Digital Immune Gene Expression Profiling Discriminates Allergic Rhinitis Responders from Non-Responders to Probiotic Supplementation.
Probiotic supplementation for eight weeks with a multi-strain probiotic by individuals with allergic rhinitis (AR) reduced overall symptom severity, the frequency of medication use and improved quality of life. The purported mechanism of action is modulation of the immune system. This analysis examined changes in systemic and mucosal immune gene expression in a subgroup of individuals, classified as either responders or non-responders based on improvement of AR symptoms in response to the probiotic supplement. Based on established criteria of a beneficial change in the mini-rhinoconjunctivitis quality of life questionnaire (mRQLQ), individuals with AR were classified as either responders or non-responders. Systemic and mucosal immune gene expression was assessed using nCounter PanCancer Immune Profiling (Nanostring Technologies, Seattle, WA, USA) kit on blood samples and a nasal lysate. There were 414 immune genes in the blood and 312 immune genes in the mucosal samples expressed above the background threshold. Unsupervised hierarchical clustering of immune genes separated responders from non-responders in blood and mucosal samples at baseline and after supplementation, with key T-cell immune genes differentially expressed between the groups. Striking differences in biological processes and pathways were evident in nasal mucosa but not blood in responders compared to non-responders. These findings support the use of network approaches to understand probiotic-induced changes to the immune system.


[Acute renal failure during alcohol-induced rhabdomyolysis].
In the light of literature data and own observations the pathogenesis, clinical manifestations, treatment and prognosis are described in acute renal failure caused by alcohol-induced rhabdomyolysis.


The effect of internet-based guided self-help cognitive-behavioral therapies on Iranian women's psychological symptoms and preferred method of childbirth.
The effectiveness of an Internet-based guided self-help cognitive-behavioral therapy (I-GSH-CBT) was assessed in alleviating childbirth fear (CBF), depression, anxiety, and stress of pregnant women during the first delivery. In a quasi-experimental study, pregnant women in the intervention group used the I-GSH-CBT program during pregnancy. The Wijma Delivery Expectancy/Experience Questionnaire, and the Depression, Anxiety, and Stress Scale 42-item (DASS-42) questionnaires were used to collect the psychometric data. Implementing the I-GSH-CBT significantly reduced CBF, DASS-42 scores, and cesarean section preference. The I-GSH-CBT program effectively decreases the adverse mood symptoms in nulliparous pregnant women.


Cross-disorder comparison of sensory over-responsivity in chronic tic disorders and obsessive-compulsive disorder.
Sensory over-responsivity (SOR) refers to excessively intense and/or prolonged behavioral responses to environmental stimuli typically perceived as non-aversive. SOR is prevalent in several neurodevelopmental disorders, including chronic tic disorders (CTDs) and obsessive-compulsive disorder (OCD). Few studies have examined the extent and clinical correlates of SOR across disorders, limiting insights into the phenomenon's transdiagnostic clinical and biological relevance. Such cross-disorder comparisons are of particular interest for CTDs and OCD given their frequent co-occurrence. We sought to compare the magnitude of SOR between adults with CTD and adults with OCD and to identify the clinical factors most strongly associated with SOR across these disorders. We enrolled 207 age- and sex-matched participants across four diagnostic categories: CTD without OCD (designated "CTD/OCD-"; n = 37), CTD with OCD ("CTD/OCD+"; n = 32), OCD without tic disorder ("OCD"; n = 69), and healthy controls (n = 69). Participants completed a self-report battery of rating scales assessing SOR (Sensory Gating Inventory, SGI), obsessive-compulsive symptoms (Dimensional Obsessive-Compulsive Scale, DOCS), inattention and hyperactivity (Adult ADHD Self-Report Screening Scale for DSM-5, ASRS-5), anxiety (Generalized Anxiety Disorder-7), and depression (Patient Health Questionnaire-9). CTD participants were also administered the Yale Global Tic Severity Scale (YGTSS). To examine between-group differences in SOR, we compared SGI score across all groups and between pairs of groups. To examine the relationship of SOR with other clinical factors, we performed multivariable linear regression. CTD/OCD-, CTD/OCD+, and OCD participants were 86.7%, 87.6%, and 89.5%, respectively, more likely to have higher SGI total scores than healthy controls. SGI total score did not differ between CTD/OCD-, CTD/OCD+, and OCD groups. In the regression model of log-transformed SGI total score, OCD diagnosis, DOCS score, and ASRS-5 score each contributed significantly to model goodness-of-fit, whereas CTD diagnosis and YGTSS total tic score did not. SOR is prevalent in adults with CTD and in adults with OCD but does not significantly differ in magnitude between these disorders. Across CTD, OCD, and healthy control adult populations, SOR is independently associated with both obsessive-compulsive and ADHD symptoms, suggesting a transdiagnostic relationship between these sensory and psychiatric manifestations. Future cross-disorder, longitudinal, and translational research is needed to clarify the role and prognostic import of SOR in CTDs, OCD, and other neurodevelopmental disorders.


Robotic-assisted knee replacement surgery & infection: A historical foundation, systematic review and meta-analysis.
An increasing proportion of Knee arthroplasty is performed using robotic-assisted surgical techniques. This study sought to use a meta-analytical approach to establish summary rates of surgical site infection in robotic-assisted procedures and compare the rate of deep infections to those seen in conventional knee arthroplasty. This study performed a literature search across four online databases to establish a summary rate of surgical site infection across two categories: deep infection and superficial and pin-site infections. This was processed with the aid of a bespoke data-extraction tool. Risk of Bias analysis was performed using the Cochrane RoB2 tool. Meta-analysis was then performed with tests for heterogeneity and a DerSimonian-Laird random effects model. A total of 17 studies were identified as appropriate for inclusion in the meta-analysis. The summary rate of overall surgical site infections within one year of robotic knee arthroplasty was found to be 0.568% (SE = 0.183, 95% CI = 0.209-0.927). Deep infections fell to 0.154% (SE = 0.069, 95% CI = 0.018-0.290) and to 0.347% (SE = 0.109, 95% CI = 0.133-0.561) in superficial and pin-site infections. The surgical site infection rates were found to be low across robotic knee arthroplasty. Further research is required to prove its superiority compared to the conventional, non-robotic technique.


