Rln3a is a prerequisite for spermatogenesis and fertility in male fish.
The essential roles of Relaxin3 (RLN3) in energy homeostasis had been well investigated, while the mechanisms of RLN3 regulating reproduction remain to be elusive in mammals. Although two rln3 paralogues have been characterized in several teleosts, their functions still remain largely unknown. In this study, two paralogous rln3 genes, represented as rln3a and rln3b, were identified from the testis of Nile tilapia (Oreochromis niloticus). Rln3a was dominantly expressed in testis, while the most abundant rln3b expression was in brain. In situ hybridization demonstrated that rln3a is abundantly expressed in the Leydig cells of the testis. To understand the role of Rln3 in the testicular development, homologous null-rln3a gene mutant line was constructed by CRISPR/Cas9 technology. Morphological observation demonstrated that null mutation of rln3a gene caused testicular hypertrophy and a significant increase of GSI. However, a significant decrease of spermatogenic cells at different phases, i.e. spermatogonia, spermatocytes, spermatids and sperms was found. Silencing of rln3a gene repressed the expression of key genes in germ cell and Leydig cell. Deficiency of Rln3a led to the significant decrease of 11-KT production, which stimulated the up-regulation of both FSH and LH production in the pituitary via a negative feedback manner possibly. Mutation of rln3a in XY fish led to the hypogonadism with sperm deformation, significant decrease of fertility, and sperm motility, revealing as the high mortality of the offspring obtained by crossing the wild type female and rln3a-/- XY fish. Interestingly, recombinant human RLN3 injection significantly enhanced the sperm motility in rln3a-/- XY fish. Moreover, hCG treatment stimulated the expression of steroidogenic enzyme genes and 11-KT production, which were repressed by rln3a mutation in XY fish. Taken together, this study, for the first time by using a gene knockout model, proved that Rln3a is an indispensable mediator for androgen production in testis via HPG axis, and plays an essential role in spermatogenesis, sperm motility and male fertility in fish.


The potential use of cell-free-circulating-tumor DNA as a biomarker for prostate cancer.
We are yet to identify an accurate, precise and non-invasive biomarker for the detection of prostate cancer. It would undoubtedly be useful to have a reliable and cost-effective biomarker to inform clinical practice, in order to make a non-invasive diagnosis and to predict risk of progression to aggressive prostate cancer. Since the detection of cell-free-circulating-tumor DNA in the body fluids of prostate cancer patients, a number of studies have been conducted to assess diagnostic and/or prognostic information. In this literature review we evaluate the utility of cell-free-circulating-tumor-DNA for the development of a diagnostic and/or prognostic tool for prostate cancer. In addition, we identify potential areas for future research. Results from both quantitative and qualitative studies are presented. Expert commentary: Evidence for the suitability of a panel of DNA methylation markers for the non-invasive diagnosis of prostate cancer is strong. This panel would likely include the assessment of methylation status in gene promoter regions within the EDNR, GSTP1 and MDR genes. TIMP3 and APC show potential as diagnostic markers and should be further researched. Similarly, quantitation of cell-free-circulating-tumor-DNA in blood and urine requires further investigation.


Value of a Dedicated Saturday Orthopaedic Trauma Operating Room.
To determine the effect of an additional scheduled operative day on length of stay, distribution of caseload, waiting time to surgery, and direct variable hospital costs. Retrospective chart review. Urban level 1 trauma center. Consecutive operative tibia and femur fractures admitted from November 1, 2009, to October 31, 2011. Addition of a dedicated Saturday orthopaedic trauma operating room. Length of stay, distribution of caseload, and waiting time to surgery. The overall length of stay for all trauma patients admitted with femur or tibia fractures was significantly reduced by 2.7 days from a mean of 14.0-11.3 days (P value 0.018). Additionally, there was a trend toward shorter waiting time to surgery (average reduction of 25.1 hours) for patients admitted on a Friday (48.6 vs. 23.5 hours, P value 0.06). Furthermore, there was an increase in the number of cases performed on Saturdays by 59% (6.2% of the total caseload), whereas the originally disproportionally high number of cases on Mondays was appropriately reduced by 33% (6.7% of the total caseload). The estimated direct variable cost savings per year for the hospital was $1.13 million. Overall, these findings support the continuation of a dedicated Saturday orthopaedic trauma operating room and can provide the foundation for other departments with similar circumstances to negotiate for more dedicated operative time on weekends to improve efficiency. Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.


Enhancement of ascites during abdominal oncological endovascular intervention without iatrogenic extravasation in patients with chronic liver disease.
To evaluate ascites enhancement during abdominal oncological endovascular intervention (IVR) without iatrogenic extravasation and the factors associated with enhancement of ascites. CT images were obtained using an IVR-CT system for 73 patients with chronic liver disease and ascites. The CT images were obtained at least twice during each IVR. Radiodensity values of ascites at CT were measured for the first and last CT images in each procedure. The factors evaluated for their association with elevated ascitic fluid density were age, interval from the first to the last CT scan, Child-Pugh score, albumin level, total bilirubin level, prothrombin activity, the need for transcatheter arterial chemoembolization (TACE), estimated glomerular filtration rate, total amount of contrast material (CM) per square metre of body surface area (/m(2)), amount of ascitic fluid, and the amount of CM entering the superior mesenteric artery (SMA) or coeliac artery/m(2). The average ascitic radiodensity values for the first and last CT images were 18 and 51 HU, respectively. The percentage of patients with "significantly elevated" ascitic fluid density (≥10 HU) was 92%. Multivariate analysis showed that the total amount of CM/m(2) and the amount of ascitic fluid were significantly correlated and inversely correlated, respectively, with elevated ascitic fluid density. Ascites enhancement without extravasation frequently occurs during abdominal oncological endovascular intervention in patients with chronic liver disease.


ATP excites a subpopulation of rat dorsal horn neurones.
The peripheral receptive properties and central projections of different classes of dorsal root ganglion neurones are well characterized. Much less is known about the transmitters used by these neurones. Excitatory amino acids have been proposed as sensory transmitters but the sensitivity of virtually all central neurones to those compounds has made it difficult to assess their precise role in sensory transmission. Several neuropeptides have been localized within discrete subclasses of primary sensory neurones that project to the superficial dorsal horn of the spinal cord and may be afferent transmitters. However, only about one-third of spinal sensory neurones have been shown to contain neuropeptides. We have recently described the presence of a 5'-nucleotide hydrolysing acid phosphatase in a separate subpopulation of dorsal root ganglion neurones that project to the superficial dorsal horn. This enzyme also appears in certain autonomic and endocrine cells that contain high concentrations of releasable nucleotides in their storage granules. It is possible that the presence of this enzyme in sensory neurones is also associated with a releasable pool of nucleotides. Holton and Holton have provided evidence that ATP is released from the peripheral terminals of unmyelinated sensory fibres and have suggested that release of ATP might also occur from central sensory terminals. To investigate the possibility that nucleotides act as central sensory transmitters we have examined their actions on rat dorsal horn and dorsal root ganglion neurones maintained in dissociated cell culture. We report here a selective and potent excitation of subpopulations of both neuronal types by ATP.


A neuromuscular monitoring system based on a personal computer.
We have developed a computerized neuromuscular monitoring system (NMMS) using commercially available subsystems, i.e., computer equipment, clinical nerve stimulator, force transducer, and strip-chart recorder. This NMMS was developed for acquisition and analysis of data for research and teaching purposes. Computer analysis of the muscle response to stimulation allows graphic and numeric presentation of the twitch response and calculated ratios. Since the system can store and recall data, research data can be accessed for analysis and graphic presentation. An IBM PC/AT computer is used as the central controller and data processor. The computer controls timing of the nerve stimulator output, initiates data acquisition, and adjusts the paper speed of the strip chart recorder. The data processing functions include establishing control response values (when no neuromuscular blockade is present), displaying force versus time and calculated data graphically and numerically, and storing these data for further analysis. The general purpose nature of the computer and strip chart recording equipment allow modification of the system primarily by changes in software. For example, new patterns of nerve stimulation, such as the posttetanic count, can be programmed into the computer system along with appropriate data display and analysis routines. The NMMS has functioned well in the operating room environment. We have had no episodes of electrocautery interference with the computer functions. The automated features have enhanced the utility of the NMMS.(ABSTRACT TRUNCATED AT 250 WORDS)


Small EV in plasma of triple negative breast cancer patients induce intrinsic apoptosis in activated T cells.
Small extracellular vesicles (sEV) in TNBC patients' plasma promote T cell dysfunction and tumor progression. Here we show that tumor cell-derived exosomes (TEX) carrying surface PDL-1, PD-1, Fas, FasL, TRAIL, CTLA-4 and TGF-β1 induce apoptosis of CD8+T and CD4+T cells but spare B and NK cells. Inhibitors blocking TEX-induce receptor/ligand signals and TEX pretreatments with proteinase K or heat fail to prevent T cell apoptosis. Cytochalasin D, Dynosore or Pit Stop 2, partly inhibit TEX uptake but do not prevent T cell apoptosis. TEX entry into T cells induces cytochrome C and Smac release from mitochondria and caspase-3 and PARP cleavage in the cytosol. Expression of survival proteins is reduced in T cells undergoing apoptosis. Independently of external death receptor signaling, TEX entry into T cells induces mitochondrial stress, initiating relentless intrinsic apoptosis, which is responsible for death of activated T cells in the tumor-bearing hosts. The abundance of TEX in cancer plasma represents a danger for adoptively transferred T cells, limiting their therapeutic potential.


Diagnostic Efficacy of Contrast-Enhanced MRI in Detecting Residual or Recurrent Hepatocellular Carcinoma After Transarterial Chemoembolization: A Systematic Review and Meta-analysis.
The diagnostic efficacy of contrast-enhanced magnetic resonance imaging (CEMRI) in diagnosing residual or recurrent hepatocellular carcinoma (HCC) after transarterial chemoembolization (TACE) is currently not completely clear. To investigate the diagnostic efficacy of CEMRI in detecting residual or recurrent HCCs after TACE by meta-analysis. Systematic review and meta-analysis. A systematic literature search was performed in PubMed, Embase, Web of Science, Ovid, and the Cochrane Library database up to June 2019 to find original studies on diagnosing patients suspected of residual or recurrent HCCs after TACE with CEMRI. Thirteen studies comprising 721 nodules were finally included. 1.5T or 3.0T, CEMRI. Quality assessment of the included studies was performed by applying the Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) tool. Sensitivity and specificity were pooled with a bivariate random-effects model. Heterogeneity was assessed by the chi-square test. The potential sources of heterogeneity were explored by subgroup and publication bias analyses. The pooled sensitivity, specificity, positive likelihood ratio, negative likelihood ratio, diagnostic odds ratio, and area under the summary receiver operating characteristic (ROC) curve (AUC) of CEMRI in diagnosing residual or recurrent HCCs after TACE were 91% (95% confidence interval [CI]: 87%-96%), 93% (95% CI: 85%-97%), 12.22 (95% CI: 5.62-26.57), 0.09 (95% CI: 0.05-0.18), 126.99 (95% CI: 34.76-436.99) and 0.97 (95% CI: 0.95-0.98), respectively. Subgroup analysis revealed that CEMRI performed significantly better in prospective studies than in retrospective studies: 0.99 (95% CI: 0.96-1.00) vs. 0.95 (95% CI: 0.92-0.96) with P < 0.05. Our meta-analysis suggested that CEMRI had high diagnostic efficacy in detecting residual or recurrent HCCs after TACE and may serve as an alternative method for further evaluation after TACE. 5 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2020;52:1019-1028.


