative emergence agitation in elderly patients due to its sedative effect. In this study, we evaluated the effect of adjuvant dexmedetomidine on smooth emergence from anaesthesia after orthopaedic surgery in elderly patients. A total 115 patients (ASA I-II, aged over 65 years) were randomly allocated into four groups. Anaesthesia was maintained with either sevoflurane or total intravenous anaesthesia (TIVA) comprising propofol and remifentanil. Patients were also administered either dexmedetomidine (0.4 μg kg(-1) hr(-1); SD and TD) intraoperatively or normal saline (SN or TN) as a control. The bispectral index (BIS) score was maintained from 40-60 intraoperatively. All anaesthetics and dexmedetomidine were discontinued at surgical conclusion, and the recovery times (durations to a BIS = 60, 70, and 80; eye opening; and extubation) were measured. The mean arterial pressure, heart rate, Ricker's agitation-sedation scale (RSAS), visual analogue scale (VAS) for pain, and incidences of emergence agitation and postoperative nausea and vomiting (PONV) were measured in the recovery room. Dexmedetomidine significantly decreased the RSAS score in the SD and TD groups, and a calm state postoperatively occurred more frequently in these groups than in the control groups. The heart rate and incidence of emergence agitation were lower in the dexmedetomidine groups. Recovery time was higher in the SD group than in the SN group, and no significant differences occurred between the TN and TD groups. The VAS score was lower in the SD group than in the SN group, and the PONV did not differ regardless of the use of dexmedetomidine. Dexmedetomidine may be an effective intraoperative adjuvant for a reducing emergence agitation and smooth emergence from anaesthesia after orthopaedic surgery in elderly patients. Current Controlled Trials NCT01851005 .


Correction to: The M-phase specific hyperphosphorylation of Staufen2 involved the cyclin-dependent kinase CDK1.
Following publication of the original article [1], the authors reported a change to one of the author names.


Chronic exposure to TNF reprograms cell signaling pathways in fibroblast-like synoviocytes by establishing long-term inflammatory memory.
Fibroblast-like synoviocytes (FLS) play a critical role in the pathogenesis of rheumatoid arthritis (RA). Chronic inflammation induces transcriptomic and epigenetic modifications that imparts a persistent catabolic phenotype to the FLS, despite their dissociation from the inflammatory environment. We analyzed high throughput gene expression and chromatin accessibility data from human and mouse FLS from our and other studies available on public repositories, with the goal of identifying the persistently reprogrammed signaling pathways driven by chronic inflammation. We found that the gene expression changes induced by short-term tumor necrosis factor-alpha (TNF) treatment were largely sustained in the FLS exposed to chronic inflammation. These changes that included both activation and repression of gene expression, were accompanied by the remodeling of chromatin accessibility. The sustained activated genes (SAGs) included established pro-inflammatory signaling components known to act at multiple levels of NF-kappaB, STAT and AP-1 signaling cascades. Interestingly, the sustained repressed genes (SRGs) included critical mediators and targets of the BMP signaling pathway. We thus identified sustained repression of BMP signaling as a unique constituent of the long-term inflammatory memory induced by chronic inflammation. We postulate that simultaneous targeting of these activated and repressed signaling pathways may be necessary to combat RA persistence.


Does diagnostic delay lead invariably to damage in episodic pelvi-ureteric junction obstruction?
To determine the relationship between the length of history and renal function in patients with symptomatic pelvi-ureteric junction (PUJ) obstruction in childhood. The study included 41 children with symptomatic PUJ obstruction. The duration and details of their symptoms were recorded and the differential renal function estimated by isotopic renography. The median (range) duration of symptoms was 24 (0.25-84) months; there was no statistically significant relationship between the duration of symptoms and differential function at presentation (P=0.148). There is no correlation between the duration of symptoms and renal function in children with PUJ obstruction. A delay in diagnosis cannot be directly linked to permanent renal compromise.


Convergence Rates for the Quantum Central Limit Theorem.
Various quantum analogues of the central limit theorem, which is one of the cornerstones of probability theory, are known in the literature. One such analogue, due to Cushen and Hudson, is of particular relevance for quantum optics. It implies that the state in any single output arm of an n-splitter, which is fed with n copies of a centred state ρ with finite second moments, converges to the Gaussian state with the same first and second moments as ρ . Here we exploit the phase space formalism to carry out a refined analysis of the rate of convergence in this quantum central limit theorem. For instance, we prove that the convergence takes place at a rate O n - 1 / 2 in the Hilbert-Schmidt norm whenever the third moments of ρ are finite. Trace norm or relative entropy bounds can be obtained by leveraging the energy boundedness of the state. Via analytical and numerical examples we show that our results are tight in many respects. An extension of our proof techniques to the non-i.i.d. setting is used to analyse a new model of a lossy optical fibre, where a given m-mode state enters a cascade of n beam splitters of equal transmissivities λ 1 / n fed with an arbitrary (but fixed) environment state. Assuming that the latter has finite third moments, and ignoring unitaries, we show that the effective channel converges in diamond norm to a simple thermal attenuator, with a rate O ( n - 1 2 ( m + 1 ) ) . This allows us to establish bounds on the classical and quantum capacities of the cascade channel. Along the way, we derive several results that may be of independent interest. For example, we prove that any quantum characteristic function χ ρ is uniformly bounded by some η ρ < 1 outside of any neighbourhood of the origin; also, η ρ can be made to depend only on the energy of the state ρ .


Microwave assisted step-by-step process for the production of fucoidan, alginate sodium, sugars and biochar from Ascophyllum nodosum through a biorefinery concept.
The biorefinery is an important concept for the development of alternative routes to a range of interesting and important materials from renewable resources. It ensures that the resources are used fully and that all parts of them are valorized. This paper develops this concept, using brown macroalgae Ascophyllum nodosum as an example, by assistance of microwave technology. A step-by-step process was designed to obtain fucoidan, alginates, sugars and biochar (alga residue) consecutively. The yields of fucoidan, alginates, sugars and biochar were 14.09%, 18.24%, 10.87% and 21.44%, respectively. To make an evaluation of the biorefinery process, seaweed sample was also treated for fucoidan extraction only, alginate extraction only and hydrothermal treatment for sugars and biochar only. The chemical composition and properties of each product were also analyzed. The results indicated that A. nodosum could be potentially used as feedstock for a biorefinery process to produce valuable chemicals and fuels.


Dynamic light scattering studies of porcine submaxillary mucin fractions in dilute solution at intermediate scattering vectors.
We report dynamic light scattering measurements over a wide range of scattering vectors for fractionated samples of porcine submaxillary mucin (PSM) glycoproteins in two different solvents: 0.1M NaCl, and 6M GdnHCl. The relaxation spectrum has been successfully resolved into a slow mode corresponding to pure translational diffusion and a fast mode containing information on the relaxation times for intramolecular motion. Analysis of the slow mode permits a light scattering evaluation of the polydispersity of these high molecular weight mucin glycoprotein fractions. Determination of the longest intramolecular relaxation times tau 1 shows that these are much longer for the PSM fractions in 0.1M NaCl compared to 6M GdnHCl. These data are consistent with earlier studies showing that the chain conformation is the same in both solvents, but that in 0.1M NaCl, the PSM glycoprotein undergoes a self-association process that is end-to-end in nature. Since the tau 1 value is intimately related to the viscoelastic behavior of PSM solutions and gels, it is interesting to speculate that the end-to-end association process may be physiologically important.