Tissue-Specific Gene Repositioning by Muscle Nuclear Membrane Proteins Enhances Repression of Critical Developmental Genes during Myogenesis.
Whether gene repositioning to the nuclear periphery during differentiation adds another layer of regulation to gene expression remains controversial. Here, we resolve this by manipulating gene positions through targeting the nuclear envelope transmembrane proteins (NETs) that direct their normal repositioning during myogenesis. Combining transcriptomics with high-resolution DamID mapping of nuclear envelope-genome contacts, we show that three muscle-specific NETs, NET39, Tmem38A, and WFS1, direct specific myogenic genes to the nuclear periphery to facilitate their repression. Retargeting a NET39 fragment to nucleoli correspondingly repositioned a target gene, indicating a direct tethering mechanism. Being able to manipulate gene position independently of other changes in differentiation revealed that repositioning contributes ⅓ to ⅔ of a gene's normal repression in myogenesis. Together, these NETs affect 37% of all genes changing expression during myogenesis, and their combined knockdown almost completely blocks myotube formation. This unequivocally demonstrates that NET-directed gene repositioning is critical for developmental gene regulation.


Periaxonal K+ regulation in the small squid Alloteuthis. Studies on isolated and in situ axons.
A novel giant axon preparation from the squid Alloteuthis is described. Properties of in situ and isolated axons are similar. Periaxonal K+ accumulation is a function of the physiological state of the animal and of the axon and its sheathing layers. Carefully dissected isolated axons, and axons in situ in a healthy mantle, show much less K+ accumulation than previously reported in squid. It is suggested that the Schwann cells are involved in the observed K+ regulation.


Epiretinal membrane recurrence: incidence, characteristics, evolution, and preventive and risk factors.
To evaluate the incidence, evolution, clinical characteristics, possible risk factors or preventive factors, and visual outcomes of epiretinal membrane (ERM) recurrence. Retrospective study of 440 consecutive patients (440 eyes) who underwent pars plana vitrectomy for ERM. The internal limiting membrane (ILM) was peeled in 266 cases, with the help of indocyanine green in 27 cases and brilliant blue in 45 cases. Cases of symptomatic ERM recurrence were reoperated. The incidence of ERM recurrence was 5% (22/440), and 2% of the patients were reoperated (9/440). Epiretinal membrane recurrence was symptomatic in 9 cases (41%) and asymptomatic in 13 cases (59%). ILM peeling was the only factor preventing ERM recurrence (adjusted odds ratio = 0.33, P = 0.026). The use of staining dyes did not prevent recurrence (adjusted odds ratio = 0.35, P = 0.338). In the case of ERM reproliferation, the absence of ILM peeling, the existence of ERM on the fellow eye, and poor visual acuity before surgery seemed to be associated with a high risk of symptomatic recurrence and reoperation. The mean duration for follow-up was 3.5 ± 1.7 years. ILM peeling not only reduces the likelihood of reproliferation of ERM but also seems to improve the visual prognosis of recurrent ERMs. The use of dyes did not reduce the rate of recurrence compared with when ILM was peeled without dyes.


Nonprescription drug use among the elderly.
We investigated the extent of the use of nonprescription drugs among an elderly population and the health and social characteristics most related to their use (nonprescription drugs referring to "medicines that don't require a prescription for slight illnesses"). The study data derive from an interview survey of a random sample of adult members of a large health maintenance organization (HMO). While most of the members we interviewed used nonprescription drugs, only one in eight were categorized as using them "very often," the category of most frequent use. Nonprescription drug use was more often associated with reports of common, largely self-limiting conditions than with less common symptoms that could be indicative of serious underlying disease. Such drugs appeared to be used in conjunction with, rather than instead of, physician services. The most frequent users also more frequently asked pharmacists for advice, had unfilled prescriptions, and did not follow physician's instructions. Emotional and mental health were the most important factors accounting for nonprescription drug use among the elderly, particularly among the most frequent users. The profile of the "most frequent" elderly user is one of having emotional health problems; engaging in self-care, but also receiving professional physician services; and engaging in some questionable health behaviors, but not skeptical of medicine in general. Our findings suggest that more attention should be paid to the emotional needs of the elderly.


[The experimental studies on cell transplantation into chronic ischemic myocardium using mesenchymal stem cells modified by recombinant adenovirus carrying vascular endothelial growth factors 165 gene].
To observe the therapeutic effect of vascular endothelial growth factors 165 (VEGF165) gene expressing mesenchymal stem cells (MSCs) in chronic myocardial infarction model by providing enhanced cardioprotection, followed by angiogenic effects in infarcted myocardium. Recombinant adenovirus vector carrying VEGF165 gene (rAd-VFGF165) was constructed. MSCs were harvested through gradient centrifugation, then were cultivated, multiplied and expanded. Recombinant adenoviruses mediated VEGF165 gene were transfected into MSCs, and the MSCs were labelled by DAPI. The left anterior descending branch of rabbits were ligated to establish a myocardial infarction model; and the animals survived for 6 weeks were randomly divided into three groups: VEGF165-expressing MSCs transplanted (Group I), MSCs transplanted (Group II) and dulbecco modified eagles medium injected (Group III). At 4 weeks after cell transplantation, the MSCs were detected by DAPI staining in infarcted region. The cardiac functions were estimated by UCG. The microvascular density in infarcted area were estimated through CD34 immunohistochemical analysis. Four weeks after cell transplantation, ejection fraction, E wave/A wave ratio and capillary density of the infarcted region were most improved in Group I compared with Group II and control group (P < 0.05). DAPI positive cells were most increased in Group I. The transplantation of VEGF165-expressing MSCs had a better therapeutic effect than the transplantation of simplex MSCs. This combined strategy of MSCs transplantation with vgene therapy could be a useful therapy for the treatment of myocardial infarction.


Green chemistry principles for the synthesis of anti fungal active gum acacia-gold nanocomposite - natamycin (GA-AuNC-NT) against food spoilage fungal strain Aspergillus ochraceopealiformis and its marked Congo red dye adsorption efficacy.
In this present study, a highly stable gum acacia -gold nanocomposite fabricated with food preservative agent natamycin (GA-AuNC-NT) was prepared via green science principles under in vitro conditions. Various characterisation techniques reveal highly stable structural, functional properties of the synthesised nanocomposite with marked antifungal activity and adsorption efficacy against congo red dye. The antifungal activity was investigated against the fungal strain Aspergillus ochraceopealiformis isolated from spoiled, expired bread. The well diffusion assay, fungal hyphae fragmentation assay and spore germination inhibition assay were used to determine the antifungal activity of the synthesised nanocomposite. Potential antifungal activity of the synthesised nanocomposite was confirmed by recording zone of inhibition, high rate of hyphae fragmentation and marked spore germination inhibition against the tested fungal strain. The molecular mechanism of antifungal activity was studied by measuring oxidative stress marker genes like catalase (CAT), superoxide dismutase (SOD), peroxidase (POD) induction adopting quantitative real-time polymerase chain reaction (q RT-PCR). Among the various treatment, a notable reduction in all the tested marker genes expression was recorded in the nanocomposite treated fungal strain. Release profile studies using different solvents reveals sustained or controlled release of natamycin at the increasing periods. The synthesised nanocomposite's high safety or biocompatibility was evaluated with the Wistar animal model by determining notable changes in behavioural, biochemical, haematological and histopathological parameters. The synthesised nanocomposite did not exhibit any undesirable changes in all the tested parameters confirming the marked biosafety or biocompatibility. The nanocomposite was coated on the bread packaging material. The effect of packaging on the proximate composition, antioxidative enzymes status, and fungal growth of bread samples incubated under the incubation period were studied. Fourier transform infrared spectroscopy (FTIR) and scanning electron microscopy (SEM) studies reveal that the nanocomposite was effectively coated on the packaging material without changing size, shape, and functional groups. No changes in the proximate composition and antioxidative enzymes of the packaged bread samples incubated under different incubation periods reveal the nanocomposite's marked safety. The complete absence of the fungal growth also indicates the uniqueness of the nanocomposite. Further, the sorption studies revealed the utilisation of Langmuir mechanism and pseudo II order model successfully The present finding implies that the synthesised nanocomposite can be used as an effective, safe food preservative agent and adsorbent of toxic chemicals.