Motor memories in manipulation tasks are linked to contact goals between objects.
Skillful manipulation requires forming memories of object dynamics, linking applied force to motion. Although it has been assumed that such memories are linked to objects, a recent study showed that people can form separate memories when these are linked to different controlled points on an object (Heald JB, Ingram JN, Flanagan JR, Wolpert DM. Nat Hum Behav 2: 300-311, 2018). In that study, participants controlled the handle of a robotic device to move a virtual bar with circles (control points) on the left and right sides. Participants were instructed to move either the left or right control point to a target on the left or right, respectively, such that the required movement was constant. When these control points were paired with opposing force fields, adaptation was observed. In this previous study, both the controlled point and the target changed between contexts. To assess which of these factors is critical for learning, here, we used a similar paradigm but with a bar that automatically rotated as it was moved. In the first experiment, the bar rotated, such that the left and right control points moved to a common target. In the second experiment, the bar rotated such that a single control point moved to a target located on either the left or right. In both experiments, participants were able to learn opposing force fields applied in the two contexts. We conclude that separate memories of dynamics can be formed for different "contact goals," involving a unique combination of the controlled point on an object and the target location this point "contacts."NEW & NOTEWORTHY Skilled manipulation requires forming memories of object dynamics, previously assumed to be associated with entire objects. However, we recently demonstrated that people can form multiple motor memories when explicitly instructed to move different locations on an object to different targets. Here, we show that separate motor memories can be learned for different contact goals, which involve a unique combination of a control point and target.


Ketoacidosis in pregnancy associated with the parenteral administration of terbutaline and betamethasone. A case report.
Diabetic ketoacidosis occurred in a woman without a prior history of glucose intolerance. The condition was associated with the combined administration of terbutaline and betamethasone. The patient required insulin therapy for the remainder of her pregnancy but had no further insulin requirements postpartum.


Health promotion strategies an other clinical issues in spina bifida.
A routine approach to reviewing spina bifida helps clinicians detect problems requiring early treatment and referral. In addition, information, such as dietary and other lifestyle information can help promote a sense of health wellbeing.


Evolution of fraction 1 protein in the genus Lycopersicon.
The large- and small-subunit polypeptide composition of fraction 1 protein contained in seven species of Lycopersicon and Solanum pennellii was determined by electrofocusing. The eight species of protein had large subunits composed of three polypeptides separated by about 0.05 pH unit, but there was no difference in the isoelectric points of the clusters of three polypeptides. By this criterion, no surviving mutations have appeared in the extranuclear DNA coding for the cluster of large-subunit polypeptides during a period of evolution which generated the eight species of plants. The genus Lycopersicon appears to be much younger than its sister genus Nicotiana in the family Solanaceae, where four types of polypeptide clusters have evolved. Three different small-subunit polypeptides whose isoelectric points are coded by nuclear DNA have arisen among the seven Lycopersicon species, and L. hirsutum and S. pennellii have proteins containing single polypeptides and are therefore considered older than L. chilense, L. chimielewskii, and L. parviflorum, whose proteins contain two polypeptides. L. cheesemanii, L. pimpinellifolium, and L. esculentum (and probably L. peruvianum) seem to be the most recently evolved species since their fraction 1 proteins have small subunits composed of three polypeptides.


Sedimentation analysis of ribonucleotide reductase activity in extracts of Pseudomonas stutzeri.
Analysis of ribonucleotide reductase and DNA polymerase activities in extracts of Pseudomonas stutzeri by centrifugation in discontinuous sucrose gradients indicated that these two enzymes are associated with two different high molecular weight cellular components. In addition, 95% of the ribonucleotide reductase activity was pelleted by centrifugation of extracts for 4 hr at 200,000 X G. The reductase activity remained particulate (sedimentable) following sonication whereas some 90% of the DNA polymerase activity was rendered soluble (non-sedimentable) by this technique. This data indicate that the P. stutzeri ribonucleotide reductase is not a cytosolic enzyme, but is associated with a macromolecular component in the cell.


Nanoseconds molecular dynamics simulation of primary mechanical energy transfer steps in F1-ATP synthase.
The mitochondrial membrane protein FoF1-ATP synthase synthesizes adenosine triphosphate (ATP), the universal currency of energy in the cell. This process involves mechanochemical energy transfer from a rotating asymmetric gamma-'stalk' to the three active sites of the F1 unit, which drives the bound ATP out of the binding pocket. Here, the primary structural changes associated with this energy transfer in F1-ATP synthase were studied with multi-nanosecond molecular dynamics simulations. By forced rotation of the gamma-stalk that mimics the effect of proton motive Fo-rotation during ATP synthesis, a time-resolved atomic model for the structural changes in the F1 part in terms of propagating conformational motions is obtained. For these, different time scales are found, which allows the separation of nanosecond from microsecond conformational motions. In the simulations, rotation of the gamma-stalk lowers the ATP affinity of the betaTP binding pocket and triggers fast, spontaneous closure of the empty betaE subunit. The simulations explain several mutation studies and the reduced hydrolysis rate of gamma-depleted F1-ATPase.


[BASIC-Program for calculation of intraocular lens refracting power].
The intraocular power of various types of lenses was calculated, based on different anterior chamber depths. If the lens type planned is changed, the lens power also must be altered, therefore, it is necessary to know the individual difference in diopters. For this purpose, a special computer program in BASIC is introduced, in which there is a table that shows the refraction after implantation of different types of lenses. Possibilities for altering this program are also shown.


Loss of diurnal rhythms of blood pressure and heart rate caused by high-fat feeding.
Diet-induced obesity using ad libitum high-fat feeding in rabbits causes losses in diurnal rhythms of blood pressure (BP) and heart rate (HR). Because obesity is associated with hypertension, it is difficult to determine independent effects of ad libitum feeding and obesity in altering diurnal rhythms. We studied diurnal rhythms of BP and HR after controlling BP during obesity development using hydralazine. New Zealand white rabbits were divided into lean control (LC), lean hydralazine-treated (LH), obese control (OC), and obese hydralazine-treated (OH) groups. Lean animals consumed a maintenance diet, whereas obese animals consumed an ad libitum high-fat diet. Over 12 weeks, BP and HR were monitored from 11:00 to 07:00 using telemetry. Hydralazine treatment consisted of 6 mg/kg/day and 10 to 14 mg/kg/day for LH and OH, respectively. Diurnal rhythms were evaluated using day-night values (day, 11:00 to 16:00 average; night, 02:00 to 07:00 average). Compared with control values, diurnal HR rhythm was abolished on day 1 of high-fat feeding (61.4 +/- 3.6 v 3.1 +/- 4.2 beats/min, respectively; P <or= .05), whereas OC and OH did not differ significantly in day-night HR over 12 weeks. Compared with control values, diurnal BP rhythm was abolished by day 2 of high-fat feeding (4.6 +/- 1.6 v -0.1 +/- 0.9 mm Hg, respectively; P <or= .05), whereas OC and OH did not differ in day-night BP despite lower BP in OH. In this study ad libitum high-fat feeding in rabbits caused immediate losses of diurnal rhythms of BP and HR that were independent of weight gain and BP elevation.


Asymmetric membrane capsules for osmotic drug delivery II. In vitro and in vivo drug release performance.
In a previous paper, we described asymmetric membrane capsules and a phase inversion process for manufacturing them. In this paper, we describe the in vitro and in vivo drug release characteristics from these capsules. The capsule formulations were developed with model drugs to understand the variables that influenced drug release. Studies were also conducted to understand the drug release mechanism and it was shown that osmotic drug delivery was possible with asymmetric membrane capsules.


Prevalence of subclinical mastitis in dairy farms in urban and peri-urban areas of Kampala, Uganda.
It is widely recognized that subclinical mastitis (SCM) is an extensive problem in the dairy industry worldwide. It is of particular concern in developing countries. The aim of this study was to establish the prevalence of SCM in dairy cattle in the urban and peri-urban areas of Kampala, Uganda and to gain information about pathogens and antibiotic resistance patterns. The study was conducted as a field study in 18 smallholder dairy farms in peri-urban Kampala, Uganda. All cows at the farms were physically examined, and cows with signs of clinical mastitis were excluded. Cows (n = 195) were tested with California Mastitis Test (CMT), and udder quarters with CMT score ≥3 (scale 1-5) were milk sampled for bacteriological analysis. To allow further sub-analysis of the results, the stage of lactation, parity, milk production, production type, udder hygiene, and cow breed were recorded. Results indicate that 86.2 % (n = 168) of the tested cows had SCM in one or more quarters. The most common bacteriological outcome was infection with coagulase-negative staphylococci (54.7 %), followed by negative growth (24.9 %) and streptococci (16.2 %); all of which (n = 34) were sensitive to penicillin. Of the tested staphylococci (n = 17), the majority (58.9 %) were positive for penicillinase production. Factors with significant impact on the prevalence of SCM at cow level were the stage of lactation, parity, and production type. The results suggest that the prevalence of SCM in Uganda is substantially higher than reported in previous studies and in other comparable developing countries. This implies that SCM deserves more attention and that improvement in dairy cow husbandry in terms of hygiene and management is necessary.


Culture Media Supplemented With 10% Equine Serum Provided Chondroprotection in an In Vitro Co-Culture of Cartilage and Synovial Membrane.
No studies have evaluated the effect of culture in serum-free media (SF) vs. media supplemented with equine serum (ES) on co-culture of synovial membrane and cartilage tissue explants. The study objective was to evaluate the effects of equine serum supplementation on induced production of inflammatory and catabolic mediators from articular cartilage and synovial explants while in co-culture. Articular cartilage and synovial membrane explants were harvested from femoropatellar joints of five adult horses. Cartilage and synovial explants were harvested from the stifle of five horses, placed in co-culture, stimulated with IL-1β (10 ng/ml) and maintained in culture for 3, 6 and 9 days in 10% ES or SF. At each time point, media was harvested for analysis of cellular viability (Lactate dehydrogenase) and elution of glycosaminoglycans (Dimethylene Blue Binding Assay). Tissue explants were harvested for histopathologic and gene expression analyses. No differences in cell viability were observed between SF and ES groups. SF culture produced an upregulation of TNF-α in synovial membrane and ADAMTS-4 and five in articular cartilage at 9 days of culture. ES produced an upregulation of aggrecan expression in cartilage at 9 days of culture. No differences in tissue viability were found between culture media, but SF media produced a higher glycosaminoglycan concentration in media at 3 days of culture. The addition of 10% ES produced a slight chondroprotective effect in an inflamed co-culture system. This effect should be considered when designing studies evaluating treatment of serum or plasma-based orthobiologic studies in vitro.