Effects of supplementation with tocotrienol-rich fraction on immune response to tetanus toxoid immunization in normal healthy volunteers.
Vitamin E is an essential fat-soluble vitamin that has been shown to induce favorable effects on animal and human immune systems. The objective of this study was to assess the effects of tocotrienol-rich fraction (TRF) supplementation on immune response following tetanus toxoid (TT) vaccine challenge in healthy female volunteers. In this double-blinded, placebo-controlled clinical trial, participants were randomly assigned to receive either placebo (control group) or 400 mg of TRF (study group) supplementation daily. Over the 2-month period of the study, volunteers were asked to attend three clinical sessions (that is, on days 0, 28 and 56) and blood samples were obtained from the volunteers during the follow-up. On day 28, all volunteers were also vaccinated with the TT vaccine (20 Lf) intramuscularly. The results from the clinical trial showed that TRF supplementation significantly increased the total vitamin E level in the plasma of the TRF-supplemented volunteers compared with the placebo group, indicating overall compliance. Volunteers supplemented with TRF showed a significantly (P < 0.05) enhanced production of interferon-γ and interleukin (IL)-4 by the mitogen or TT-stimulated leukocytes compared with the control group. Volunteers from the TRF group produced significantly (P < 0.05) lower amounts of IL-6 compared with the placebo group. Anti-TT IgG production was also significantly (P < 0.05) augmented in the TRF-supplemented group compared with the placebo group. We conclude that TRF has immunostimulatory effects and potential clinical benefits to enhance immune response to vaccines.


Difference between planned and delivered radiotherapy dose to the internal mammary nodes in high-risk breast cancer patients.
Chest wall movement during radiotherapy can impact the delivered dose to the internal mammary nodes (IMN) in high-risk breast cancer patients. Using portal imaging and dose reconstruction we aimed to examine the delivered IMN dose coverage. Cine MV images were recorded for 39 breast cancer patients treated with daily image-guided radiotherapy (IGRT) in deep-inspiration breath-hold (DIBH). On the final frame of each cine MV recording the chest wall was matched with the Digitally Reconstructed Radiograph (DRR) from the treatment plan. The geometrical chest wall error was determined in the imager-plane perpendicular to the cranio-caudal direction, rounded to integer millimeters, and binned. For each 1 mm bin, an isocenter-shifted treatment plan was recalculated assuming that the projected error observed in the cine MV image was caused by anterior-posterior chest wall movement in the IMN region. A weighted plan sum yielded the IMN clinical target volume receiving at least 90% dose (V90_CTVn_IMN). The mean number of cine MV observations per patient was 36 (range 26-55). Most patients (67%) had on average a posterior chest wall position at treatment compared to planned. This translated into a change in the delivered median V90_CTVn_IMN of -0.7% (range, -11.9-2.9%; p < 0.001). The V90_CTVn_IMN reduction was greater than 9% in three patients. No clinically relevant differences were found for the mean lung dose or mean heart dose. Using cine MV images, we found that the delivered V90_CTVn_IMN was significantly lower than planned. In 8% of the patients, the V90_CTVn_IMN reduction exceeded 9%.


Commentary on: Combat-related gunshot wounds in the United States military: 2000-2009.
Gunshot wounds are an important cause of both morbidity and mortality within the military. With the deployment of the United States military into a two theater campaign over the past decade, the role of gunshot wounds in military personnel has come to the forefront. Gunshot wounds are often used and glamourized in popular culture. They are also fascinating to clinicians due to the difficulty in assessing such patients for injuries and treatment options.(1) Gunshot wounds also provide an opportunity to develop certain aspects of trauma management.(2) Walker et al. provide a coherent analysis of gunshot wounds to US military personnel during this period.(3).


Impact of the induced organic anion transporter 1 (Oat1) renal expression by furosemide on the pharmacokinetics of organic anions.
Furosemide is a loop diuretic. Different authors demonstrated that continuous administration of furosemide modulates the expression of organic anion transporters. This study was undertaken to simultaneously evaluate the effects of furosemide pretreatment on organic anion transporter 1 (Oat1) and multidrug resistance protein 2 (Mrp2) renal expressions, on p-aminohippurate (PAH) pharmacokinetics and on renal and urinary PAH levels in rats. Male Wistar rats were treated with furosemide (6 mg/100 g body weight per day, subcutaneously, 4 days) (treated group) or saline (control group). On the fifth day, PAH was administered as a bolus infusion in the femoral vein, and plasma samples were obtained from femoral artery at different time points. PAH levels in renal tissue and urine were also assessed. Renal Oat1 and Mrp2 expressions were evaluated by western blotting. Furosemide pretreatment increased both the expression of Oat1 and Mrp2. PAH plasma concentrations decreased following a biexponential function. The furosemide-treated group showed higher PAH plasma levels, a lower systemic clearance and elimination rate constant from the peripheral compartment, indicating that PAH renal elimination was decreased. PAH levels in renal tissue were significantly elevated and in urine appeared to be significantly lower as compared with control animals. Furosemide pretreatment caused a significant decrease of PAH renal elimination, despite Oat1 and Mrp2 augmented renal expression. The goal of the present study is the addition of important information in the wide gap of knowledge that exists about drug-drug interactions. Because of furosemide worldwide use, the data obtained are interesting and useful in terms of translation to clinical practice.


Using imaginary worlds for real social benefits.
We argue that imaginary worlds gain much of their appeal because they fulfill the fundamental need of human beings to feel connected to other humans. Immersion into story worlds provides a sense of social connection to the characters and groups represented in the world. By fulfilling the need to belong, imaginary worlds provide a buffer against rejection and loneliness.


Synaptic dysfunction connects autism spectrum disorder and sleep disturbances: A perspective from studies in model organisms.
Sleep disturbances (SD) accompany many neurodevelopmental disorders, suggesting SD is a transdiagnostic process that can account for behavioral deficits and influence underlying neuropathogenesis. Autism Spectrum Disorder (ASD) comprises a complex set of neurodevelopmental conditions characterized by challenges in social interaction, communication, and restricted, repetitive behaviors. Diagnosis of ASD is based primarily on behavioral criteria, and there are no drugs that target core symptoms. Among the co-occurring conditions associated with ASD, SD are one of the most prevalent. SD often arises before the onset of other ASD symptoms. Sleep interventions improve not only sleep but also daytime behaviors in children with ASD. Here, we examine sleep phenotypes in multiple model systems relevant to ASD, e.g., mice, zebrafish, fruit flies and worms. Given the functions of sleep in promoting brain connectivity, neural plasticity, emotional regulation and social behavior, all of which are of critical importance in ASD pathogenesis, we propose that synaptic dysfunction is a major mechanism that connects ASD and SD. Common molecular targets in this interplay that are involved in synaptic function might be a novel avenue for therapy of individuals with ASD experiencing SD. Such therapy would be expected to improve not only sleep but also other ASD symptoms.