Using Forum Theater as a Teaching Tool to Combat Patient Bias Directed Toward Health Care Professionals.
Health care professionals who identify as members of underrepresented and racial minority groups may experience bias from patients and patient families. These occurrences disrupt the educational and therapeutic environments, distress the targeted individuals and allies, and create potential legal liability. Yet there are few educational opportunities for individuals to brainstorm and implement strategies for responding professionally during such instances. Presented first as a grand rounds, then an invited workshop, and finally an invited series, this educational activity was developed in a stepwise manner over the course of a year. Each format was sequentially modified based on feedback from participants-more than 200 physicians and other health care professionals-using evaluation forms that were voluntary and anonymous. The educational activity used an adaptation of forum theater, in which participants role-played an instance of oppression with a goal of altering the ultimate outcome. This approach provided participants with the opportunity to develop and rehearse responses to workplace bias in a way that preserved the provider-patient relationship. Feedback for these educational sessions was overwhelmingly positive. Participants noted the importance of acknowledging and addressing bias in the workplace and encouraged facilitators to expand the sessions in length, frequency, and scope. Forum theater is a methodology that can be employed in health care to teach appropriate and authentic responses to expressed patient bias while maintaining the therapeutic relationship. The positive reception from participants in our preliminary sessions established a strong foundation for future improvements to this work.


3D screen printing - An innovative technology for large-scale manufacturing of pharmaceutical dosage forms.
Three-dimensional (3D) screen printing was used to fabricate oral dosage forms of different geometry and size. The paste required as starting material for the 3D screen printing process was designed for delayed release and contained the model drug paracetamol (acetaminophen). A prototype screen printing unit was used to fabricate different tablets in a single production process. The resulting tablets were produced with three different sizes and designed geometries (disk, donut, cuboid, oval and grid). Investigation of size and mass of the individual tablets demonstrated high uniformity within the various groups of tablets. Further characterization of their physical properties, such as breaking force and friability, yielded results comparing favorably to conventionally produced tablets. Finally, drug release tests in artificial gastric media showed paracetamol release to depend on the surface-area-to-volume ratio. In conclusion, the study shows the potential of 3D screen printing to fabricate more complex oral dosage forms in the setting of mass production with high reproducibility.


Variations of ATP and its metabolites in the hippocampus of rats subjected to pilocarpine-induced temporal lobe epilepsy.
Although purinergic receptor activity has lately been associated with epilepsy, little is known about the exact role of purines in epileptogenesis. We have used a rat model of temporal lobe epilepsy induced by pilocarpine to study the dynamics of purine metabolism in the hippocampus during different times of status epilepticus (SE) and the chronic phase. Concentrations of adenosine 5'-triphosphate (ATP), adenosine diphosphate (ADP), adenosine monophosphate (AMP), and adenosine in normal and epileptic rat hippocampus were determined by microdialysis in combination with high-performance liquid chromatography (HPLC). Extracellular ATP concentrations did not vary along 4 h of SE onset. However, AMP concentration was elevated during the second hour, whereas ADP and adenosine concentrations augmented during the third and fourth hour following SE. During chronic phase, extracellular ATP, ADP, AMP, and adenosine concentrations decreased, although these levels again increased significantly during spontaneous seizures. These results suggest that the increased turnover of ATP during the acute period is a compensatory mechanism able to reduce the excitatory role of ATP. Increased adenosine levels following 4 h of SE may contribute to block seizures. On the other hand, the reduction of purine levels in the hippocampus of chronic epileptic rats may result from metabolic changes and be part of the mechanisms involved in the onset of spontaneous seizures. This work provides further insights into purinergic signaling during establishment and chronic phase of epilepsy.


Diagnosis of tuberculosis in dialysis and kidney transplant patients.
In patients with chronic kidney disease the risk of developing Tuberculosis is increased, while the presentation is often atypical making the diagnosis more difficult. The aim of this study is to describe the presentation of Tuberculosis in dialysis and kidney transplant patients, including the range of diagnostic approaches and the utility of different sample types. In this retrospective study, case records of dialysis and kidney transplant patients were reviewed, including all those treated for Tuberculosis between January 2009 and December 2020. Over 12 years, there were 143 cases of Tuberculosis in 141 patients (aged 17-86, 50.4% male). Tuberculosis was most common in Asian patients (64%) and those receiving hemodialysis (82%), particularly during the first year after dialysis initiation (54% of dialysis cases). Non-pleural/pulmonary disease accounted 40% of cases, and non-organ-specific presenting features were prominent including fever, lymphadenopathy, and weight loss. The diagnosis was confirmed microbiologically or histologically in 87 cases (61%), with low sensitivity observed for many types of samples including sputum (18%) and pleural fluid (12%). Higher sensitivity was observed with tissue samples including bronchoscopic lymph node aspiration (75%) and other lymph node sampling (92%). In the 52 cases where drug sensitivities were available, resistance to a first line treatment, most commonly isoniazid, was seen in 12 cases (23%). Furthermore, 1- and 5-year survival from diagnosis were 78% and 61%, respectively. Baseline variables independently associated with poorer survival were age (OR 1.8 per decade, 95% CI 1.4-2.3), weight loss over 10% (OR 1.9, 95% CI 1.0-3.5), and a non-confirmed diagnosis (OR 1.6, 95% CI 1.2-2.1). Tuberculosis is common in dialysis and kidney transplant patients, particularly during the first year of dialysis. Short-term mortality is high, but the diagnostic sensitivity of many types of samples is low, so that diagnosis is difficult, with treatment often initiated without confirmation. These data highlight the importance of judgment and clinical experience with this complex patient group.