Improving the evaluation of model fit in confirmatory factor analysis: A commentary on Gundy, C.M., Fayers, P.M., Groenvold, M., Petersen, M. Aa., Scott, N.W., Sprangers, M.A.J., Velikov, G., Aaronson, N.K. (2011). Comparing higher-order models for the EORTC QLQ-C30. Quality of life research, doi:10.1007/s11136-011-0082-6.
This article is a brief commentary in response to "Gundy, C.M., Fayers, P.M., Groenvold, M., Petersen, M. Aa., Scott, N.W., Sprangers, M.A.J., Velikov, G., Aaronson, N.K. (2011). Comparing higher-order models for the EORTC QLQ-C30. Quality of life research, doi: 10.1007/s11136-011-0082-6 ." The commentary argues that approximate goodness-of-fit indexes cannot be used to salvage confirmatory factor models rejected by the Chi-square test of exact fit. Instead, rigorous diagnostic procedures should be used to identify and resolve the particular sources of model misspecification.


Chloride-dependency of amyloid beta protein-induced enhancement of glutamate neurotoxicity in cultured rat hippocampal neurons.
In our previous studies, pathophysiological concentrations of amyloid-beta (Abeta) proteins increased intracellular Cl(-) concentration ([Cl(-)]i) and enhanced glutamate neurotoxicity in primary cultured neurons, suggesting Cl(-)-dependent changes in glutamate signaling. To test this possibility, we examined the effects of isethionate-replaced low Cl(-) medium on the Abeta-induced enhancement of glutamate neurotoxicity in the primary cultured rat hippocampal neurons. In a normal Cl(-) (135 mM) medium, treatment with 10 nM Abeta25-35 for 2 days increased neuronal [Cl(-)]i to a level three times higher than that of control as assayed using a Cl(-)-sensitive fluorescent dye, while in a low Cl(-) (16 mM) medium such an Abeta25-35-induced increase in [Cl(-)]i was not observed. The Abeta treatment aggravated glutamate neurotoxicity in a normal Cl(-) medium as measured by mitochondrial reducing activity and lactate dehydrogenase (LDH) release, while in a low Cl(-) medium the Abeta treatment did not enhance glutamate toxicity. Upon such Abeta plus glutamate treatment under a normal Cl(-) condition, activated anti-apoptotic molecule Akt (Akt-pS473) level monitored by Western blot significantly decreased to 74% of control. Under a low Cl(-) condition, a resting Akt-pS473 level was higher than that under a normal Cl(-) condition and did not significantly change upon Abeta plus glutamate treatment. Tyrosine phosphorylation levels of 110 and 60 kDa proteins (pp110 and pp60) increased upon Abeta plus glutamate treatment under a normal Cl(-), but not low Cl(-), condition. These findings indicated that Abeta-induced enhancement of glutamate neurotoxicity is Cl(-)-dependent. Chloride-sensitive Akt pathway and tyrosine phosphorylation of proteins (pp110 and pp60) may be involved in this process.


Effects of anticoagulants on outcome of femoral neck fracture surgery.
To review records of 330 patients who underwent surgery for femoral neck fractures with or without preoperative anticoagulation therapy. Medical records of 235 women and 95 men aged 48 to 103 years (mean, 81.6; standard deviation [SD], 13.1) who underwent surgery for femoral neck fractures with or without preoperative anticoagulation therapy were reviewed. 30 patients were on warfarin, 105 on aspirin, 28 on clopidogrel, and 167 were controls. The latter 3 groups were combined as the non-warfarin group and compared with the warfarin group. Hospital mortality, time from admission to surgery, length of hospital stay, return to theatre, and postoperative complications (wound infection, deep vein thrombosis, and pulmonary embolism) were assessed. The warfarin and control groups were significantly younger than the clopidogrel and aspirin groups (80.8 vs. 80.0 vs. 84.2 vs. 83.7 years, respectively, p<0.05). 81% of the patients underwent surgery within 48 hours of admission. The overall mean time from admission to surgery was 1.8 days; it was longer in the warfarin than the aspirin, clopidogrel, and control groups (3.3 vs. 1.8 vs. 1.6 vs. 1.6 days, respectively, p<0.001). The mean length of hospital stay was 17.5 (SD, 9.6; range, 3-54) days. The overall hospital mortality was 3.9%; it was 6.7% in the warfarin group, 3.8% in the aspirin group, 3.6% in the clopidogrel group, and 3.6% in the control group (p=0.80). Four patients returned to theatre for surgery: one in the warfarin group for washout of a haematoma, 2 in the aspirin group for repositioning of a mal-fixation and for debridement of wound infection, and one in the control group for debridement of wound infection. The warfarin group did not differ significantly from non-warfarin group in terms of postoperative complication rate (6.7% vs. 2.7%, p=0.228) and the rate of return to theatre (3.3% vs. 1%, p=0.318). It is safe to continue aspirin and clopidogrel prior to surgical treatment for femoral neck fracture. The risk of delaying surgery outweighs the peri-operative bleeding risk.


Association of egg intake with risks of cardiometabolic factors among adults in China.
To explore the association between egg intake and cardiometabolic factors (CMFs) in Chinese adults. The subjects were 6,182 adults aged 18-64 who had complete survey data and had no CMFs at baseline. Egg intake was assessed with 3 days-24 h dietary recalls in all waves of the China Health and Nutrition Survey (CHNS). Multivariate Cox proportional risk regression model and restricted cubic spline (RCS) model were used to analyze the association and dose-response relationship between egg intake and CMFs. Of the 6,182 participants who did not have metabolic syndrome (MetS) at baseline, 1,921 developed this disease during an average follow-up of 5.71 years, with an incidence of 31.07%. Central obesity, elevated TG, decreased HDL-C, elevated blood pressure and elevated plasma glucose were 38.65, 26.74, 30.21, 40.64, and 30.64%, respectively. After adjusting for demographic characteristics, lifestyle, energy and BMI, using the lowest quintile (Q1) as a reference, the risk of central obesity, elevated TG, decreased HDL-C, and elevated plasma glucose in the highest quintile (Q5) were reduced by 15% (HR = 0.85, 95% CI = 0.73-0.98, P = 0.16), 33% (HR = 0.67, 95% CI = 0.57-0.78), 25% (HR = 0.75, 95% CI = 0.63 0.90, p = 0.05), and 28% (HR = 0.72, 95% CI = 0.63-0.83, p < 0.05), respectively. The risk of elevated blood pressure was reduced by 26% in the fourth quintile (HR = 0.74, 95% CI = 0.64-0.85, P = 0.85). RCS analysis show that the overall correlation and nonlinear relationship between egg intake and CMFs were statistically significant (P < 0.05). When the intake was lower than 20 g/days, the risk of MetS, central obesity, elevated blood pressure and elevated plasma glucose were negatively correlated with egg intake, while elevated TG was negatively correlated with eggs when the intake was lower than 60 g/days. There was no statistically significant association between egg intake and CMFs at higher egg intake. There was a U-shaped association between egg intake and CMFs in Chinese adults.


Ultrasound enhancement of fibrinolysis at frequencies of 27 to 100 kHz.
Ultrasound (US) accelerates enzymatic fibrinolysis in vitro and in animal models, and may be a useful adjunctive therapy for clinical thrombolysis. Successful clinical application will depend on the selection of appropriate US parameters to optimize fibrinolytic enhancement while limiting adverse effects, including heating. Most studies have been done at megahertz frequencies, but tissue penetration is better and heating less at lower frequencies. We have, therefore, now investigated the effects of continuous-wave and pulsed US on fibrinolysis at midkilohertz frequencies. Fibrinolysis with tissue plasminogen activator (t-PA) was measured by solubilization of radiolabeled fibrin exposed to a calibrated US field in a temperature-controlled water bath. There was significant enhancement of fibrinolysis at frequencies of 27, 40 and 100 kHz, with the greatest effect observed at 27 kHz. The largest effect was observed with continuous-wave US, but significant acceleration was also observed with peak intensities of 1 W/cm(2) duty cycles of 10% and 1%. At a 10% duty cycle, there was approximately 60% of the fibrinolytic enhancement observed with continuous-wave exposure, indicating a clear advantage of pulsing to optimize fibrinolytic effect and limit exposure. We conclude that US in the range of 27 to 100 kHz is effective in accelerating fibrinolysis at intensities and pulsing conditions that minimize the probability of heating and cavitation in clinical applications.


Trends in Use of Medication to Treat Opioid Use Disorder During the COVID-19 Pandemic in 10 State Medicaid Programs.
Federal and state agencies granted temporary regulatory waivers to prevent disruptions in access to medication for opioid use disorder (MOUD) during the COVID-19 pandemic, including expanding access to telehealth for MOUD. Little is known about changes in MOUD receipt and initiation among Medicaid enrollees during the pandemic. To examine changes in receipt of any MOUD, initiation of MOUD (in-person vs telehealth), and the proportion of days covered (PDC) with MOUD after initiation from before to after declaration of the COVID-19 public health emergency (PHE). This serial cross-sectional study included Medicaid enrollees aged 18 to 64 years in 10 states from May 2019 through December 2020. Analyses were conducted from January through March 2022. Ten months before the COVID-19 PHE (May 2019 through February 2020) vs 10 months after the PHE was declared (March through December 2020). Primary outcomes included receipt of any MOUD and outpatient initiation of MOUD via prescriptions and office- or facility-based administrations. Secondary outcomes included in-person vs telehealth MOUD initiation and PDC with MOUD after initiation. Among a total of 8 167 497 Medicaid enrollees before the PHE and 8 181 144 after the PHE, 58.6% were female in both periods and most enrollees were aged 21 to 34 years (40.1% before the PHE; 40.7% after the PHE). Monthly rates of MOUD initiation, representing 7% to 10% of all MOUD receipt, decreased immediately after the PHE primarily due to reductions in in-person initiations (from 231.3 per 100 000 enrollees in March 2020 to 171.8 per 100 000 enrollees in April 2020) that were partially offset by increases in telehealth initiations (from 5.6 per 100 000 enrollees in March 2020 to 21.1 per 100 000 enrollees in April 2020). Mean monthly PDC with MOUD in the 90 days after initiation decreased after the PHE (from 64.5% in March 2020 to 59.5% in September 2020). In adjusted analyses, there was no immediate change (odds ratio [OR], 1.01; 95% CI, 1.00-1.01) or change in the trend (OR, 1.00; 95% CI, 1.00-1.01) in the likelihood of receipt of any MOUD after the PHE compared with before the PHE. There was an immediate decrease in the likelihood of outpatient MOUD initiation (OR, 0.90; 95% CI, 0.85-0.96) and no change in the trend in the likelihood of outpatient MOUD initiation (OR, 0.99; 95% CI, 0.98-1.00) after the PHE compared with before the PHE. In this cross-sectional study of Medicaid enrollees, the likelihood of receipt of any MOUD was stable from May 2019 through December 2020 despite concerns about potential COVID-19 pandemic-related disruptions in care. However, immediately after the PHE was declared, there was a reduction in overall MOUD initiations, including a reduction in in-person MOUD initiations that was only partially offset by increased use of telehealth.