Intraoperative electrocorticography and successful focus resection in a case of Sturge-Weber syndrome.
This paper reports a surgically treated case of Sturge-Weber syndrome (SWS) in which the epileptic foci and haemangiomatosis were successfully resected under monitoring of intraoperative electrocorticography. The patient was a 19-month-old female infant who was referred to our hospital because of frequent hemi-tonic-clonic convulsions that were resistant to anticonvulsant therapy. Serial MRI showed progressive atrophy in the left fronto-parieto-temporal lobe, and gyral enhancement by gadolinium corresponded to venous haemangiomatosis of SWS. Three-dimensional reconstruction of the MR images was performed using the Viewing Wand System. Conventional EEG taken before the operation showed slow activity in the left frontal lobe. Intraoperative ECoG revealed spike focus at the posterior temporal cortex to the margin of the haemangiomatosis. Lesionectomy with lobar corticectomy of the total frontal and parietal lobe and part of the temporal lobe was performed. The epileptogenic focus detected by ECoG in the posterior temporal lobe was also resected. In post-excisional ECoG, epileptogenic activities had disappeared. The patient had hemiparesis and hemihypesthesia just after the surgery, but gradually recovered from the paresis and almost has normal motor function except for right-hand clumsiness up to 1 year after Surgery. The present study demonstrated that lobar corticectomy of the haemangiomatosis-affected cortex with resection of the neighbouring epileptogenic focus is a good surgical alternative even if a haemangiomatosis of the SWS affected multilobar corti of the hemisphere.


Cancer diagnosis and suicide outcomes: Umbrella review and methodological considerations.
Suicide outcomes in cancer patients represent a major public health concern. We performed an umbrella review (UR) including all meta-analyses (MAs) and systematic reviews (SRs) published on the association between cancer and suicide outcomes. Eligible studies were searched in the main scientific databases up to January 23rd, 2021. Eligible MAs/SRs focused on all suicide phenotypes among cancer patients. Evidence of the association was extracted; the credibility and quality of the included studies were evaluated using ad-hoc tools, including "A MeaSurement Tool to Assess systematic Reviews-2-Revised" (AMSTAR-2-R). Six MAs and 6 SRs were included. The standardized mortality ratio of suicide in cancer patients was 1.5 to 1.7-fold higher than in the general population. Risk factors for suicide outcomes among cancer patients were male sex and older age, a cancer diagnosis within the prior year, and some specific cancer sites. Among 107 associations, 90 (84.1%) were supported by high credibility of evidence (class II). However, all studies reported a large heterogeneity (I2> 50%) and the majority of them reported considerable heterogeneity (I2> 75%). All MAs used random-effects measures. All MAs but one assessed publication bias and only one disclosed it. The majority of MAs/SRs showed critically low quality based on AMSTAR-2-R. We could not perform additional analyses due to the limited number of MAs. This UR underlines the inflated risk for suicide among cancer patients. Upcoming, well-designed studies are needed to account for a broader set of variables. Several methodological issues likewise warrant attention.


Partial anomalous pulmonary venous return in Turner syndrome.
The aim of this study is to describe the prevalence, anatomy, associations and clinical impact of partial anomalous pulmonary venous return in patients with Turner syndrome. All Turner patients who presented at our Turner clinic, between January 2007 and October 2015 were included in this study and underwent ECG, echocardiography and advanced imaging such as cardiac magnetic resonance or computed tomography as part of their regular clinical workup. All imaging was re-evaluated and detailed anatomy was described. Partial anomalous pulmonary venous return was diagnosed in 24 (25%) out of 96 Turner patients included and 14 (58%) of these 24 partial anomalous pulmonary venous return had not been reported previously. Right atrial or ventricular dilatation was present in 11 (46%) of 24 partial anomalous pulmonary venous return patients. When studied with advanced imaging modalities and looked for with specific attention, PAPVR is found in 1 out of 4 Turner patients. Half of these patients had right atrial and/or ventricular dilatation. Evaluation of pulmonary venous return should be included in the standard protocol in all Turner patients.


Aging of the population may not lead to an increase in the numbers of acute coronary events: a community surveillance study and modelled forecast of the future.
To examine the incidence, mortality and case fatality of acute coronary syndrome (ACS) in Finland during 1993-2007 and to create forecasts of the absolute numbers of ACS cases in the future, taking into account the aging of the population. Community surveillance study and modelled forecasts of the future. Two sets of population-based coronary event register data from Finland (FINAMI and the National Cardiovascular Disease Register (CVDR)). Bayesian age-period-cohort (APC) modelling. 24 905 observed ACS events in the FINAMI register and 364 137 in CVDR. Observed trends of ACS events during 1993-2007, forecasted numbers of ACS cases, and the prevalence of ACS survivors until the year 2050. In the FINAMI register, the average annual declines in age-standardised incidence of ACS were 1.6% (p<0.001) in men and 1.8% (p<0.001) in women. For 28-day case fatality of incident ACS, the average annual declines were 4.1% (p<0.001) in men and 6.7% (p<0.001) in women. Findings in the country-wide CVDR data were consistent with the FINAMI register. The APC model, based on the CVDR data, suggested that both the absolute numbers of ACS events and the prevalence of ACS survivors reached their peak in Finland around 1990, have declined since then, and very likely will continue to decline until 2050. The ACS event rates and absolute numbers of cases have declined steeply in Finland. The declining trends are likely to continue in the future despite the aging of the population.


Upregulation of mitochondrial telomerase reverse transcriptase mediates the preventive effect of physical exercise on pathological cardiac hypertrophy via improving mitochondrial function and inhibiting oxidative stress.
Physical exercise is a non-pharmacological intervention that helps prevent pathological cardiac hypertrophy. However, the underlying molecular mechanisms remain unclear. Telomerase reverse transcriptase (TERT) has non-telomeric functions such as protection against mitochondrial dysfunction and oxidative stress, and its myocardial expression is upregulated by physical exercise. Here, we found that physical exercise caused myocardial upregulation of mitochondrial TERT and sustenance during transverse aortic constriction (TAC)-induced cardiac hypertrophy. Overexpression of mitochondrial-targeted TERT (mito-TERT) via adeno-associated virus serotype 9 carrying the TERT-coding sequence fused with N-terminal mitochondrial-targeting sequence improved cardiac function and attenuated cardiac hypertrophy. Mechanistically, mito-TERT ameliorated mitochondrial dysfunction and oxidative stress, which were associated with improving the activity and subunit composition of complex I. Remarkably, the telomerase activator TA-65 also exhibited an antihypertrophic effect. Collectively, our results reveal a significant role for mito-TERT in mediating the antihypertrophic effect of physical exercise and demonstrate that TERT is a potential drug target for treating cardiac hypertrophy.