Proteoglycans of developing bone.
We purified and characterized the bone proteoglycans from fetal calves, growing rats, and human fetuses. The major proteoglycan is part of the mineralized tissue matrix and only 10-20% can be extracted prior to demineralization. This bone proteoglycan is a small glycoconjugate (Mr = 80,000-120,000) containing approximately 20-30% protein and either one or two chondroitin sulfate chains (Mr = 40,000) attached to a relatively monodisperse protein core (Mr = 38,000). "O"-linked and "N"-linked oligosaccharide units are also present. Antibodies directed against the protein core of calf bone proteoglycan do not cross-react with cartilage, skin, corneal, or basement membrane proteoglycans in immunoassays and have minimal cross-reactivity with scleral proteoglycans. Quantitative immunoassays and indirect immunofluorescence were used to show that the molecule is localized to forming bone trabeculae and dentin, but not to any other tissue. Osteoblasts and osteoprogenitor cells adjacent to areas undergoing rapid osteogenesis also contain this small proteoglycan. A second proteoglycan (Mr approximately equal to 1,000,000) was extracted from newly forming bone prior to demineralization. This large proteoglycan, which was isolated from the cartilage-free areas of developing intramembranous bone, has a protein core similar to that of the cartilage aggregating proteoglycan and cross-reacts with antisera raised against these cartilage proteoglycans but not with the small mineral-entrapped proteoglycan. It contains larger (Mr = 40,000) and fewer chondroitin sulfate chains than its cartilage-derived analogue, and is localized to the soft connective tissue mesenchyme lying between growing bone trabeculae. More fully formed compact bone did not contain detectable quantities of this proteoglycan.


Analysis of lower urinary tract signs and bacteriuria in cats with subcutaneous ureteral bypass systems.
Distinguishing bacterial cystitis from subclinical bacteriuria is necessary for feline treatment protocols and antimicrobial stewardship. This can be challenging in cats with subcutaneous ureteral bypass (SUB) systems because they may present with lower urinary tract signs without bacteriuria. We investigated the relationship between positive urine culture and lower urinary tract signs in cats with SUBs, including factors associated with each. Clinical records were retrospectively reviewed to identify cats presenting with ureteral obstruction that underwent placement of a SUB device(s). The relationship between a positive urine culture and lower urinary tract signs was determined by chi-squared analysis. Univariable and multivariable logistic regression models were performed to identify factors associated with positive urine cultures and lower urinary tract signs. Two hundred and thirty visits were recorded for 61 cats, with 36 of 230 (16%) positive cultures in 21 of 61 (34%) cats. Lower urinary tract signs were documented at 97 of 230 (42%) visits, with 37 of 61 (61%) cats demonstrating lower urinary tract signs at some point. No relationship was found between culture results and lower urinary tract signs. Risk factors for a positive culture were higher urine pH, higher urine white blood cells and the presence of bacteriuria on microscopy. Risk factors for lower urinary tract signs were younger age and being a purebred cat (vs. non-purebred). A high proportion of cats with SUBs exhibited sterile lower urinary tract signs, making differentiation between bacterial cystitis and subclinical bacteriuria difficult. This highlights the need for clearer guidelines on when to treat bacteriuria in cats with SUBs.


Magnetization transfer from inhomogeneously broadened lines (ihMT): Improved imaging strategy for spinal cord applications.
Inhomogeneous magnetization transfer (ihMT) shows great promise for specific imaging of myelinated tissues. Whereas the ihMT technique has been previously applied in brain applications, the current report presents a strategy for cervical spinal cord (SC) imaging free of cerebrospinal fluid (CSF) pulsatility artifacts. A pulsed ihMT preparation was combined with a single-shot HASTE readout. Electrocardiogram (ECG) synchronization was used to acquire all images during the quiescent phase of SC motion. However ihMT signal quantification errors may occur when a variable recovery delay is introduced in the sequence as a consequence of variable cardiac cycle. A semiautomatic retrospective correction algorithm, based on repetition time (TR) -matching, is proposed to correct for signal variations of long T1 -components (e.g., CSF). The proposed strategy combining ECG synchronization and retrospective data pairing led to clean SC images free of CSF artifacts. Lower variability of the ihMT metrics were obtained with the correction algorithm, and allowed for shorter TR to be used, hence improving signal-to-noise ratio efficiency. The proposed methodology enabled faster acquisitions, while offering robust ihMT quantification and exquisite SC image quality. This opens great perspectives for widening the in vivo characterization of SC physiopathology using MRI, such as studying white matter tracts microstructure or impairment in degenerative pathologies. Magn Reson Med 77:581-591, 2017. © 2016 International Society for Magnetic Resonance in Medicine.


A method for the production of highly specific polyclonal antibodies.
Two polyclonal antibodies directed against paramyosin and tropomyosin from Owenia fusiformis (a marine polychete annelid) were obtained using a new method of immunization. After purification by two-dimensional gel electrophoresis, proteins were transferred onto a nitrocellulose sheet using the Western blot technique. The proteins bound to their cellulose support were injected into rabbits without Freund's adjuvant and without solubilization of nitrocellulose with dimethyl sulfoxide. Highly specific polyclonal antibodies were generated.


Suboptimally controlled asthma in patients treated with inhaled ICS/LABA: prevalence, risk factors, and outcomes.
This observational claims-linked survey study assessed the prevalence of and risk factors for suboptimal asthma control and healthcare utilization in adults with asthma receiving fixed-dose combination (FDC) inhaled corticosteroid/long-acting β2-agonist (ICS/LABA). Commercially insured adults from the Optum Research Database were invited to complete the Asthma Control Test (ACT) and Asthma Control Questionnaire-6 (ACQ-6). Among participants (N = 428), 36.4% (ACT-assessed) and 55.6% (ACQ-6-assessed) had inadequately controlled asthma. Asthma-related quality of life was worse and asthma-related healthcare resource utilization was higher in poorly controlled asthma. Factors associated with ACT-defined suboptimal asthma control in multivariate analysis included: frequent short-acting β2-agonist (SABA) use, asthma-related outpatient visits, lower treatment adherence, and lower education levels. During follow-up, factors associated with asthma exacerbations and/or high SABA use included: inadequately controlled asthma (ACT-assessed), body mass index ≥30 kg/m2, and high-dose ICS/LABA. Approximately 35-55% of adults with asthma were inadequately controlled despite FDC ICS/LABA; poor control was associated with worse disease outcomes.