Skinflammation and drug toxicity--a delicate balance.
Loss of epidermal growth factor receptor function in epidermal keratinocytes triggers a disfiguring acneiform rash through the coordinate activation of innate and adaptive immune defense mechanisms (Mascia et al. and Lichtenberger et al., this issue).


Risk stratification of clinically relevant delayed gastric emptying after pancreaticoduodenectomy.
Delayed gastric emptying (DGE) remains one of the major complications after pancreaticoduodenectomy (PD), with discrepant reports of its contributing factors. This study aimed to develop a nomogram to identify potential predictors and predict the probability of DGE after PD. This retrospective study enrolled 422 consecutive patients who underwent PD from January 2019 to December 2021 at our institution. The LASSO algorithm and multivariate logistic regression were performed to identify independent risk and protective factors associated with clinically relevant delayed gastric emptying (CR-DGE). A nomogram was established based on the selected variables. Then, the calibration curve, ROC curve, decision curve analysis (DCA), and clinical impact curve (CIC) were applied to evaluate the predictive performance of our model. Finally, an independent cohort of 45 consecutive patients from January 2022 to March 2022 was enrolled to further validate the nomogram. Among 422 patients, CR-DGE occurred in 94 patients (22.2%). A previous history of chronic gastropathy, intraoperative plasma transfusion ≥ 400 ml, end-to-side gastrointestinal anastomosis, intra-abdominal infection, incisional infection, and clinically relevant postoperative pancreatic fistula (CR-POPF) were identified as risk predictors. Minimally invasive pancreaticoduodenectomy (MIPD) was demonstrated to be a protective predictor of CR-DGE. The areas under the curve (AUCs) were 0.768 (95% CI, 0.706-0.830) in the development cohort, 0.766 (95% CI, 0.671-0.861) in the validation cohort, and 0.787 (95% CI, 0.633-0.940) in the independent cohort. Then, we built a simplified scale based on our nomogram for risk stratification. Our study identified seven predictors and constructed a validated nomogram that effectively predicted CR-DGE for patients who underwent PD.


Investigating structural changes in the lipid bilayer upon insertion of the transmembrane domain of the membrane-bound protein phospholamban utilizing 31P and 2H solid-state NMR spectroscopy.
Phospholamban (PLB) is a 52-amino acid integral membrane protein that regulates the flow of Ca(2+) ions in cardiac muscle cells. In the present study, the transmembrane domain of PLB (24-52) was incorporated into phospholipid bilayers prepared from 1-palmitoyl-2-oleoyl-sn-glycero-phosphocholine (POPC). Solid-state (31)P and (2)H NMR experiments were carried out to study the behavior of POPC bilayers in the presence of the hydrophobic peptide PLB at temperatures ranging from 30 degrees C to 60 degrees C. The PLB peptide concentration varied from 0 mol % to 6 mol % with respect to POPC. Solid-state (31)P NMR spectroscopy is a valuable technique to study the different phases formed by phospholipid membranes. (31)P NMR results suggest that the transmembrane protein phospholamban is incorporated successfully into the bilayer and the effects are observed in the lipid lamellar phase. Simulations of the (31)P NMR spectra were carried out to reveal the formation of different vesicle sizes upon PLB insertion. The bilayer vesicles fragmented into smaller sizes by increasing the concentration of PLB with respect to POPC. Finally, molecular order parameters (S(CD)) were calculated by performing (2)H solid-state NMR studies on deuterated POPC (sn-1 chain) phospholipid bilayers when the PLB peptide was inserted into the membrane.


Analysis of N-benzoyl-L-tyrosyl-p-aminobenzoic acid (bentiromide) metabolites in urine by ion-pair high-performance liquid chromatography.
A high-performance liquid chromatographic method is described for the analysis of bentiromide metabolites in urine. The procedure involves no more than direct injection of the diluted urine sample, obviating the need for an extraction step or an internal standard. A mu Bondapak C18 column is used with a mobile phase of 0.01 M tetrabutylammonium chloride (pH 7.4)--methanol (9:1). A flow-rate of 1.4 ml/min, detection at 254 nm and column temperature of 40 degrees C are employed. These conditions were achieved by investigating the effects of mobile phase pH, and concentrations and types of organic modifiers, buffers and ion-pairing agents on the resolution of the metabolites. The analysis time is 18 min per sample and the coefficient of variation on replicate assays is less than 10% for most concentrations studied. Analytical recoveries were between 95 and 100% throughout the appropriate concentration ranges and no interferences were obtained with the exception of p-acetamidobenzoyl glucuronide which could be eliminated by treatment of the samples with beta-glucuronidase. Concentration profiles of the metabolites were studied in normal subjects, and the method was found to be potentially useful for clinical situations in which the existing bentiromide test leads to ambiguous results because of small bowel and hepatic dysfunctions.


Effects of e-aid cognitive behavioural therapy for insomnia (eCBTI) to prevent the transition from acute insomnia to chronic insomnia: study protocol for a randomised controlled trial.
Previous evidence suggested that online self-guided sleep intervention is efficacious in improving treatment outcomes in patients with chronic insomnia [corrected]. However, research on online sleep interventions targeting acute insomnia [corrected] has been scarce. This study aims to evaluate the effectiveness of brief e-aid cognitive behavioural therapy for insomnia (eCBTI) in preventing transition from acute insomnia to chronic insomnia [corrected]. This is a pragmatic two-arm multicentre, randomised controlled trial comparing eCBTI with treatment as usual (TAU) in outpatients. Two hundred patients with acute insomnia [corrected] (as defined by DSM-5) will be recruited. Patients will be randomly assigned to receive 1 week eCBTI via a Smartphone application, or to receive TAU. Treatment effects will be assessed at 1 week and 3 months after intervention. The primary outcome of the study, whether the eCBTI program is sufficient in preventing transition from short-term to chronic insomnia [corrected], is measured by the Insomnia Severity Index. Secondary outcome measurements include the Dysfunctional Beliefs and Attitudes about Sleep Scale, Ford Insomnia Response to Stress Test, Sleep Hygiene and Practices Scale, Pre-sleep Arousal Scale and Epworth Sleepiness Scale. Additionally, the Hospital Anxiety and Depression Scale and the Short-Form 12-Item Health Survey will be used for measurement of mood symptoms and quality of life. Ethical approval for the study has been obtained from the Ethics Committee of Southern Medical University (reference number: NFEC-2017-131). The results of the investigation will be published in scientific papers. The data from the investigation will be made available online if necessary. NCT03302455 (clinicaltrials.gov). Date of registration: October 5, 2017.


The effects of pentoxifylline on the relative perfusion of tumours growing in three sites in the mouse.
The haemorheological agent pentoxifylline (PTX) has been shown to improve the relative perfusion and oxygenation of subcutaneous tumours in the mouse. In order to establish whether this effect is dependent on the site of tumour growth, we have looked at changes in the distribution of the cardiac output (COD) to the murine NT carcinoma grown either intradermally (i.d.), intramuscularly (i.m.), on the wall of the caecum, or in all three sites, following i.p. administration of 50 mg kg-1 PTX. In animals bearing a single tumour, PTX treatment significantly increases the COD to tumours located in the caecum, but has no significant effect on the COD to those located in the i.d. or i.m. sites. If all three tumours are present in a single animal, the COD to all three tumours is significantly enhanced by PTX. This appears to reflect the presence of the caecum tumour and does not appear to relate to changes in tumour size or to the haematocrit (HCT) of the blood. We propose that this site dependency implies that a significant increase in blood viscosity only occurs in animals with tumours located in specific sites. Therefore, the potential radiosensitising capability of PTX is highly dependent on tumour location.


Monoclonal antibodies to human DNA topoisomerase I and the two isoforms of DNA topoisomerase II: 170- and 180-kDa isozymes.
Several monoclonal antibodies of different isotypes specific to human DNA topoisomerase I, to 170- and 180-kDa DNA topoisomerase II isozymes, were produced and characterized. The specificity of monoclonal antibodies was confirmed by comparison with polyclonal antibodies by Western blot, by immunoprecipitation of enzyme activity, and by immunoprecipitation of DNA topoisomerases with characterized polyclonal antisera. Morphological studies performed by immunofluorescence indicate that the three groups of monoclonal antibodies (MoAbs) stain the nucleus with characteristic patterns, which can be compared with those obtained with polyclonal antibodies. In particular the MoAbs to the 100-kDa DNA topoisomerase I stain the nucleolus and the nucleoplasm; the MoAbs to 170- and 180-kDa DNA topoisomerase II give completely distinct intranuclear patterns: those to the 170-kDa protein stain mainly the nucleoplasm, whereas those to the 180-kDa protein stain only the nucleolus. The two DNA topoisomerase II isozymes clearly exhibit fluctuations in their expression during cell growth: the 170-kDa isozyme is more abundant during the logarithmic phase of growth, while the 180-kDa isozyme is mainly present during the plateau phase of growth.


Neurocognitive effects of a training program for poor face recognizers using shape and texture caricatures: A pilot investigation.
Recent research suggested disproportional usage of shape information by people with poor face recognition, although texture information appears to be more important for familiar face recognition. Here, we tested a training program with faces that were selectively caricatured in either shape or texture parameters. Forty-eight young adults with poor face recognition skills (1 SD below the mean in at least 2/3 face processing tests: CFMT, GFMT, BFFT) were pseudo-randomly assigned to either one of two training groups or a control group (n = 16 each). Training comprised six sessions over three weeks. Per session, participants studied ten unfamiliar facial identities whose shape or texture characteristics were caricatured. Before and after training (or waiting in the control group), all participants completed EEG experiments on face learning and famous face recognition, and behavioral face processing tests. Results showed small but specific training-induced improvements: Whereas shape training improved face matching (training tasks, and to some extent GFMT), texture training elicited marked improvements in face learning (CFMT). Moreover, for the texture training group the N170 ERP was enhanced for novel faces post-training, suggesting training-induced changes in early markers of face processing. Although further research is necessary, this suggests that parameter-specific caricature training is a promising way to improve performance in people with poor face recognition skills.


Genome Sequence of a Novel Polymer-Grade L-Lactate-Producing Alkaliphile, Exiguobacterium sp. Strain 8-11-1.
Exiguobacterium sp. strain 8-11-1 is a newly isolated alkaliphile, which was reported to efficiently produce l-lactate using NaOH as the neutralizing agent. Here, we present the first 2.9-Mb assembly of its genome sequence, which may provide useful information related to its efficient lactate production and sodium ion tolerance capacities.