Kinetic and pharmacologic characterization of gamma-aminobutyric acid receptive sites from mammalian brain.
Sodium-dependent (+Na) and sodium-independent (-Na) receptive sites for gamma-aminobutyric acid (GABA) have been characterized using synaptic plasma membranes from bovine and rat brain. Synaptic plasma membranes were prepared from either rat cerebellar cortex or calf cerebral cortex by discontinuous sucrose gradient flotation centrifugation of crude mitochondrial pellets, and assayed using equilibrium ligand binding assays to obtain the maximum binding capacity (Bmax) and the thermodynamic constant (KD). Values for KD from equilibrium studies were subsequently confirmed by kinetic analyses of association and dissociation reactions. The KD for +Na GABA binding (5.0 +/- 0.2 micron) corresponds to the apparent Michaelis constant for neuronal GABA transport (3.8 +/- 0.1 micron)22, while the KD for -Na binding (0.17 +/- 0.04 micron) agrees with that determined by Enna and Snyder for the putative postsynaptic receptor. Maximal binding activities of about 5 and 55 pmole/mg protein were obtained for -Na and +Na binding respectively. The pharmacologic specificities of the two sites were determined using competition binding studies. Nipecotic acid and diaminobutyric acid inhibit both synaptosomal GABA uptake (Ki approximately 25 micron and 120 micron respectively) and +Na binding of GABA to synaptic plasma membrane (IC50 approximately 40 micron and 350 micron respectively) but do not inhibit -Na binding. Bicuculline inhibits -Na [3H]GABA binding at low concentrations (IC50 approximately 15 micron), while affecting the uptake and +Na binding of [3H]GABA only at high concentrations (IC50 approximately 520 micron and 300 micron respectively). beta-Alanine inhibits the -Na binding site (IC50 approximately 100 micron), but is ineffective at the +Na binding site and does not interfere with synaptosomal uptake of GABA. Finally, chlorpromazine and N-ethylmaleimide inhibit the +Na binding, albeit at high concentrations (IC50 approximately 600 micron and 5 mM respectively) but are ineffective at the -Na binding site. From these results the -Na binding site is tentatively identified as a postsynaptic receptor and the +Na binding site is identified as the neuronal uptake receptive site.


Low zinc environment induces stress signaling, senescence and mixed cell death modalities in colon cancer cells.
Currently it is not clear what type of the final cellular response (i.e. cell death modality or senescence) is induced upon chronic intracellular zinc depletion in colon cancer cells. To address this question, isogenic colon cancer lines SW480 and SW620 exposed to low zinc environment were studied over the period of 6 weeks. Low zinc environment reduced total as well as free intracellular zinc content in both cell lines. Decreased intracellular zinc content resulted in changes in cellular proliferation, cell cycle distribution and activation of stress signaling. In addition, colonocytes with low zinc content displayed increased levels of oxidative stress, changes in mitochondrial activity but in the absence of significant DNA damage. Towards the end of treatment (4th-6th week), exposed cells started to change morphologically, and typical markers of senescence as well as cell death appeared. Of two examined colon cancer cell lines, SW480 cells proved to activate predominantly senescent phenotype, with frequent form of demise being necrosis and mixed cell death modality but not apoptosis. Conversely, SW620 cells activated mostly cell death, with relatively equal distribution of apoptosis and mixed types, while senescent phenotypes and necrosis were present only in a small fraction of cell populations. Addition of zinc at the beginning of 4th week of treatment significantly suppressed cell death phenotypes in both cell lines but had no significant effect on senescence. In conclusion, presented results demonstrate variability of responses to chronic zinc depletion in colon cancer as modeled in vitro.


Preoperative diagnosis of a paraesophageal bronchogenic cyst using endosonography.
Preoperative diagnosis of paraesophageal bronchogenic cysts is difficult, and its management remains controversial. We describe the case of an incidental paraesophageal bronchogenic cyst, suspected preoperatively with endoscopic ultrasound and established intraoperatively by thoracoscopic inspection. Surgical treatment was achieved by cyst excision using a needlescopic technique. Endoscopic ultrasound seems to be the preoperative diagnostic test of choice for paraesophageal bronchogenic cysts.


Templates for design of inhibitors for serine proteases: application of the program DOCK to the discovery of novel inhibitors for thrombin.
The program DOCK was used to search for novel inhibitors for alpha-thrombin. Four among the top twelve best scoring compounds from the Cambridge Structural Data Base inhibited this enzyme, and three of them inhibited alpha-thrombin in a competitive mode. These molecules are expected to serve as general templates for structural elaboration in targeting diverse serine proteases for selective inhibition.


Inhibition of tumour cell growth by hyperforin, a novel anticancer drug from St. John's wort that acts by induction of apoptosis.
Hyperforin is a plant derived antibiotic from St. John's wort. Here we describe a novel activity of hyperforin, namely its ability to inhibit the growth of tumour cells by induction of apoptosis. Hyperforin inhibited the growth of various human and rat tumour cell lines in vivo, with IC(50) values between 3-15 microM. Treatment of tumour cells with hyperforin resulted in a dose-dependent generation of apoptotic oligonucleosomes, typical DNA-laddering and apoptosis-specific morphological changes. In MT-450 mammary carcinoma cells hyperforin increased the activity of caspase-9 and caspase-3, and hyperforin-mediated apoptosis was blocked by the broad-range caspase inhibitor zVAD.fmk. When added to MT-450 cells, hyperforin, but not paclitaxel, induced a rapid loss of the mitochondrial transmembrane potential Deltapsi(m), and subsequent morphological changes such as homogenization and vacuolization of mitochondria. Monitoring of Deltapsi(m) revealed that the hyperforin-mediated mitochondrial permeability transition can not be prevented by zVAD.fmk. This indicates that mitochondrial permeabilization is a cause rather than a consequence of caspase activation. Moreover, hyperforin was capable of releasing cytochrome c from isolated mitochondria. These findings suggest that hyperforin activates a mitochondria-mediated apoptosis pathway. In vivo, hyperforin inhibited the growth of autologous MT-450 breast carcinoma in immunocompetent Wistar rats to a similar extent as the cytotoxic drug paclitaxel, without any signs of acute toxicity. Owing to the combination of significant antitumour activity, low toxicity in vivo and natural abundance of the compound, hyperforin holds the promise of being an interesting novel antineoplastic agent that deserves further laboratory and in vivo exploration.