Comparative efficacy of two once daily methylphenidate formulations (Ritalin LA and Concerta) and placebo in children with attention deficit hyperactivity disorder across the school day.
The primary objective was to compare the differences in clinical efficacy of the starting dose of Ritalin LA (20mg) to the starting dose of Concerta (18mg), in a laboratory school setting for the duration of an entire school day. Secondary objectives were to compare Ritalin LA 20mg with Concerta 36mg, and Ritalin LA and both Concerta doses versus placebo across the school day. Thirty-six children (29 males, 7 females), aged 6-12 years, with attention deficit hyperactivity disorder, previously stabilized on methylphenidate (MPH), completed this four-way, randomized, single-blind crossover, analog classroom study. Patients were evaluated on day 0 and randomized to receive treatment on days 7, 14, 21, and 28 (Ritalin LA 20mg, Concerta 18mg, Concerta 36mg, or placebo). Swanson, Kotkin, Agler, M-Flynn and Pelham Rating Scale (SKAMP)-attention: The effect of Ritalin LA 20mg across the morning was statistically different from that of Concerta 18mg and 36mg, as demonstrated by the change in the area under the curve (AUC) during the first 4 hours (0-4) from pre-dose. AUC((0-4)) for RitalinLA was -2.48 versus -1.36 for Concerta 18mg (p = 0.015), and -1.55 for Concerta 36mg (p = 0.043). AUC((0-8)) change from pre-dose for Ritalin LA was -4.48 versus -2.72 for Concerta 18mg (p = 0.074), and -3.24 for Concerta 36mg (p = 0.208).SKAMP-deportment: AUC((0-4)) for Ritalin LA was -1.67 compared with -0.28 for Concerta 18mg (p < 0.001), and -0.55 for Concerta 36mg (p = 0.004). AUC((0-8)) change from pre-dose for Ritalin LA was -2.81 compared with -0.82 for Concerta 18mg (p = 0.018), and -1.34 for Concerta 36mg (p = 0.078).Combined: Mean AUC((0-4)) change from pre-dose for Ritalin LA was -2.05 compared with -0.78 for Concerta 18mg (p < 0.001), -1.01 for Concerta 36mg (p = 0.003). The mean AUC((0-8)) change from pre-dose for Ritalin LA was -3.58 compared with -1.70 for Concerta 18mg (p = 0.010), -2.22 for Concerta 36mg (p = 0.061). Math test-attempted: Mean pre-dose score for Ritalin LA was about 73 compared with 74, 90, and 81 for Concerta 18mg, 36mg, and placebo, respectively. Mean AUC((0-8)) change from pre-dose for Ritalin LA was 202 compared with 115 for Concerta 18mg (p = 0.135), 137 for Concerta 36mg (p = 0.265). Math test-correct: Mean pre-dose score for Ritalin LA was 68 compared with 64, 78, and 76 for Concerta 18mg, 36mg, and placebo, respectively. Mean AUC((0-8)) change from pre-dose for Ritalin LA was 183 compared with 100 for Concerta 18mg (p = 0.144), and 117 for Concerta 36mg (p = 0.245). One patient from each treatment group experienced a single mild adverse event that included abdominal pain, nausea, and dyspnea. While both Ritalin LA and Concerta were shown to be effective, the different release profiles of each formulation can result in distinct differences between the effects on measures of attention and deportment.


Efficacy of Low-Frequency Electroacupuncture on Urinary Retention After Spinal Anesthesia.
This study was designed to evaluate the efficacy of low-frequency electroacupuncture (EA) in the prevention of urinary retention after orthopedic surgery. A double-blind placebo-controlled clinical trial. Eighty patients with spinal anesthesia were randomly allocated into the groups of EA (40 cases) and control (40 cases). In the first group, the EA was applied to four points of SP6, SP9, ST28, and CV2; 4 Hz, retaining for 20 minutes in the postanesthesia care unit (PACU). In the control group, no intervention was applied. The incidence of postoperative urinary retention, incomplete or difficult urination, and the first automatic micturition time since spinal anesthesia were compared between the two groups. The incidence of urinary retention and incomplete urination in the EA group was significantly lower than that in the control group; the time to first urination was shorter in the intervention group than in the control group (P < .05). Electroacupuncture after spinal anesthesia improves bladder function and reduces the need for a urinary catheter and its possible complications.


A quantitative index derived from 99mTc-pertechnetate scintigraphy to assist in the diagnosis of primary Sjögren's syndrome.
A safe and simple technique is reported by which primary Sjögren's syndrome can be detected with a relatively high specificity and sensitivity. The method of serial scintigraphy has been used with reasonable success; however, the application of the linearity index as described here produced superior results. In 71 patients investigated, a sensitivity of 87% and specificity of 93% were recorded and make this the method of choice for evaluating patients suspected of having primary Sjögren's syndrome.


[The Norton Scale as predictor of health-related quality of life in institutionalized elderly].
A low Norton Scale (NS) score predicts pressure ulcer risk and several adverse outcomes in the elderly. On the other hand, health-related quality of life (HRQOL) is an indicator with clinical and predictive utilities. The aim was to assess the relationship between NS and HRQOL, in a gender analysis. Fifty-one women and 39 men, institutionalized and aged≥65 years, were evaluated through personal interview and medical records. The NS, HRQOL -with EuroQol-5D-, age, body mass index, falls, use of psychoactive drugs, cognitive function and Charlson, Barthel and Tinetti indexes, were assessed. Two regression models were developed, with EuroQol-5D as dependent variable. The NS showed the same score in both sexes, with a median (interquartile range) value of 19 (2). Women presented a worse HRQOL, with an EuroQol-5D=0.78, whereas it was 0.87 in men (P=.02). The NS score was correlated with HRQOL in women (r=0.57; P<.001) but not in men (r=0.15; P=.36). After adjusting for confounders, the NS showed a β value of 0.54 (P=.02) in women and β=0.35 (P=.14) in men. The NS has shown to be the strongest factor on HRQOL in women, regardless of age, comorbidity and the rest of covariates. Conversely, the relationship was weaker and non-significant in men.


The merits of the ICD for inherited heart rhythm disorders: A critical re-appraisal.
The implantable cardioverter defibrillator (ICD) is often considered a routine intervention for an inherited heart rhythm disorder (IHRD) despite there being little to no randomized data for non-ischemic indications. Furthermore, existing IHRD studies often do not report adverse ICD outcomes, and observational data increasingly show that complications are under-recognized. Only recently have tools emerged to address the rational use of ICDs for specific forms of IHRD, although the acceptable risk of device complications remains unestablished. Here, we summarize the evidence of ICD benefit and harm in IHRD, highlight current knowledge gaps, and propose alternative and adjunctive options to the transvenous ICD.