A Prospective Trial to Assess the Efficacy of Eye-Tracking-Based Binocular Treatment versus Patching for Children's Amblyopia: A Pilot Study.
To assess visual acuity (VA) and stereoacuity (SA) improvements in children with amblyopia treated with either binocular dichoptic treatment or patching treatment. In this pilot prospective coherent study, 34 participants between 4 and 9 years of age with unilateral anisometropic amblyopia and without history of prior amblyopia treatment were enrolled into three groups. Full treatment group (FTG; n = 12): participants were prescribed the binocular dichoptic treatment to watch for 90 minutes per day, 5 days a week. Part-time treatment group (PTTG; n = 8): participants were prescribed the same binocular treatment as FTG, 90 minutes per day, 3 days per week. Patching treatment group (PTG; n = 14): participants wore an adhesive patch over the dominant eye for 2 hours per day, 7 days per week. Amblyopic-eye distance visual acuity (DVA), near visual acuity (NVA) and SA were evaluated at baseline, 4, 8, and 12 weeks. At 12 weeks, mean amblyopic-eye DVA improved 1.8 lines (95% CI, 1.1-2.5) in FTG, 1.5 lines (95% CI, 0.4-2.7) in PTTG and 3.0 lines (95% CI, 2.0-4.0) in PTG. The amblyopic-eye NVA improved 2.9 lines (95% CI, 2.4-3.5) in FTG, 1.7 lines (95% CI, 0.5-3.0) in PTTG and 2.8 lines (95% CI, 1.8-3.9) in PTG. The SA improved 0.38 log-arcseconds (95% CI, 0.24-0.53) in FTG, 0.59 log-arcseconds (95% CI, 0.36-0.82) in PTTG and 0.40 log-arcseconds (95% CI, 0.13-0.67) in PTG. No significant differences were found in DVA, NVA or SA improvement between FTG and PTG at 12 weeks. VA and SA after binocular dichoptic treatment produced a similar therapeutic outcome to patching, suggesting a potential value for binocular therapy when treating anisometropic moderate degree of Children's amblyopia.


Hyperpnoea and CO2 sensitivity of the respiratory centres during exercise.
The aim of this study was to specify whether exercise hyperpnoea was related to the CO2 sensitivity of the respiratory centres measured during steady-state exercise of mild intensity. Thus, ventilation (VE), breathing pattern [tidal volume (VT), respiratory frequency (f), inspiratory time (TI), total time of the respiratory cycle (TTOT), VT/TI, TI/TTOT] and CO2 sensitivity of the respiratory centres determined by the rebreathing method were measured at rest (SCO2re) and during steady-state exercise (SCO2ex) of mild intensity [CO2 output (VCO2) = 20 ml.kg-1.min-1] in 11 sedentary male subjects (aged 20-34 years). The results showed that SCO2re and SCO2ex were not significantly different. During exercise, there was no correlation between VE and SCO2ex and, for the same VCO2, all subjects had very close VE values normalized for body mass (bm), regardless of their SCO2ex (VEbm0.75 = 1.44 l.min-1.kg-1 SD 0.10). A highly significant positive correlation between SCO2ex and VT (normalised for bm) (r = 0.80, P less than 0.01), TI (r = 0.77, P less than 0.01) and TTOT (r = 0.77, P less than 0.01) existed, as well as a highly significant negative correlation between SCO2ex and (normalised for bm-0.25) (r = -0.73, P less than 0.01). We conclude that the hyperpnoea during steady-state exercise of mild intensity is not related to the SCO2ex. The relationship between breathing pattern and SCO2ex suggests that the breathing pattern could influence the determination of the SCO2ex. This finding needs further investigation.


Decreased cyclic GMP levels in rat cecum mucosa during adaptive stimulation of Na-K-ATPase.
In rat cecal mucosa, Na-K-ATPase specific activity and sodium and fluid absorption were increased by giving polyethylene glycol administration with the drinking water. Whereas cyclic AMP levels were unchanged, cyclic GMP was reduced by about 50%. This finding suggests a regulatory role of cyclic GMP in intestinal sodium and fluid absorption.


Results of the international Pu-2000 exercise for plutonium isotopic composition measurements.
An international comparison for plutonium isotopic composition measurement, known as the Pu-2000 exercise, was organized by the ESARDA NDA-WG (European Safeguards Research and Development Association, Working Group on Techniques and Standards for Non-Destructive Assay). The aim of this comparison was to test X- and gamma-ray spectrometry methods over a large range of isotopic ratios. These methods are based on the complex analysis of several X- and gamma-rays in the KX region of the plutonium spectrum and also in the 120-700 keV energy range. The results obtained by the participants with their corresponding uncertainties are presented in this document and compared to the declared values. The main conclusions of the work are also given. No important bias due to an inadequate knowledge of the nuclear data for plutonium isotopes was observed.


Screening of siblings to patients with abdominal aortic aneurysms in Sweden.
The prevalence of Abdominal Aortic Aneurysm (AAA) is higher for First Degree Relatives to AAA-patients compared to the general population, regardless of sex. The prevalence of AAA is also higher in the North of Sweden compared to the Mid and South. A regional strong hereditary trait has been suggested as an explanation to this. The aim of this study was to investigate if siblings to AAA-patients in the North have a higher prevalence of AAA compared to siblings in the Mid-region. Cohort study. All patients treated for AAA in a northern region (Norrbotten county, North) were screened for siblings. Consenting siblings, age 40-80, were examined (n = 379) with ultrasound. The results were compared to the previously published results of 150 ultrasound-screened siblings in the Mid-region (Stockholm county). The male/female ratio in the sibling cohort was 48% vs 52%. The prevalence of AAA in siblings in the North was 37/379 (brothers 14%, sisters 6%). This was not different from the prevalence among the Mid-region siblings 16/150 (brothers 17%, sisters 6% (p = 0.75). The distribution of risk factors was similar in the two regions. The results reinforce the importance of a more systematic approach towards selective screening of all siblings to AAA patients. Ultrasound should be performed in all eligible siblings, since the distribution of AAA is similar over regions. A correlation between the familial distribution and the reported high prevalence of AAA in general population in the North could not be shown.


Perceptual category learning in autism spectrum disorder: Truth and consequences.
The ability to categorize is fundamental to cognitive development. Some categories emerge effortlessly and rapidly while others can take years of experience to acquire. Children with autism spectrum disorder (ASD) are often able to name and sort objects, suggesting that their categorization abilities are largely intact. However, recent experimental work shows that the categories formed by individuals with ASD may diverge substantially from those that most people learn. This review considers how atypical perceptual category learning can affect cognitive development in children with ASD and how atypical categorization may contribute to many of the socially problematic symptoms associated with this disorder. Theoretical approaches to understanding perceptual processing and category learning at both the behavioral and neural levels are assessed in relation to known alterations in perceptual category learning associated with ASD. Mismatches between the ways in which children learn to organize perceived events relative to their peers and adults can accumulate over time, leading to difficulties in communication, social interactions, academic performance, and behavioral flexibility.


P53-response circRNA_0006420 aggravates lung cancer radiotherapy resistance by promoting formation of HUR/PTBP1 complex.
p53 wild-type lung cancer cells can develop radiation resistance. Circular RNA (circRNA) consists of a family of transcripts with exclusive structures. circRNA is critical in tumorigenesis and is a potential biomarker or therapeutic target. It is uncertain how circRNA expression and functions are regulated post-radiation in p53 wild-type cancer cells. A549 or H1299 cells were divided into p53-wt and p53-KO groups by CRISPR/Cas9; both groups were subjected to 4 Gy ionizing radiation (IR: p53-wt-IR and p53-KO-IR). RNA-seq, CCK8, cell cycle, and other functional and mechanism experiments were performed in vivo. p53 gene knockout mice were generated to test the cell results in vitro. circRNAs were found in differential groups. circRNA_0006420 (IRSense) was upregulated in p53-wt cells but had the same expression level as p53-KO cells after radiation, indicating that p53 silencing prevents its upregulation after IR. In the presence of p53, upregulated IRSense post-radiation induces G2/M arrest by regulating DNA damage repair (DDR) pathway-related proteins. Meanwhile, upregulated IRSense post-radiation aggravates the radiation-induced epithelial-mesenchymal transition (EMT). Interestingly, in the presence of p53, it promotes IRSense/HUR/PTBP1 complex formation resulting in the promotion of the radiation-induced EMT. Moreover, c-Jun regulates the upregulation of p53 transcription after radiation treatment. For these lung cancer cells with p53, upregulated IRSense aggravates lung cancer cell proliferation and increases radiation resistance by interacting with HUR (ElAV-like protein 1) and PTBP1 (polypyrimidine tract-binding protein 1) in the nucleus. Lung cancer cells retaining p53 may upregulate circRNA_0006420 (IRSense) expression post radiation to form an IRSense/HUR/PTBP1 complex leading to radiotherapy resistance. This study furthers our understanding of the roles of circRNA in regulating the effect of radiotherapy and provides novel therapeutic avenues for effective clinical lung cancer therapies.


Elevated 4R-tau in astrocytes from asymptomatic carriers of the MAPT 10+16 intronic mutation.
The microtubule-associated protein tau gene (MAPT) 10+16 intronic mutation causes frontotemporal lobar degeneration (FTLD) by increasing expression of four-repeat (4R)-tau isoforms. We investigated the potential role for astrocytes in the pathogenesis of FTLD by studying the expression of 4R-tau. We derived astrocytes and neurons from induced pluripotent stem cells from two asymptomatic 10+16 carriers which, compared to controls, showed persistently increased 4R:3R-tau transcript and protein ratios in both cell types. However, beyond 300 days culture, 10+16 neurons showed less marked increase of this 4R:3R-tau transcript ratio compared to astrocytes. Interestingly, throughout maturation, both 10+16 carriers consistently displayed different 4R:3R-tau transcript and protein ratios. These elevated levels of 4R-tau in astrocytes implicate glial cells in the pathogenic process and also suggests a cell-type-specific regulation and may inform and help on treatment of pre-clinical tauopathies.


The transcriptional control of female puberty.
The initiation of mammalian puberty requires a sustained increase in pulsatile release of gonadotrophin releasing hormone (GnRH) from the hypothalamus. This increase is brought about by coordinated changes in transsynaptic and glial-neuronal communication, consisting of an increase in neuronal and glial stimulatory inputs to the GnRH neuronal network and the loss of transsynaptic inhibitory influences. GnRH secretion is stimulated by transsynaptic inputs provided by excitatory amino acids (glutamate) and at least one peptide (kisspeptin), and by glial inputs provided by growth factors and small bioactive molecules. The inhibitory input to GnRH neurons is mostly transsynaptic and provided by GABAergic and opiatergic neurons; however, GABA has also been shown to directly excite GnRH neurons. There are many genes involved in the control of these cellular networks, and hence in the control of the pubertal process as a whole. Our laboratory has proposed the concept that these genes are arranged in overlapping networks internally organized in a hierarchical fashion. According to this concept, the highest level of intra-network control is provided by transcriptional regulators that, by directing expression of key subordinate genes, impose genetic coordination to the neuronal and glial subsets involved in initiating the pubertal process. More recently, we have begun to explore the concept that a more dynamic and encompassing level of integrative coordination is provided by epigenetic mechanisms.