ER-mitochondrial contact protein Miga regulates autophagy through Atg14 and Uvrag.
Mitochondrial malfunction and autophagy defects are often concurrent phenomena associated with neurodegeneration. We show that Miga, a mitochondrial outer-membrane protein that regulates endoplasmic reticulum-mitochondrial contact sites (ERMCSs), is required for autophagy. Loss of Miga results in an accumulation of autophagy markers and substrates, whereas PI3P and Syx17 levels are reduced. Further experiments indicated that the fusion between autophagosomes and lysosomes is defective in Miga mutants. Miga binds to Atg14 and Uvrag; concordantly, Miga overexpression results in Atg14 and Uvrag recruitment to mitochondria. The heightened PI3K activity induced by Miga requires Uvrag, whereas Miga-mediated stabilization of Syx17 is dependent on Atg14. Miga-regulated ERMCSs are critical for PI3P formation but are not essential for the stabilization of Syx17. In summary, we identify a mitochondrial protein that regulates autophagy by recruiting two alternative components of the PI3K complex present at the ERMCSs.


Effects of calcium depletion and loading on injury during metabolic inhibition of isolated adult rat myocytes.
The hypothesis that calcium influxes from the extracellular space play an important role in the pathogenesis of irreversible anoxic injury was tested using isolated adult rat myocytes. Myocytes treated with 6 mM amytal and 3 mM iodoacetate and subsequently incubated in either calcium-containing (1.12 mM) or calcium-free media (with or without 1 mM EGTA) developed rigor contracture (cell squaring) and cell death (trypan blue permeability) at the same rate. The rates of cell death in both calcium-containing and calcium-free media were increased by incubation in hypotonic media even though the rates of contracture development remained unaltered. Cells developed osmotic fragility prior to membrane permeability increases. The calcium ionophore, A23187 (10 microM), induced rapid rounding of rod-shaped cells subjected only to mitochondrial inhibition in calcium containing media, confirming its ability to cause an increase in cellular permeability to calcium. However, A23187 did not alter the rates of cell death of totally metabolically inhibited myocytes in either calcium-containing or calcium-free media with EGTA. The results indicate that influxes of calcium are not necessary for the development of irreversible injury in metabolically inhibited, isolated myocytes.


Molecular study of mucin-procyanidin interaction by fluorescence quenching and Saturation Transfer Difference (STD)-NMR.
Astringency is closely related to the interaction between procyanidins and salivary proteins (SP). The aim of this work was to study the interaction between mucin, a SP responsible for saliva lubricating properties, with different procyanidins (B4 dimer, tetramer (TT) and fractions of oligomeric procyanidins), and the influence of several conditions [pH, ionic strength, procyanidins' mean degree of polymerization (mDP) and different solvents (ethanol or dimethylsulfoxide)] on this interaction by fluorescence quenching and Saturation Transfer Difference (STD)-NMR. For fractions of oligomeric procyanidins, the mucin-procyanidin interaction increased with mDP; however, for pure compounds, procyanidin TT has lower affinity than dimer B4 which could be due to a lower structural flexibility imposed by its complex structure. Furthermore, EtOH and DMSO can disrupt the main driving forces of these interactions, hydrophobic interactions and hydrogen bonds, respectively, lowering significantly the binding constants.


Dental status and oral health of patients with epilepsy: an epidemiologic study.
We performed a dental survey of epilepsy patients to examine their oral health by statistical means and to provide a guide for the dental treatment of these patients. We first set up four "dental" subgroups of epilepsy patients, based on the types of seizures, seizure frequency, and mental state. One hundred one patients underwent a survey concerning their dental, medical, and epilepsy histories, followed by a dental examination. Indexes quantifying oral hygiene, the number and condition of the remaining teeth, periodontium, and the degree of prosthetic treatment were measured. An age-matched control group of general (nonepilepsy) population underwent an identical dental examination. Statistical comparison was performed between the patient and the control groups and between subgroups of epilepsy patients. In almost all aspects of oral health and dental status, patients with epilepsy showed a significantly worse condition compared with the control group. Comparison of the subgroups of epilepsy patients revealed that the most severe findings concern patients who have poorly controlled epilepsy, especially those who have frequent generalized tonic-clonic seizures. The observed difference probably results from a combination of factors such as the effect of the seizures themselves, socioeconomic conditions, and the negative attitude of dentists. We recommend that the planning of dental treatment of such patients should start with the assessment of their disease and determination of the "dental" subgroup to which they belong. For each subgroup, specific recommendations for interventions are given.


Temporal uncertainty analysis of human errors based on interrelationships among multiple factors: a case of Minuteman III missile accident.
In traditional approaches of human reliability assessment (HRA), the definition of the error producing conditions (EPCs) and the supporting guidance are such that some of the conditions (especially organizational or managerial conditions) can hardly be included, and thus the analysis is burdened with incomprehensiveness without reflecting the temporal trend of human reliability. A method based on system dynamics (SD), which highlights interrelationships among technical and organizational aspects that may contribute to human errors, is presented to facilitate quantitatively estimating the human error probability (HEP) and its related variables changing over time in a long period. Taking the Minuteman III missile accident in 2008 as a case, the proposed HRA method is applied to assess HEP during missile operations over 50 years by analyzing the interactions among the variables involved in human-related risks; also the critical factors are determined in terms of impact that the variables have on risks in different time periods. It is indicated that both technical and organizational aspects should be focused on to minimize human errors in a long run.


Characterization of very-low-density lipoproteins isolated from baboons, and fractionated using heparin-Sepharose chromatography.
Plasma very-low-density lipoproteins (VLDL) (d less than 1.006 g/ml) were purified from baboons by repeated ultracentrifugation. The weight composition of VLDL purified from these animals was 59% triacylglycerol, 17% phospholipid, 13% cholesterol plus cholesteryl esters, and 11% protein. When purified VLDL was fractionated using heparin-Sepharose chromatography, an average of 33% of the total recovered proteins were unbound in a saline solution, and 67% (range, 31 to 92%) were bound by the column, but could be eluted with 3 M NaCl. Recoveries of starting protein and the major classes of lipids in the two fractions were 70-80%. The two fractions differed in both apolipoprotein and lipid compositions. Analysis of sodium dodecyl sulfate-treated apolipoproteins using 3-21.5% acrylamide gradient gel electrophoresis indicated that both VLDL fractions contained apolipoprotein B, but only the bound fraction possessed significant amounts of apolipoprotein E. On a weight percent basis, the apolipoprotein-E-rich (bound) VLDL fraction contained significantly more cholesterol and cholesteryl esters (P less than 0.001) and less phospholipids (P less than 0.005) compared to the apolipoprotein E-poor (unbound) VLDL. Apolipoprotein-E-poor VLDL had shorter retention times than E-rich VLDL upon gel filtration chromatography, suggesting a larger size. There was no significant correlation between plasma levels of apolipoprotein-E-poor VLDL and levels of apolipoprotein B. These results demonstrate that baboons possess VLDL which can be separated into apolipoprotein-E-poor and E-rich fractions and these fractions differ in protein and lipid composition and in size.