Natural product (-)-gossypol inhibits colon cancer cell growth by targeting RNA-binding protein Musashi-1.
Musashi-1 (MSI1) is an RNA-binding protein that acts as a translation activator or repressor of target mRNAs. The best-characterized MSI1 target is Numb mRNA, whose encoded protein negatively regulates Notch signaling. Additional MSI1 targets include the mRNAs for the tumor suppressor protein APC that regulates Wnt signaling and the cyclin-dependent kinase inhibitor P21(WAF-1). We hypothesized that increased expression of NUMB, P21 and APC, through inhibition of MSI1 RNA-binding activity might be an effective way to simultaneously downregulate Wnt and Notch signaling, thus blocking the growth of a broad range of cancer cells. We used a fluorescence polarization assay to screen for small molecules that disrupt the binding of MSI1 to its consensus RNA binding site. One of the top hits was (-)-gossypol (Ki = 476 ± 273 nM), a natural product from cottonseed, known to have potent anti-tumor activity and which has recently completed Phase IIb clinical trials for prostate cancer. Surface plasmon resonance and nuclear magnetic resonance studies demonstrate a direct interaction of (-)-gossypol with the RNA binding pocket of MSI1. We further showed that (-)-gossypol reduces Notch/Wnt signaling in several colon cancer cell lines having high levels of MSI1, with reduced SURVIVIN expression and increased apoptosis/autophagy. Finally, we showed that orally administered (-)-gossypol inhibits colon cancer growth in a mouse xenograft model. Our study identifies (-)-gossypol as a potential small molecule inhibitor of MSI1-RNA interaction, and suggests that inhibition of MSI1's RNA binding activity may be an effective anti-cancer strategy.


The characteristics and outcomes of small bowel adenocarcinoma: a multicentre retrospective observational study.
Small bowel adenocarcinoma (SBA) is a rare malignancy that accounts for 1-2% of gastrointestinal tumours. We investigated the clinical characteristics, outcomes, and prognostic factors of primary SBA. We retrospectively analysed the characteristics and clinical courses of 205 SBA patients from 11 institutions in Japan between June 2002 and August 2013. The primary tumour was in the duodenum and jejunum/ileum in 149 (72.7%) and 56 (27.3%) patients, respectively. Sixty-four patients (43.0%) with duodenal adenocarcinoma were asymptomatic and most cases were detected by oesophagogastroduodenoscopy (EGD), which was not specifically performed for the detection or surveillance of duodenal tumours. In contrast, 47 patients (83.9%) with jejunoileal carcinoma were symptomatic. The 3-year survival rate for stage 0/I, II, III, and IV cancers was 93.4%, 73.1%, 50.9%, and 15.1%, respectively. Multivariate analysis revealed performance status 3-4, high carcinoembryonic antigen, high lactate dehydrogenase (LDH), low albumin, symptomatic at diagnosis, and stage III/IV disease were independent factors for overall survival (OS). Ten patients (18.5%) with stage IV disease were treated with a combination of resection of primary tumour, local treatment of metastasis, and chemotherapy; this group had a median OS of 36.9 months. Although most SBA patients were diagnosed with symptomatic, advanced stage disease, some patients with duodenal carcinoma were detected in early stage by EGD. High LDH and symptomatic at diagnosis were identified as novel independent prognostic factors for OS. The prognosis of advanced SBA was poor, but combined modality therapy with local treatment of metastasis might prolong patient survival.


Chronic antidepressant treatment increases enkephalin levels in n. accumbens and striatum of the rat.
Chronic (21 consecutive days) and not acute administration of typical (clomipramine, desipramine, amitriptyline) or atypical (iprindole, nomifensin) antidepressant drugs was found to provoke a selective increase in [Met5]enkephalin-like immunoreactivity ([Met5]ELI) in striatum and nucleus accumbens of rat brain. In parallel experiments, following chronic treatment with clomipramine, iprindole and nomifensin striatal [Leu5]enkephalin-like immunoreactivity ([Leu5]ELI) was also significantly enhanced. No variations in enzymatic activity of either enkephalinase or aminopeptidase were detected when assayed in several brain parts of animals chronically treated with antidepressants. Elevation of ELI in discrete regions of the brain might play a part in the mechanism of action of these centrally acting agents.


Window current through the T-type Ca2+ channel triggers the mechanism for cellular apoptosis via mitochondrial pathways.
We hypothesized that Ca(2+) entry through the window T-type Ca(2+) current causes apoptosis. To test this hypothesis, we transfected human embryonic kidney (HEK) 293 cells to express recombinant Cav3.2 T-type Ca(2+) channels (hereafter called HEK-Cav3.2 cells). After incubation in media containing a high concentration (7.2 mM) of Ca(2+), intracellular Ca(2+) levels increased in HEK-Cav3.2 cells without electrical stimulation but not in untransfected HEK293 cells. In quiescent HEK-Cav3.2 cells exposed to high Ca(2+) media, apoptosis, as indicated by the appearance of hypodiploid cells, loss of mitochondrial transmembrane potential, and activation of caspases-3 and -9 was observed, while caspase-8 was not activated. These apoptosis-associated changes were blunted by pretreatment with the R(-)-isomer of efonidipine, a selective blocker of T-type Ca(2+) channels. High Ca(2+) did not induce apoptosis in untransfected HEK293 cells. Our findings show that Ca(2+) entry through the steady-state window current of T-type Ca(2+) channels causes apoptosis via mitochondrial pathways, and suggests that T-type Ca(2+) channels may be novel therapeutic targets for several diseases associated with abnormal apoptosis.


Regulation of the sarcoplasmic reticulum ryanodine receptor by inorganic phosphate.
To better understand the mechanisms regulating myoplasmic Ca2+ during muscle activity, we have examined the effect of inorganic phosphate (P(i)) on the ryanodine receptor (RyR) Ca2+ release channel of the sarcoplasmic reticulum (SR). We report that P(i) at concentrations reached in exercising skeletal muscle (3-30 mM) produced a dose-dependent stimulation of ryanodine binding to skeletal muscle SR. Ryanodine binding was increased by 84% in the presence of 30 mM P(i) with half-maximal stimulation at 4 mM P(i). In contrast to its effect on skeletal muscle SR, ryanodine binding to cardiac muscle SR was not stimulated by P(i) (3-30 mM). Stimulation of ryanodine binding to skeletal muscle SR was maximal in the presence of micromolar Ca2+ and was associated with an increased affinity of the RyR for ryanodine (Kd = 204 nM in the absence, versus 107 nM in the presence of 10 mM P(i)). P(i) (10 mM) also increased the rate of Ca2+ release from 45Ca(2+)-filled skeletal muscle SR vesicles by 50% in the presence of micromolar Ca2+. Conversely, arsenate and sulfate (10 mM) had no effect on either ryanodine binding or Ca(2+)-induced Ca2+ release, demonstrating the specificity of the P(i) effect. Single-channel recordings of purified skeletal muscle SR RyR incorporated into planar lipid bilayers showed that addition of 10 mM P(i) to the cis chamber increased the open probability of the channel by 91%. These results demonstrate that concentrations of P(i) which occur in vivo during exercise significantly stimulate the in vitro activity of the skeletal muscle RyR Ca2+ release channel.