Differentiating the aging of the mitral valve from human and canine myxomatous degeneration.
During the course of both canine and human aging, the mitral valve remodels in generally predictable ways. The connection between these aging changes and the morbidity and mortality that accompany pathologic conditions has not been made clear. By exploring work that has investigated the specific valvular changes in both age and disease, with respect to the cells and the extracellular matrix found within the mitral valve, heretofore unexplored connections between age and myxomatous valve disease can be found. This review addresses several studies that have been conducted to explore such age and disease related changes in extracellular matrix, valvular endothelial and interstitial cells, and valve innervation, and also reviews attempts to correlate aging and myxomatous disease. Such connections can highlight avenues for future research and help provide insight as to when an individual diverts from an aging pattern into a diseased pathway. Recognizing these patterns and opportunities could result in earlier intervention and the hope of reduced morbidity and mortality for patients.


Comparison of membrane phospholipid and its fatty acid compositions in developing rat salivary glands.
1. Membrane phospholipid and its fatty acid compositions have been analyzed in 3- and 9-week-old rat salivary glands. 2. When compared between the three major glands (parotid, submandibular, sublingual) in adult rats, phospholipid compositions were similar, but for their fatty acid, characteristic properties from each phospholipid were shown. 3. Alterations in their compositions were also observed during development of the salivary glands.


Ischemic-hypoxic mechanisms leading to hippocampal dysfunction as a consequence of status epilepticus.
Status epilepticus (SE) is one of the recognized primary precipitating events that can lead to temporal lobe epilepsy (TLE) associated with hippocampal sclerosis. This type of epilepsy is characterized by poor response to drug treatment, often requiring surgical intervention to remove the mesial temporal regions involved in the seizure onset. However, even neurosurgery may not be completely successful. Thus, the prevention of hippocampal damage and epileptogenesis is currently evaluated as a possible alternative therapeutic approach to prevent the development of pharmacoresistant TLE. Lines of evidence suggest that ischemic-hypoxic lesions might occur in different brain regions, including the hippocampus, during SE. Especially in the hippocampal CA3 region, an ischemic-like lesion develops in the stratum lacunosum-moleculare and is mainly characterized by a loss of astrocytes and neuronal processes and increased immunostaining of pimonidazole which probes areas exposed to hypoxia. Interestingly, these mechanisms can contribute to neuronal cell loss and may be counteracted by drugs that can afford vascular protection, as in the case of ligands of the ghrelin receptor. Notably, some of the ghrelin receptor ligands possess a double edge effect, since they are anticonvulsant and vascular-protective, thus, potentially representing new tools to counteract the consequences of SE. This article is part of a Special Issue entitled "Status Epilepticus".


Impact of universal testing and treatment on sexual risk behaviour and herpes simplex virus type 2: a prespecified secondary outcomes analysis of the HPTN 071 (PopART) community-randomised trial.
Comprehensive HIV prevention strategies have raised concerns that knowledge of interventions to reduce risk of HIV infection might mitigate an individual's perception of risk, resulting in riskier sexual behaviour. We investigated the prespecified secondary outcomes of the HPTN 071 (PopART) trial to determine whether a combination HIV prevention strategy, including universal HIV testing and treatment, changed sexual behaviour; specifically, we investigated whether there was evidence of sexual risk compensation. HPTN 071 (PopART) was a cluster-randomised trial conducted during 2013-18, in which we randomly assigned 21 communities with high HIV prevalence in Zambia and South Africa (total population, approximately 1 million) to combination prevention intervention with universal antiretroviral therapy (ART; arm A), prevention intervention with ART provided according to local guidelines (universal since 2016; arm B), or standard of care (arm C). The trial included a population cohort of approximately 2000 randomly selected adults (aged 18-44 years) in each community (N=38 474 at baseline) who were followed up for 36 months. A prespecified secondary objective was to evaluate the impact of the PopART intervention compared with standard of care on herpes simplex virus type 2 (HSV-2) and sexual behaviour (N=20 422 completed final visit). Secondary endpoints included differences in sexual risk behaviour measures at 36 months and were assessed using a two-stage method for matched cluster-randomised trials. This trial is registered with ClinicalTrials. gov, number NCT01900977. The PopART intervention did not substantially change probability of self-reported multiple sex partners, sexual debut, or pregnancy in women at 36 months. Adjusted for baseline community prevalence, reported condomless sex was significantly lower in arm A versus arm C (adjusted prevalence ratio 0·80 [95% CI 0·64-0·99]; p=0·04) but not in arm B versus arm C (0·94 [0·76-1·17]; p=0·55). 3-year HSV-2 incidence was reduced in arm B versus arm C (adjusted risk ratio 0·76 [95% CI 0·63-0·92]; p=0·010); no significant change was shown between arm A versus arm C (0·89 [0·73-1·08]; p=0·199). We found little evidence of any change in sexual behaviour owing to the PopART interventions, and reassuringly for public health, we saw no evidence of sexual risk compensation. The findings do not help to explain the differences between the two intervention groups of the HPTN 071 (PopART) trial. National Institute of Allergy and Infectious Diseases, the National Institutes of Health, the International Initiative for Impact Evaluation (3ie), the Bill & Melinda Gates Foundation, the US President's Emergency Plan for AIDS Relief, and the Medical Research Council UK.


Pulsed ultraviolet (PUV) disinfection of artificially contaminated seawater seeded with high levels of pathogen disease indicators as an alternative for the shellfish industry depuration systems.
The increase in pathogen levels in seawater threatens the safety of entire aquatic ecosystems. Foodborne pathogens can potentially accumulate in shellfish, especially in filter feeders such as bivalves, requiring an efficient depuration process before consumption. Alternative approaches to promote a cost-efficient purge at depuration plants are urgently needed. A small prototype pulsed ultraviolet (PUV) light recirculation system was designed, and its depuration potential was tested in a seawater matrix artificially contaminated with high levels of microbial pathogens Escherichia coli, Staphylococcus aureus, Salmonella typhimurium, Bacillus cereus and Candida albicans. The analysis of treatment parameters including voltage, number of pulses and duration of treatment was performed to ensure the highest reduction in contaminant levels. Optimal PUV disinfection was attained at 60 pulses/min at 1 kV for 10 min (a UV output of 12.9 J/cm2). All reductions were statistically significant, and the greatest was observed for S. aureus (5.63 log10), followed by C. albicans (5.15 log10), S. typhimurium (5 log10), B. cereus (4.59 log10) and E. coli (4.55 log10). PUV treatment disrupted the pathogen DNA with the result that S. aureus, C. albicans and S. typhimurium were not detectable by PCR. Regulations were reviewed to address the applicability of PUV treatment as a promising alternative to assist in the reduction of microbial pathogens at depuration plants due to its high efficiency, short treatment period, high UV dose and recirculation system as currently employed in shellfish depuration plants.


Different photoreduction processes of Cr(VI) on cellulose-rich and lignin-rich biochar.
In this study, a series of biochar were prepared via pyrolyzing cellulose-rich pakchoi (PBC) and lignin-rich corncob (CBC) to explore the photoreduction process of Cr(VI). X-ray photoelectron spectroscopy and Fourier transform infrared spectroscopy confirmed higher oxygenated functional groups in PBC (48.9%-57.1%), whereas CBC exhibited more aromatization properties due to the stable aromatic network in lignin. For PBC, the valence bands decreased from 1.42 eV to 1.20 eV with the increase of pyrolysis temperature from 300 °C to 500 °C; however, an opposite trend was observed for CBC. The photoreduction of Cr(VI) clearly showed that both PBC and CBC had the best performance at the carbonization temperature of 300 °C (named PBC300 and CBC300). It is noted that PBC300 exhibited the most effective photoreduction of Cr(VI), which was about 1.3 times higher than that of CBC300. The maximum reduction capacities of Cr(VI) were 68.2 mg g-1 on PBC300 and 66.1 mg g-1 on CBC300 at pH∼2.0. Compared with the insoluble char substances, dissolved black carbons made more contributions for Cr(VI) photoreduction, ∼70% in PBC and almost 100% in CBC, which suggested that in the case of PBC, the insoluble char and the corresponding dissolved black carbons play an important role in the photoreduction of Cr(VI). However, only dissolved black carbons contributed to Cr(VI) photoreduction on CBC. As the key reaction pathway, the interfacial electron transport dominated Cr(VI) reduction on PBC and CBC. Moreover, the radical of •O2- had some contribution to the reduction of Cr(VI) only in the PBC system. Interestingly, •OH could promote the photoreduction of Cr(VI) in both PBC and CBC systems, which might be due to the fact that •OH facilitated the formation of small molecule fragments. These findings provide an essential basis for evaluating the environmental impact of photocatalytic behaviors of biochar.


The efficacy of dental sealant used with bonding agent on occlusal caries (ICDAS 2-4): A 24-month randomized clinical trial.
Bonding before sealant application enhances retention on saliva-contaminated sound teeth; however, there are few studies of bonding's efficacy on sealant retention on occlusal caries. To evaluate a bonding agent's efficacy on sealant retention on occlusal caries and caries transition. One hundred twenty pairs of first permanent molars with occlusal caries (ICDAS 2-4) from 98 children aged 7.3-9.9 years were included. One molar was randomly selected to use bonding (Adper™ Single Bond 2, 3M ESPE) applied before sealant application (Helioseal® clear, Ivoclar Vivadent). Bonding was not used on the contralateral tooth. Retention was determined using Simonsen's criteria; caries transition was evaluated using ICDAS scores, DIAGNOdent values, and bitewings at baseline, 6, 12, and 24 months. Data were analyzed with McNemar's and Fisher's exact tests. Bonding agent use significantly increased sealant retention rates (P < .001). Bonded (B) sealants had a higher retention rate (83.3%) than non-bonded (NB) sealants (53.7%). The difference in the caries-transition rate was not significant between the groups (P > .05). Three teeth (1.4%; NB:B = 2:1) were restored due to radiographic dentin-caries progression. Using a bonding agent before applying sealant on permanent molar occlusal caries (ICDAS 2-4) significantly enhanced sealant retention. Caries progression was rarely detected at the 24-month follow-up.