Application of hot-melt extrusion technology for designing an elementary osmotic pump system combined with solid dispersion for a novel poorly water-soluble antidepressant.
TP1 is a novel antidepressant with poor solubility. To reduce fluctuations in blood concentration and increase oral bioavailability, a controlled-release system was developed by combining a solid dispersion (SD) and an elementary osmotic pump (EOP). The study compared different methods of preparing SDs. Hot-melt extrusion (HME) exhibited clear advantages over the traditional melting technique. An in vitro release study demonstrated that HME-EOP tablets released TP1 in a zero-order manner over 12 h and the drug release was in dependent of the release medium and agitation speed, whereas release from molten-EOP tablets lasted only 8 h. In contrast to immediate-release tablets, the HME-EOP tablets exhibited less fluctuation in blood concentration and higher bioavailability in vivo. In summary, the osmotic pump system combined with an HME-based SD of TP1 presented controlled release in vitro, high bioavailability in vivo and a good in vivo-in vitro correlation.


[Morphofunctional changes in the heart, liver and skeletal muscles during temporary occlusion of the abdominal aorta].
Experimental abdominal aorta ligation at the bifurcation site was performed in anesthetized mongrel dogs (body mass 12-17 kg) under controlled respiration. Aortic ligation produced a significant effect on the physiological indices of cardiac function, ultrastructure of the myocardium, liver and musculus quadriceps femoris, as well as on the content of macroergic compounds in these organs. One-hour aortic occlusion caused mainly reversible dystrophic changes in the tissues studied; 2-8-hour aortic ligation led to much more severe changes in the skeletal musculature, liver, and heart, while reperfusion, as a rule, impaired the cardiac and hepatic status. The latter may be attributed to the release of neuromediators and intermediate metabolism products from the ischemic skeletal muscles.


Imaging a microfocus X-ray focal spot with a thin coded aperture.
Imaging of the focal spot size in X-ray generators can be achieved by means of a pinhole in a highly attenuating material, such as gold. For microfocus generators with spot sizes of only around 10 microns or less, the material must be very thin to avoid an impractical aspect ratio. With a 90 kV source, only 11% attenuation is attained with 5 µm gold. For a pinhole that is smaller than the focal spot, the signal-to-noise ratio (SNR) may be less than 1. To image the focal spot of a medical X-ray generator, a coded aperture has been used previously to reduce the exposure time required, however the same technique does not appear to have been used to increase the SNR when the attenuation is very low. Such a method is used here, using a no-two-holes-touching variation of a modified uniformly redundant array (MURA). In a prototype sample, with only 5 µm gold having 2.75 µm holes, the focal spot of a microfocus X-ray generator used in a micro-CT system could be clearly visualised and quantified. Directionality of the aberrations made focussing of the X-ray spot more intuitive and reduced the time required to obtain an optimal, quantifiable focus.


Correction to: The Italian multiple sclerosis register.
Unfortunately in the original publication, the affiliation of the author Maria Pia Amato was incorrect. The author inadvertently missed out to include her second affiliation.


Characteristics and stability of spaced dentition.
A serial study of changes in spacing between teeth during the period of facial maturation, finding tendencies toward closure of buccal spaces and opening of anterior spaces. Spacing in females is equally distributed between upper and lower arches; in males it is more prevalent in the upper arch.


A novel classification model based on cerebral 18F-FDG uptake pattern facilitates the diagnosis of acute/subacute seropositive autoimmune encephalitis.
To explore the intrinsic alteration of cerebral 18F-FDG metabolism in acute/subacute seropositive autoimmune encephalitis (AE) and to propose a universal classification model based on 18F-FDG metabolic patterns to predict AE. Cerebral 18F-FDG PET images of 42 acute/subacute seropositive AE patients and 45 healthy controls (HCs) were compared using voxelwise and region of interest (ROI)-based schemes. The mean standardized uptake value ratios (SUVRs) of 59 subregions according to a modified Automated Anatomical Labeling (AAL) atlas were compared using a t-test. Subjects were randomly divided into a training set (70%) and a testing set (30%). Logistic regression models were built based on the SUVRs and the models were evaluated by determining their predictive value in the training and testing sets. The 18F-FDG uptake pattern in the AE group was characterized by increased SUVRs in the brainstem, cerebellum, basal ganglia, and temporal lobe, and decreased SUVRs in the occipital, and frontal regions with voxelwise analysis (false discovery rate [FDR] p<0.05). Utilizing ROI-based analysis, we identified 15 subareas that exhibited statistically significant changes in SUVRs among AE patients compared to HC (FDR p<0.05). Further, a logistic regression model incorporating SUVRs from the calcarine cortex, putamen, supramarginal gyrus, cerebelum_10, and hippocampus successfully enhanced the positive predictive value from 0.76 to 0.86 when compared to visual assessments. This model also demonstrated potent predictive ability, with AUC values of 0.94 and 0.91 observed for the training and testing sets, respectively. During the acute/subacute stages of seropositive AE, alterations in SUVRs appear to be concentrated within physiologically significant regions, ultimately defining the general cerebral metabolic pattern. By incorporating these key regions into a new classification model, we have improved the overall diagnostic efficiency of AE.


Lung transplantation for interstitial lung disease in idiopathic inflammatory myositis: A cohort study.
In patients with interstitial lung disease (ILD) complicating classical or amyopathic idiopathic inflammatory myopathy (IIM), lung transplantation outcomes might be affected by the disease and treatments. Here, our objective was to assess survival and prognostic factors in lung transplant recipients with IIM-ILD. We retrospectively reviewed data for 64 patients who underwent lung transplantation between 2009 and 2021 at 19 European centers. Patient survival was the primary outcome. At transplantation, the median age was 53 [46-59] years, 35 (55%) patients were male, 31 (48%) had classical IIM, 25 (39%) had rapidly progressive ILD, and 21 (33%) were in a high-priority transplant allocation program. Survival rates after 1, 3, and 5 years were 78%, 73%, and 70%, respectively. During follow-up (median, 33 [7-63] months), 23% of patients developed chronic lung allograft dysfunction. Compared to amyopathic IIM, classical IIM was characterized by longer disease duration, higher-intensity immunosuppression before transplantation, and significantly worse posttransplantation survival. Five (8%) patients had a clinical IIM relapse, with mild manifestations. No patient experienced ILD recurrence in the allograft. Posttransplantation survival in IIM-ILD was similar to that in international all-cause-transplantation registries. The main factor associated with worse survival was a history of muscle involvement (classical IIM). In lung transplant recipients with idiopathic inflammatory myopathy, survival was similar to that in all-cause transplantation and was worse in patients with muscle involvement compared to those with the amyopathic disease.