Down-regulation of activated factor XIII by polymorphonuclear granulocyte proteases within fibrin clot.
Activated clotting factors are down-regulated by two major mechanisms which involve protease inhibitors or proteolytic degradation. To date, no down-regulating mechanism for activated factor XIII (FXIIIa) has been demonstrated. As the hemostatic plug contains polymorphonuclear granulocytes (PMNs) rich in proteolytic enzymes, we tested if these proteases are released in fibrin clots, and become involved in the down-regulation of FXIIIa. The supernatant of stimulated granulocytes proteolytically degraded and inactivated FXIIIa. In the fibrin clot formed from fibrinogen solution elastase, cathepsin G and matrix metalloprotease-9 (MMP-9) were released from granulocytes without any external stimulus. PMN proteases released in fibrin clot exerted a fibrinolytic effect and almost completely degraded both FXIII subunits. The elastase inhibitor, ONO 5046, partially inhibited the proteolytic degradation of FXIII in PMN-supplemented fibrin clots. Cathepsin G and MMP-9 inhibitors provided less protection; in these cases intermediate split products accumulated. The proteolytic degradation of FXIII by PMNs was also significant when the clot was made from whole plasma. The main plasma protease inhibitor, alpha1-antitrypsin, provided only partial protection. In the fibrin clot which contained alpha1-antitrypsin FXIIIa was degraded by PMN proteases significantly faster than cross-linked fibrin. The results suggest that the degradation of FXIII subunits by the concerted action of PMN proteases released within the clot represents a novel mechanism for the down-regulation of FXIIIa.


Association of rotating night shift work, CLOCK, MTNR1A, MTNR1B genes polymorphisms and their interactions with type 2 diabetes among steelworkers: a case-control study.
The purpose of this study is to investigate the association of rotating night shift work, CLOCK, MTNR1A, MTNR1B genes polymorphisms and their interactions with type 2 diabetes among steelworkers. A case-control study was conducted in the Tangsteel company in Tangshan, China. The sample sizes of the case group and control group were 251 and 451, respectively. The logistic regression, log-linear model and generalized multifactor dimensionality (GMDR) method were used to investigate the interaction between circadian clock gene, melatonin receptor genes and rotating night shift work on type 2 diabetes among steelworkers. Relative excess risk due to interaction (RERI) and attributable proportions (AP) were used to evaluate additive interactions. Rotating night shift work, current shift status, duration of night shifts, and average frequency of night shifts were associated with an increased risk of type 2 diabetes after adjustment for confounders. Rs1387153 variants in MTNR1B was found to be associated with an increased risk of type 2 diabetes, which was not found between MTNR1A gene rs2119882 locus, CLOCK gene rs1801260 locus and the risk of type 2 diabetes. The association between rotating night shift work and risk of type 2 diabetes appeared to be modified by MTNR1B gene rs1387153 locus (RERI = 0.98, (95% CI, 0.40-1.55); AP = 0.60, (95% CI, 0.07-1.12)). The interaction between MTNR1A gene rs2119882 locus and CLOCK gene rs1801260 locus was associated with the risk of type 2 diabetes (RERI = 1.07, (95% CI, 0.23-1.91); AP = 0.77, (95% CI, 0.36-1.17)). The complex interaction of the MTNR1A-MTNR1B-CLOCK-rotating night shift work model based on the GMDR methods may increase the risk of type 2 diabetes (P = 0.011). Rotating night shift work and rs1387153 variants in MTNR1B were associated with an increased risk of type 2 diabetes among steelworkers. The complex interaction of MTNR1A-MTNR1B-CLOCK-rotating night shift work may increase the risk of type 2 diabetes.


Spindle cells and their role in Kaposi's sarcoma.
Spindle cells represent the main cell type of the advanced final nodular stage of Kaposi's sarcoma lesions. Despite some clinical and epidemiological differences, the four Kaposi's sarcoma forms (classic, endemic, post-transplant and epidemic) display very similar histopathological features, with the proliferation of spindle cells (considered as the Kaposi's sarcoma tumor cells) associated with inflammation and neo-angiogenesis. Electron-microscopy and immuno-histochemistry studies have led to the consensus that the spindle cells originated from the endothelial lineage. However, only recently, studies that used specific lymphatic immunological markers (such as podoplanin) and molecular features (gene expression microarrays) strongly linked Kaposi's sarcoma spindle cells to the endothelium lymphatic cell lineage. Both hybridization and immuno-histochemistry techniques have demonstrated that human herpesvirus 8 also known as Kaposi's sarcoma associated herpesvirus was present in spindle cells at all stages of the disease (patch, plaque, nodule). Interestingly, while the human herpesvirus 8 latent genes are expressed in nearly all tumor spindle cells, only a small fraction of them expresses markers of viral lytic replication. Recent findings showing that nodular Kaposi's sarcoma lesions display all patterns of human herpesvirus 8 clonality support the model according to which this tumor begins as a polyclonal disease with a subsequent evolution to a mono/oligoclonal process involving infected spindle cells. Spindle cells appear to be the central masterpiece in KS tumorigenesis, however the exact respective role of each human herpesvirus 8 gene, in the initiation and the disease progression is still under investigation and the question of whether or not this tumor is a reactive process or a true malignant proliferation of spindle cells remains yet unclear.


Directed air flow to reduce airborne particulate and bacterial contamination in the surgical field during total hip arthroplasty.
This study evaluated the use of a system that delivers a small field of local, directed air from a high-efficiency particulate air (HEPA) filter to reduce airborne particulate and airborne bacteria in the surgical field during total hip arthroplasty. Thirty-six patients were randomized into 3 groups: with directed air flow, with the directed air flow system present but turned off, and control. Airborne particulate and bacteria were collected from within 5 cm of the surgical wound. All particulate and bacterial counts at the surgical site were significantly lower in the directed air flow group (P < .001). The directed air flow system was effective in reducing airborne particulate and colony-forming units in the surgical field during total hip arthroplasty.