Bone-Targeted Alkaline Phosphatase Treatment of Mandibular Bone and Teeth in Lethal Hypophosphatasia via an scAAV8 Vector.
Hypophosphatasia is an inherited disease caused by mutations in the gene encoding tissue-nonspecific alkaline phosphatase (TNALP), the major symptom of which is hypomineralization of the bones and teeth. We had recently demonstrated that TNALP-deficient (Akp2-/- ) mice, which mimic the phenotype of the severe infantile form of hypophosphatasia, can be treated by intramuscular injection of a self-complementary (sc) type 8 recombinant adeno-associated virus (rAAV8) vector expressing bone-targeted TNALP with deca-aspartates at the C terminus (TNALP-D10) via the muscle creatine kinase (MCK) promoter. In this study, we focused on the efficacy of this scAAV8-MCK-TNALP-D10 treatment on the mandibular bone and teeth in neonatal Akp2-/- mice. Upon scAAV8-MCK-TNALP-D10 injection, an improvement of mandibular growth was observed by X-ray analysis. Micro-computed tomography analysis revealed progressive mineralization of the molar root in the treated Akp2-/- mice, and morphometric parameters of the alveolar bone were improved. These results suggest that the mandibular bones and teeth of hypophosphatasia were effectively treated by muscle directed rAAV-mediated TNALP-D10 transduction. Our strategy would be promising for future hypophosphatasia gene therapy because it induces dentoalveolar mineralization and reduces the risk of tooth exfoliation.


Identification of a novel, orally bioavailable histamine H(3) receptor antagonist based on the 4-benzyl-(1H-imidazol-4-yl) template.
A novel series of histamine H(3) receptor antagonists, based on the 4-benzyl-(1H-imidazole-4-yl) template, incorporating urea and carbamate linkers has been prepared. Compound 3j is a selective H(3) antagonist and demonstrates excellent oral plasma levels in the rat and monkey.


Environmental impact of diets for dogs and cats.
Food production is responsible for almost one-quarter of the environmental impact and, therefore, its importance regarding sustainability should not be overlooked. The companion animal population is increasing, and an important part of pet food is composed of ingredients that have a high environmental impact. This study aimed to evaluate the impact of dry, wet, and homemade pet diets on greenhouse gas emission, land use, acidifying emission, eutrophying emissions, freshwater withdrawals, and stress-weighted water use. The wet diets were responsible for the highest impact, and dry diets were the type of diet that least impacted the environment, with a positive correlation between the metabolizable energy provided by animal ingredients and the environmental impact. It is necessary to consider the environmental impact of pet food since it is significant, and the population of pets tends to increase.


Excellent midterm survival and functional outcomes of a fully hydroxyapatite-coated cementless stem: first results of a prospective multicenter study.
The Polarstem (Smith & Nephew, Baar, Switzerland) is a tapered straight stem, an implant with an excellent survival rate. Although the most recent annual report of the National Joint Registry in the United Kingdom also reports excellent survivorship for the cementless Polarstem, no prospective studies have been published focusing on both its efficacy and clinical performance. Therefore, the present study was designed to prospectively evaluate its functional and radiographic outcomes at midterm. This prospective observational study conducted at 3 independent orthopaedic hospitals was designed to collect data in patients undergoing cementless primary total hip arthroplasty (THA). A total of 225 total hip arthroplasties (75 at each site) were performed. The predominant diagnosis was primary osteoarthritis. Anteroposterior and lateral radiographs were obtained at each follow-up (3 months, and 1, 3, and 5 years). Survivorship and the Harris Hip Score (HHS) and Western Ontario and McMaster Universities Index (WOMAC) were calculated. Subjects experienced statistically significant improvements from baseline in mean HHS (48.5 to 88.0, P < .01) and WOMAC scores (58.6 to 9.3, P < .01) at all intervals through 5 years. The stem survivorship was 99.6% at 5 years with stem revision due to any reason. There were no observed cases of mechanical failure of the stem or signs of radiographic loosening. A revision rate of the femoral stem for any reason of 0.4%, as well as good clinical results based on HHS and WOMAC scores, was noted at 5-year follow-up. Therefore, safety and efficacy of the cementless Polarstem at midterm follow-up is confirmed.


Identification of the active-site arginine in rat neutral endopeptidase 24.11 (enkephalinase) as arginine 102 and analysis of a glutamine 102 mutant.
Neutral endopeptidase 24.11 contains an active-site arginine residue involved in binding the free carboxylate of substrate peptides and inhibitors. This arginine reacts rapidly with [14C]phenylglyoxal, and its reaction is selectively blocked by the presence of either the substrate Met5-enkephalin, the competitive inhibitor phenylalanylalanine, or the transition state analog phosphoramidon. The phenylglyoxal-modified peptide was isolated by a procedure involving limited digestion by trypsin, separation of the tryptic peptides by high pressure liquid chromatography (HPLC), further digestion of the modified peptide by pepsin, and a final purification by HPLC. By this procedure arginine 102 was identified as the active-site arginine. Verification of this finding came from the use of site-directed mutagenesis in which this arginine was replaced by glutamine. Both the mutant and wild-type enzyme reacted equally well with an amide containing substrate, glutaryl-Ala-Ala-Phe-4-methoxy-2-naphthylamide. However, reaction of the mutant enzyme with a substrate containing a free COOH-terminal carboxylate, 5-dimethylaminonaphthalene-1-sulfonyl-D-Ala-Gly-(NO2)Phe-Gly, was barely detectable with the mutant enzyme. Similarly the mutant enzyme showed a loss of selectivity in inhibition by D-Ala2-Met5-enkephalin compared to the corresponding amide but exhibited no difference in the maximal velocity for hydrolysis of D-Ala2-Met5-enkephalin and its amide.


Correlation between plasma milrinone concentration and renal function in patients with cardiac disease.
The dose of milrinone should be reduced in patients with renal failure. However, there is little data examining the relationship between plasma concentration of milrinone (pCmil) and renal function in intravenous infusion. We evaluated the pCmil relative to renal function during intravenous infusion. We enrolled 10 heart failure patients. Milrinone was continuously infused at a rate of 0.2 microg/kg/min. Blood samples were collected at 6, 12, 24, and 48 h after the beginning of infusion. Urine was sampled during the first 24 h to calculate creatinine clearance (CLcr) and renal clearance of milrinone (rCLmil). The pCmil exhibited stability over 6 h after the beginning of infusion. During the first 24 h, CLcr and rCLmil were 62.2+/-30.6 ml/min and 1.67+/-0.77 ml/kg/min (106.2+/-60.3 ml/min), respectively. The rCLmil was highly correlated with CLcr. Y=1.77X-3.89 (X, CLcr; Y, rCLmil; R(2)=0.809, P<0.0001). Significant correlations were observed between CLcr and the plasma concentration during the continuous infusion. This correlation was expressed as the equation Y=51.1 x (BW/X)+28.2 (X; CLcr, Y; plasma concentration; BW, body weight; R(2)=0.695, P<0.01). The pCmil exhibited stability 6 h or later after the continuous infusion of milrinone 0.2 microg/kg/min. The pCmil can be estimated by the value of CLcr and BW.


A lightweight classification of adaptor proteins using transformer networks.
Adaptor proteins play a key role in intercellular signal transduction, and dysfunctional adaptor proteins result in diseases. Understanding its structure is the first step to tackling the associated conditions, spurring ongoing interest in research into adaptor proteins with bioinformatics and computational biology. Our study aims to introduce a small, new, and superior model for protein classification, pushing the boundaries with new machine learning algorithms. We propose a novel transformer based model which includes convolutional block and fully connected layer. We input protein sequences from a database, extract PSSM features, then process it via our deep learning model. The proposed model is efficient and highly compact, achieving state-of-the-art performance in terms of area under the receiver operating characteristic curve, Matthew's Correlation Coefficient and Receiver Operating Characteristics curve. Despite merely 20 hidden nodes translating to approximately 1% of the complexity of previous best known methods, the proposed model is still superior in results and computational efficiency. The proposed model is the first transformer model used for recognizing adaptor protein, and outperforms all existing methods, having PSSM profiles as inputs that comprises convolutional blocks, transformer and fully connected layers for the use of classifying adaptor proteins.


A mosaic of endogenous and plant-derived courtship signals in moths.
Insects rely on olfaction to guide a wide range of adaptive behaviors, including mate and food localization, mate choice, oviposition site selection, kin recognition, and predator avoidance.1 In nocturnal insects, such as moths2 and cockroaches,3 mate finding is stimulated predominantly by long-range species-specific sex pheromones, typically emitted by females. During courtship, at close range, males in most moth species emit a blend of pheromone compounds from an everted, often large, pheromone gland. While long-distance communication with sex pheromones has been remarkably well characterized in thousands of moth species,2,4 close-range chemosensory sexual communication remains poorly understood. We reveal that in the moth Chloridea virescens, the male pheromone consists of three distinct classes of compounds: de novo biosynthesized alcohols, aldehydes, acetates, and carboxylic acids that resemble the female's emissions; newly identified compounds that are unique to the male pheromone, such as aliphatic polyunsaturated hydrocarbons; and sequestered plant secondary compounds and hormone derivatives, including methyl salicylate (MeSA). Thus, males employ a mosaic pheromone blend of disparate origins that may serve multiple functions during courtship. We show that two olfactory receptors in female antennae are tuned to MeSA, which facilitates female acceptance of the male. Because MeSA is emitted by plants attacked by pathogens and herbivores,5 the chemosensory system of female moths was likely already tuned to this plant volatile, and males appear to exploit the female's preadapted sensory bias. Interestingly, while female moths (largely nocturnal) and butterflies (diurnal) diverged in their use of sensory modalities in sexual communication,6 MeSA is used by males of both lineages.


[Focus on unfollowed pregnancies: history, maternal-fetal outcome and become].
In France, pregnant women's medical follow-up is a full part of the pregnancy care path, and is sometimes so dominant that it becomes, in itself, the main worrying subject for patients and physicians. When an unfollowed patient gets to the maternity hospital - an otherwise well known situation - she is often surrounded by worried expectations. However, there is no universality whether in time or space, in the pregnancy care path we strongly recommend to our patients. Until the century's beginning, our former obstetricians mostly applied hygienic and behavioral measures, and sometimes harmful cares. We can easily notice that our Europeans neighbors' or Americans' official recommendations are far from being the same as ours, with same morbidity results. Insufficient pregnancy following-up may thus recover several definitions. Medical literature about the lack of medical follow-up during pregnancy is quite limited, though national perinatal enquiries exist, like in France.