Influence of maternal antibodies on vaccine responses: inhibition of antibody but not T cell responses allows successful early prime-boost strategies in mice.
The transfer of maternal antibodies to the offspring and their inhibitory effects on active infant immunization is an important factor hampering the use of certain vaccines, such as measles or respiratory syncytial virus vaccine, in early infancy. The resulting delay in protection by conventional or novel vaccines may have significant public health consequences. To define immunization approaches which may circumvent this phenomenon, experiments were set up to further elucidate its immunological bases. The influence of maternal antibodies on antibody and T cell responses to measles hemagglutinin (MV-HA) were analyzed following MV-HA immunization of pups born to immune or control BALB/c mothers using four different antigen delivery systems: live or inactivated conventional measles vaccine, a live recombinant canarypox vector and a DNA vaccine. High levels (> 5 log10) of maternal anti-HA antibodies totally inhibited antibody responses to each of the vaccine constructs, whereas normal antibody responses were elicited in presence of lower titers of maternal antibodies. However, even high titers of maternal antibodies affected neither the induction of vaccine-specific Th1/Th2 responses, as assessed by proliferation and levels of IFN-gamma and IL-5 production, nor CTL responses in infant mice. On the basis of these unaltered T cell responses, very early priming and boosting (at 1 and 3 weeks of age, respectively) with live measles vaccine allowed to circumvent maternal antibody inhibition of antibody responses in pups of immune mothers. This was confirmed in another immunization model (tetanus toxoid). It suggests that effective vaccine responses may be obtained earlier in presence of maternal antibodies through the use of appropriate immunization strategies using conventional or novel vaccines for early priming.


Two-dimensional immunoelectrophoretic analysis of urinary ultraconcentrates: antigenic differences between bladder cancer positive patients, normal individuals, and patients with urinary tract infections.
Urine ultraconcentrates (100-fold) from bladder cancer patients, patients suffering from urinary tract infection, and normal individuals were analyzed using polyacrylamide gel electrophoresis (PAGE) and two-dimensional immunoelectrophoresis. A combined sample of normal urine was resolved into 1 to 3 protein bands by PAGE, whereas a single concentrated bladder cancer urine was resolved into 10-12 protein bands. Yet, this same concentrated urine sample was resolved into 17-20 antigen peaks by two-dimensional immunoelectrophoresis (2DIEP) against antihuman serum. A significant (P less than 0.05) increase was observed in the relative antigen concentration when comparing 2DIEP profiles of bladder cancer urines to normal controls. A significant increase in the relative antigen concentration and the number of antigen peaks was also found when comparing immunoelectrophoretic patterns obtained from ultraconcentrated urine specimens of bladder cancer positive urine and normal controls using a rabbit antibladder cancer urine antisera (P less than 0.002 and P less than 0.02, respectively). In addition, significant (P less than 0.02) antigenic differences were found when comparing concentrated urine samples from bladder cancer positive individuals to those with urinary tract infection. The bladder cancer group demonstrated 8/9 positive results for relative antigen concentrations greater than 3.0. Fifteen of 16 normal or urinary tract infected individuals combined had relative antigen concentrations less than 3.0. These differences were highly significant (P less than 0.001). No differences were found between concentrated bladder cancer and normal urine specimens tested against rabbit antinormal urine antisera.


Soil organic matter turnover rates increase to match increased inputs in grazed grasslands.
Managed grasslands have the potential to store carbon (C) and partially mitigate climate change. However, it remains difficult to predict potential C storage under a given soil or management practice. To study C storage dynamics due to long-term (1952-2009) phosphorus (P) fertilizer and irrigation treatments in New Zealand grasslands, we measured radiocarbon (14C) in archived soil along with observed changes in C stocks to constrain a compartmental soil model. Productivity increases from P application and irrigation in these trials resulted in very similar C accumulation rates between 1959 and 2009. The ∆14C changes over the same time period were similar in plots that were both irrigated and fertilized, and only differed in a non-irrigated fertilized plot. Model results indicated that decomposition rates of fast cycling C (0.1 to 0.2 year-1) increased to nearly offset increases in inputs. With increasing P fertilization, decomposition rates also increased in the slow pool (0.005 to 0.008 year-1). Our findings show sustained, significant (i.e. greater than 4 per mille) increases in C stocks regardless of treatment or inputs. As the majority of fresh inputs remain in the soil for less than 10 years, these long term increases reflect dynamics of the slow pool. Additionally, frequent irrigation was associated with reduced stocks and increased decomposition of fresh plant material. Rates of C gain and decay highlight trade-offs between productivity, nutrient availability, and soil C sequestration as a climate change mitigation strategy. The online version contains supplementary material available at 10.1007/s10533-021-00838-z.


Isolated renal artery dissection secondary to medial degeneration.
Renal artery aneurysms can have variable presentations, often resulting in a therapeutic dilemma to the clinician. We review the causes, clinical features, pathological conditions and treatment options for this problem. We report a case of a thrombus in 1 of 2 left renal arteries, which resulted in uncontrollable hypertension. At nephrectomy the angiographically normal vessel had medial degeneration, demonstrating the diffuse nature of this disease. Conservative renal-sparing management should be considered whenever possible.


Hypertension and chronic inhibition of endocannabinoid degradation modify the endocannabinoid system and redox balance in rat heart and plasma.
The interaction between the endocannabinoid and ROS signaling systems has been demonstrated in different organs. Inhibitors of fatty acid amide hydrolase (FAAH), the key enzyme responsible for degradation of the endocannabinoid anandamide, are postulated to possess anti-hypertensive potential. Here, we compared the effects of hypertension and chronic FAAH inhibition by URB597 on the endocannabinoid system and redox balance in spontaneously hypertensive rats (SHR) and hypertensive deoxycorticosterone acetate (DOCA)-salt rats. Enhanced oxidative stress and lipid peroxidation were found in both hypertension models. Hypertension affected cardiac and plasma endocannabinoid systems in a model-dependent manner: anandamide and 2-arachidonoylglycerol levels decreased in SHR and increased in DOCA-salt. Cardiac CB1 receptor expression increased in both models while higher CB2 receptor expression was only in DOCA-salt. URB597 increased endocannabinoid levels in both models but produced the partial reduction of oxidative stress in DOCA-salt but not in SHR. Notably, URB597 decreased antioxidant defense and increased lipid peroxidation products in normotension. Therefore, the therapeutic potential of FAAH inhibitors should be interpreted cautiously.


A novel longitudinal clustering approach to psychopathology across diagnostic entities in the hospital-based PsyCourse study.
Biological research and clinical management in psychiatry face two major impediments: the high degree of overlap in psychopathology between diagnoses and the inherent heterogeneity with regard to severity. Here, we aim to stratify cases into homogeneous transdiagnostic subgroups using psychometric information with the ultimate aim of identifying individuals with higher risk for severe illness. 397 participants of the PsyCourse study with schizophrenia- or bipolar-spectrum diagnoses were prospectively phenotyped over 18 months. Factor analysis of mixed data of different rating scales and subsequent longitudinal clustering were used to cluster disease trajectories. Five clusters of longitudinal trajectories were identified in the psychopathologic dimensions. Clusters differed significantly with regard to Global Assessment of Functioning, disease course, and-in some cases-diagnosis while there were no significant differences regarding sex, age at baseline or onset, duration of illness, or polygenic burden for schizophrenia. Longitudinal clustering may aid in identifying transdiagnostic homogeneous subgroups of individuals with severe psychiatric disease.


Development and evaluation of an algorithm for computer analysis of maternal heart rate during labor.
Maternal heart rate (MHR) recordings are morphologically similar and sometimes coincident with fetal heart rate (FHR) recordings and may be useful for maternal-fetal monitoring if appropriately interpreted. However, similarly to FHR, visual interpretation of MHR features may be poorly reproducible. A computer algorithm for on-line MHR analysis was developed based on a previously existing version for FHR analysis. Inter-observer and computer-observer agreement and reliability were assessed in 40 one-hour recordings obtained from 20 women during the last 2h of labor. Agreement and reliability were evaluated for the detection of basal MHR, long-term variability (LTV), accelerations and decelerations, using proportions of agreement (PA) and Kappa statistic (K), with 95% confidence intervals (95% CI). Changes in MHR characteristics between the first and the second hour of the tracings were also evaluated. There was a statistically significant inter-observer and computer-observer agreement and reliability in estimation of basal MHR, accelerations, decelerations and LTV, with PA values ranging from 0.72 (95% CI: 0.62-0.79) to 1.00 (95% CI: 0.99-1.00), and K values ranging from 0.44 (95% CI: 0.28-0.60) to 0.89 (95% CI: 0.82-0.96). Moreover, basal MHR, number of accelerations and LTV were significantly higher in the last hour of labor, when compared to the initial hour. The developed algorithm for on-line computer analysis of MHR recordings provided good to excellent computer-observer agreement and reliability. Moreover, it allowed an objective detection of MHR changes associated with labor progression, providing more information about the interpretation of maternal-fetal monitoring during labor.


Tobacco use transitions in the United States: The National Longitudinal Study of Adolescent Health.
The purpose of this study is to evaluate and describe transitions in cigarette and smokeless tobacco (ST) use, including dual use, prospectively from adolescence into young adulthood. The current study utilizes four waves of the National Longitudinal Study of Adolescent Health (Add Health) to examine patterns of cigarette and ST use (within 30 days of survey) over time among a cohort in the United States beginning in 7th-12th grade (1995) into young adulthood (2008-2009). Transition probabilities were estimated using Markov modeling. Among the cohort (N=20,774), 48.7% reported using cigarettes, 12.8% reported using ST, and 7.2% reported dual use (cigarettes and ST in the same wave) in at least one wave. In general, the risk for transitioning between cigarettes and ST was higher for males and those who were older. Dual users exhibited a high probability (81%) of continuing dual use over time. Findings suggest that adolescents who use multiple tobacco products are likely to continue such use as they move into young adulthood. When addressing tobacco use among adolescents and young adults, multiple forms of tobacco use should be considered.


Anosmia predicts memory impairment in post-COVID-19 syndrome: results of a neuropsychological cohort study.
Recovered COVID-19 patients frequently suffer of cognitive disorders. Several etiopathogenetic mechanisms have been considered for the brain complications in COVID-19 but results are uncertain. Amongst them, an olfactory route to SARS-CoV-2 brain infection might explain cognitive and memory disturbances in post-COVID-19 patients, given the cooccurrence of anosmia and possible underlying limbic involvement. The aims of the study are to investigate cognition of patients with post-COVID-19 syndrome, and to find clinical factors predicting cognitive and memory impairments. 18 patients with post-COVID-19 syndrome underwent neuropsychological assessment and evaluation of clinical parameters. Stepwise regression analysis was used between clinical parameters as factors and cognitive global scores as dependent variables. Since only anosmia predicted memory performances, repeated measures ANOVA of memory scores was conducted between anosmic and non-anosmic patients. We found lack of association between clinical parameters and cognitive performances. Only anosmia was a good predictor for memory performances, with anosmic subjects showing a temporo-mesial amnesic profile. Our study shows novel findings of causal association between transient anosmia during COVID-19 and memory disorders with temporo-mesial dysfunction, probably sharing a common pathophysiological mechanism, and suggesting a possible SARS-CoV 2 infection of the limbic brain via the olfactory route. In contrast to previous studies, cognitive dysfunctions were not associated with respiratory distress, comorbidity, and depression.


Draft genome sequence of the novel agarolytic bacterium Aquimarina agarilytica ZC1.
The marine bacterium ZC1 is the type strain of the recently identified novel species Aquimarina agarilytica. It can produce multiple agarases. Here we report the draft genome sequence of strain ZC1 (4,253,672 bp, with a GC content of 32.8%) and major findings from its annotation. It is the first reported genome in the genus Aquimarina.


Pediatric Malignant Bone Tumors: A Review and Update on Current Challenges, and Emerging Drug Targets.
Osteosarcoma (OS) and the Ewing sarcoma family of tumors (ESFT) are the most common malignant bone tumors in children and adolescents. While significant improvements in survival have been seen in other pediatric malignancies the treatment and prognosis for pediatric bone tumors has remained unchanged for the past 3 decades. This review and update of pediatric malignant bone tumors will provide a general overview of osteosarcoma and the Ewing sarcoma family of tumors, discuss bone tumor genomics, current challenges, and emerging drug targets.


[Correlation analysis of increase in serum level of leptin with that of C reactive protein, troponin T and endothelin in patients with acute myocardial infarction].
To determine serum leptin levels in patients with acute myocardial infarction (AMI) and coronary atherosclerosis (CS), and to analyze its correlation with C reactive protein (CRP), troponin T (TnT) and endothelin (ET). Serum samples from confirmed AMI and CS patients were collected. Leptin and ET were assayed with high sensitive radioimmunoassay, TnT was determined with automatic biochemical analyser, and CRP was determined with enzyme-linked immunosorbant assay (ELISA). Compared with normal control group, serum leptin, TnT, CRP and ET levels increased significantly (all P<0.01) in AMI patients. Serum levels of other cytokines, except TnT in CS patients, increased significantly compared with normal control group (all P<0.01). Correlation analysis showed that all the changes were not correlated with each other, each being an independent factor. Only serum TnT levels of AMI and CS patients showed a significant difference (P<0.01). Serum leptin levels of both AMI and CS patients increase significantly without a significant difference between each other, and there is no correlation for leptin with CRP, TnT and ET.


Comparison of two methods for transformation of Plasmodium knowlesi: Direct schizont electroporation and spontaneous plasmid uptake from plasmid-loaded red blood cells.
Human infections from Plasmodium knowlesi present challenges to malaria control in Southeast Asia. P. knowlesi also offers a model for other human malaria species including Plasmodium vivax. P. knowlesi parasites can be cultivated in the laboratory, and their transformation is standardly performed by direct electroporation of schizont-infected red blood cells (RBCs) with plasmid DNA. Here we show that the efficiency of direct electroporation is exquisitely dependent on developmental age of the schizonts. Additionally, we show that transformation of P. knowlesi can be achieved without direct electroporation by using the parasite's ability to infect and take up DNA from plasmid-loaded RBCs. Transformation with plasmid-loaded RBCs does not require labor-intensive preparations of schizont-infected RBCs as for direct electroporation, and parasite damage from high voltage discharge is avoided. Further studies of the mechanism of spontaneous DNA uptake may suggest strategies for improved transformation and provide insights into the transport pathways of apicomplexans.