T-cell receptor phenotype pattern in atopic children using commercial fluorescently labeled antibodies against 21 human class-specific v segments for the tcrβ chain (vβ) of peripheral blood: a cross sectional study.
T-cell receptor (TCR) repertoire development is an integral part of the adaptive immune response. T-cell activation requires recognition of appropriately processed antigens by the TCR. Development of a diverse repertoire of TCRs is therefore essential to ensure adequate protection from potential threats. The majority of T-cells in peripheral blood have TCRs composed of an alpha and a beta chain. At the DNA level, the TCR genes are formed through directed recombination from germline sequences-the so-called VDJ recombination [variable (V) joining (J) diversity (D) gene segments] which results in variations in the repertoire. The most variable part of TCRs is the Vβ region (VβTCR), which has multiple V segment families that can be quantitatively measured. However, only sparse data exists on the normal levels of the VβTCR repertoire in healthy children. We aimed to establish normal values for the VβTCR repertoire in atopic children without immunodeficiency. Fifty-three children were recruited from food allergy, drug allergy, chronic urticaria and anaphylaxis registries and were divided into groups based on age: >0-2 years, 3-6 years, and 6-18 years. We used commercially available and fluorescently labeled antibodies against 21 human class-specific V segments of the TCRβ chain (Vβ) to study in peripheral blood the quantitative pattern of Vβ variation by flow cytometry. Children of all ages exhibited a similar pattern of TCR Vβ expression. Vβ 2 was the most commonly expressed family in all three age groups [9.5 % (95 % CI, 8.9, 10 %), 8.8 % (95 % CI, 7.4, 10.2 %) and 7.6 % (7.0, 8.3 %) respectively]. However, the percentage of Vβ 2 decreased in older children and the percentage of Vβ 1 was higher in males. TCR Vβ expression in our sample of atopic children did not differ substantially from previously published levels in non-atopic cohorts. TCR Vβ diversity follows a predictable and comparable pattern in atopic and healthy non-atopic children. Establishing normal levels for healthy children with and without atopy will contribute to a better definition of Vβ receptor deviation in children with primary immunodeficiency and/or immunodysregulation conditions.


Phthalates: European regulation, chemistry, pharmacokinetic and related toxicity.
Phthalates are chemicals widely used in industry and the consequences for human health caused by exposure to these agents are of significant current interest. Phthalate toxicity targets the reproductive and respiratory systems primarily, but they also may be involved in the processes of carcinogenesis and even in autism spectrum disorders. This article discusses the molecular and cellular mechanisms involved in organ toxicity of phthalates; furthermore, pharmacokinetic, chemistry and the European regulation are summarized.


Central cord lesions in cervical spondylotic myelopathy.
Two patients with cervical spondylotic myelopathy presented with features suggesting syringomyelia. One patient had a Charcot joint of the wrist, and both had dissociated sensory loss in the upper limbs. The possible vascular basis of these central cord lesions is discussed.


H₂ Adsorbed Site-to-Site Electronic Delocalization within IRMOF-1: Understanding Non-Negligible Interactions at High Pressure.
Isoreticular metal organic frameworks (IRMOFs) have shown high uptake capabilities for storage of H₂ (11.5 wt % at 77 K and 170 bar). A significant literature has employed fragment models and a single adsorbed H₂ to identify adsorption sites within IRMOFs, as well as the necessary adsorbate-adsorbent interactions needed to reach sufficient adsorption enthalpy for practical usage, however at high pressures it remains to be seen if H₂···H₂ intermolecular interactions may influence the energetics. This study focuses upon IRMOF-1 (also known as MOF-5), and examines the individual H₂ stabilization energies at different sites using Möller-Plesset perturbation theory and density functional theory alongside chemical models that consist of isolated fragment models and a cubic super cell cluster consisting of both the face- and edge-cube's of IRMOF-1. Optimization of twenty stable configurations of singly adsorbed H₂ in the super-cell cluster is observed to be essential to obtain energy ordering of the five primary sites consistent with experiment and prior benchmark calculations (α >> β > γ > δ ≈ ε). To examine site-to-site interactions that may occur in the high-pressure regime, 64 co-adsorbed H₂ within a super-cell cluster have been studied (a theoretical maximum of all adsorption sites, 14 wt %). There, delocalization and/or charge transfer of electrons is observed from the σ orbitals of the H₂ bound at the γ positions into the σ* orbitals of H₂ bound at the α sites leads to stabilization of the interaction of H₂ at the γ, by 1.4 kJ/mol, respectively (using M06-2X/LANL2DZ). This effect has been confirmed to be charge transfer, and not a manifestation of enhanced dispersion at high loading, through natural bond order (NBO) analysis and by comparisons of the square of off-diagonal NBO Fock matrix elements for both density functionals that account for dispersion interactions and Hartree-Fock calculations that ignore dispersion.


Valproic acid induced selective apoptosis of ocular fibrous tunic in mice fetuses.
Valproic acid (VPA), a prescribed drug commonly used for various neurological perturbations, has been implicated in teratogenic inflictions on developing fetuses during pregnancy. The purpose of this research was to delineate the gross morphological and histological effects of VPA in the developing eye tunics and lens. A time-dependent administration of 500 mg/kg VPA to BALB/c groups of female mice was coordinated during organogenesis (gestational days 7, 8, and 9) and compared to controls that received normal saline. Seized fetuses were checked for macroscopic eye anomalies, histological malformations with Azan trichrome staining, and levels of apoptotic activity with the terminal deoxynucleotidyl transferase-mediated nick end labeling (TUNEL) assay. Histochemical analysis showed that VPA-treated groups exhibited collagen deficiency (2.5-50% decrease in aniline blue intensity) and a marked increase in TUNEL-positive cells (p < .05) in corneal stroma and sclera/choroid layers while less was detected in retina and lens, when compared to controls. Since the evaluation of the inner structures did not manifest major differences, we conclude that VPA teratogenic influence display eclectic toxicity, as seen by increased apoptosis to eye layers with high degree fibrous context, particularly the outer tunics.


Pseudomonas maltophilia infection in an abattoir worker.
A case of infection with Pseudomonas maltophilia is described. The clinical record and bacteriological findings are reported, and the possible aetiology is discussed.


Concanamycin A, a vacuolar type H(+)-ATPase inhibitor, induces cell death in activated CD8(+) CTL.
Concanamycin A (CMA) and concanamycin B (CMB) are specific inhibitors of vacuolar type H(+)-ATPase (V-ATPase). In our previous studies, intraperitoneal injection of CMB was shown to suppress the increase in CD8(+) CTL population, but not to affect CD4(+) and B220(+) populations, in mice immunized with allogeneic tumors. To clarify the molecular basis of the selective decrease in the CD8(+) CTL population by CMB, we have performed a series of in vitro experiments with use of CMA. Cell viability of the CD8(+) population prepared from the immunized mice was preferentially decreased by CMA treatment. Moreover, in the CD8(+) CTL clone, CMA induced a marked DNA fragmentation and nuclear condensation characteristic of apoptosis. Anti-CD3 or phorbol ester accelerated the CMA-induced reduction in cell viability of the CD8(+) CTL clone, but not CD4(+) T cell clones. However, this rapid cell death was not accompanied by DNA fragmentation and nuclear condensation. Perforin and granzyme B were unlikely to be involved in such cell death. Thus, our data suggest that V-ATPase activity is essential for survival of CD8(+) CTL especially when activated.


[Biomechanical tests of various operative techniques for recurrent inferior radioulnar dislocation (author's transl)].
Among the great number of operative techniques for stabilization of the distal end of the ulna by grafts in recurrent inferior radioulnar dislocation 6 different methods were tested biomechanically and compared among each other. Those techniques which permit successful treatment of the dislocation are pointed out.


Combination of GC/FID/Mass spectrometry fingerprints and multivariate calibration techniques for recognition of antimicrobial constituents of Myrtus communis L. essential oil.
Myrtus communis L. is an aromatic evergreen shrub and its essential oil possesses known powerful antimicrobial activity. However, the contribution of each component of the plant essential oil in observed antimicrobial ability is unclear. In this study, chemical components of the essential oil samples of the plant were identified qualitatively and quantitatively using GC/FID/Mass spectrometry system, antimicrobial activity of these samples against three microbial strains were evaluated and, these two set of data were correlated using chemometrics methods. Three chemometric methods including principal component regression (PCR), partial least squares (PLS) and orthogonal projections to latent structures (OPLS) were applied for the study. These methods showed similar results, but, OPLS was selected as preferred method due to its predictive and interpretational ability, facility, repeatability and low time-consuming. The results showed that α-pinene, 1,8 cineole, β-pinene and limonene are the highest contributors in antimicrobial properties of M. communis essential oil. Other researches have reported high antimicrobial activities for the plant essential oils rich in these compounds confirming our findings.


Differential coupling of G alpha q family of G-protein to muscarinic M1 receptor and neurokinin-2 receptor.
The ligand binding signals to a wide variety of seven transmembrane cell surface receptors are transduced into intracellular signals through heterotrimeric G-proteins. Recently, there have been reports which show diverse coupling patterns of ligand-activated receptors to the members of Gq family alpha subunits. In order to shed some light on these complex signal processing networks, interactions between G alpha q family of G protein and neurokinin-2 receptor as well as muscarinic M1 receptor, which are considered to be new therapeutic targets in asthma, were studied. Using washed membranes from Cos-7 cells co-transfected with different G alpha q and receptor cDNAs, the receptors were stimulated with various concentrations of carbachol and neurokinin A and the agonist-dependent release of [3H]inositol phosphates through phospholipase C beta-1 activation was measured. Differential coupling of G alpha q family of G-protein to muscarinic M1 receptor and neurokinin-2 receptor was observed. The neurokinin-2 receptor shows a ligand-mediated response in membranes co-transfected with G alpha q, G alpha 11 and G alpha 14 but not G alpha 16 and the ability of the muscarinic M1 receptor to activate phospholipase C through G alpha q/11 but not G alpha 14 and G alpha 16 was demonstrated. Clearly G alpha q/11 can couple M1 and neurokinin-2 receptor to activate phospholipase C. But, there are differences in the relative coupling of the G alpha 14 and G alpha 16 subunits to these receptors.


Yolk sac tumor of the ovary during pregnancy: a case report.
There is a therapeutic dilemma for the pregnant patient with malignancy requiring chemotherapy. We had a case of a 30-year-old pregnant woman with a yolk sac tumor who underwent right salpingo-oophorectomy at 22 weeks gestation. Chemotherapy during pregnancy was postponed because of concern with the risks of the chemotherapy to the fetus. After the operation, L2 fraction of alpha-fetoprotein (AFP) depending on the affinity for Lens culinaris agglutinin (LCA) as an indicator for a maternal source of AFP had been detectable since 30 weeks gestation and elevated rapidly with advancing gestation. Tumor recurrence was confirmed clinically at 34 weeks gestation. She was induced, delivering a healthy baby, and received seven complete chemotherapy courses (cisplatin, etoposide, and peplomycin). Currently, the mother (39 months after last chemotherapy) and child are doing well. AFP-L2 may be a sensitive indicator for a yolk sac tumor derived AFP, leading to an earlier detection of tumor recurrence during pregnancy.


BioNTech/Pfizer vaccine after Oxford/AZ vaccine increased immune response vs. no second vaccine.
Borobia AM, Carcas AJ, Perez-Olmeda M, et al. Immunogenicity and reactogenicity of BNT162b2 booster in ChAdOx1-S-primed participants (CombiVacS): a multicentre, open-label, randomised, controlled, phase 2 trial. Lancet. 2021;398:121-30. 34181880.