Postoperative relapse after mandibular setback surgery with perioperative counterclockwise rotation of the mandibular proximal segment.
This study aimed to evaluate whether the perioperative counterclockwise rotation (CCWR) of the proximal segment (PS) can reduce relapse after mandibular setback surgery. Patients who underwent less than 1° of bilateral perioperative rotation of the PS were assigned to group I (n = 15). Group II (n = 14) included patients who showed greater than 1° of perioperative CCWR bilaterally. To evaluate the PS rotation and the relapse, three-dimensional computed tomography (CT) and lateral cephalography scans were analyzed. Even with significantly different perioperative CCWR of the PS (.07 ± .53° vs -3.47 ± 1.55°), the relapse was not significantly different between group I (1.96 ± 1.15 mm) and group II (1.81 ± .92 mm). However, postoperative CCWR of the PS was significantly greater in group I. The relapse was not influenced by the amount of setback. A small degree of relapse is expected after mandibular setback surgery, even with perioperative CCWR of the PS.


Towards an understanding of the malignant transformation of diploid human fibroblasts.
This paper reviews the major reports of the spontaneous or carcinogen-induced transformation of human fibroblasts to the malignant state, to infinite lifespan, or to anchorage independence. In some cases, the transformed cells and the parent cell with which the work began were made available to us to be tested to determine whether the cells shared common isozymes, HLA antigens, restriction-fragment length polymorphisms, marker chromosomes, etc., as one would expect. When we examined the normal fibroblastic cell line KD for these markers, and the transformed HuT cell lines developed from it by Kakunaga (Proc. Natl. Acad. Sci. (U.S.A.), 75, 1334, 1978) for these markers, we found marked differences, indicating that KD cells and HuT cells are derived from different individuals. When we applied these techniques to the 3 human fibroblast cell lines transformed by Namba to acquire infinite lifespan in culture (Gann, 27, 221, 1981), it became clear that KSMT-6 was derived from the parent cell, KMS-6, but that both cell lines CT-1 and SUSM-1 were derived from the same parental cell line, AD387. Similar studies with other sets of cell lines are also reported. In the light of these studies, it appears that there is no example of the malignant transformation of human fibroblasts by carcinogen treatment. However, neoplastic transformation and transformation to infinite lifespan by carcinogen treatment have been achieved by a number of workers. We speculate as to how malignant transformation might be obtained by carcinogen treatment.


Intensive uric acid-lowering therapy in CKD patients: the protocol for a randomized controlled trial.
Hyperuricemia would be a risk factor for the development/progression of CKD. However, several studies showed U-shape association between serum uric acid level and renal impairment, suggesting that hypouricemia was rather associated with renal dysfunction. Perhaps, there is the optimal target level of serum UA for renal function. The Target-UA study is a multicenter randomized controlled trial. Eligible CKD patients (eGFR ≥ 30, < 60 mL/min/1.73 m2 and urine protein < 0.5 g/gCr or urine albumin to creatinine ratio (ACR) < 300 mg/gCr) with serum UA ≥ 8.0 mg/dL (≥ 7.0 mg/dl: under the treatment) will be enrolled and be randomly assigned to the intensive therapy group (target serum UA level ≥ 4.0 mg/dL, < 5.0 mg/dL) or the standard therapy group (serum UA level ≥ 6.0 mg/dL, < 7.0 mg/dL). Topiroxostat, a new xanthine oxidase inhibitor, will be administered to treat hyperuricemia. The primary endpoint is a change in logarithmic value of urine ACR between baseline and week 52 of treatment. The secondary endpoints include changes in serum UA, eGFR, urine protein, lipid profile, and onset of composite cardiovascular events, renal events, gouty arthritis, and attack of urolithiasis. The number of subjects has been set to be 185 in each group for a total of 370. This is the first study, to the best of our knowledge, to determine the optimal target level of serum UA for renal protection and is expected to lead to progress in CKD treatment. (UMIN000026741 and jRCTs051180146).


Interleukin 6-174 G/C promoter polymorphism and pregnancy complications: results of a prospective cohort study in 1626 pregnant women.
To investigate the frequency of the interleukin-6 (IL-6) -174 G/C single nucleotide polymorphism (SNP) in women with intrauterine fetal death (IUFD), pre-eclampsia (PE), preterm delivery (PD), and small for gestational age (SGA) infants. In a prospective cohort study, DNA from 1626 consecutive pregnant women was analyzed for IL-6 -174 G/C. Women who developed at least one of the predefined pregnancy complications were used as cases and compared with women without pregnancy complications. Of 1626 women, 259 (15.9%) developed at least one pregnancy complication. IL-6 -174 G/C allele frequencies and genotype distributions were not significantly different between cases and controls. Similarly, no statistically significant difference in IL-6 -174 G/C genotype distribution in women with IUFD, PE, PD <34 weeks, PD >34 weeks and SGA infants <10th percentile was observed. IL-6 -174 G/C is not a genetic marker for identifying women at increased risk of common pregnancy complications.


Anal endosonography in the diagnosis and management of perianal endometriosis: report of a case.
We report a rare case of perianal endometriosis, diagnosed in a 39-year-old woman who presented with a several-day history of a painful mass in the perineum. Perianal examination showed redness and swelling in the right anterior direction. A soft tumor was palpated, but there was no evidence of an episiotomy scar, or of fistula orifices. An anal endosonography in the right anterior direction revealed a sharply defined lesion, 17 x 14 mm in diameter, with high echoic enhancement at its center. The lesion was located along the edge of the external anal sphincter but did not involve it. Based on these endosonographic findings, the tumor was not considered to be an abscess or fistula. We detected its location, and judged it possible to enucleate the tumor under local anesthesia without injuring the anal sphincter. The operation was performed uneventfully and a histological diagnosis of endometriosis was confirmed. Using anal endosonography, we were able to determine the exact anatomic relationship of the lesion in the internal and external sphincter, which substantially influenced the diagnosis and operative procedures.


Comparison between DySc2N@C80 and Dy2ScN@C80 single-molecule magnetic metallofullerenes encapsulated in single-wall carbon nanotubes.
Encapsulation of a metallofullerene single-molecule magnet, Dy2ScN@C80, into single-wall carbon nanotubes (SWCNTs) accelerates magnetic relaxation processes. In contrast, encapsulation of DySc2N@C80 suppresses them. The effects of the encapsulation are discussed in terms of intermolecular magnetic interactions and charge transfer among metallofullerenes and SWCNTs.


Synthesis and comparative evaluation of two antiviral agents: beta-L-Fd4C and beta-D-Fd4C.
The synthesis of beta-D-Fd4C was achieved in a stereoselective fashion from D-xylose. The antiviral activity and cytotoxicity of beta-D-Fd4C was compared with that of beta-L-Fd4C and 3TC (Lamivudine). Of the three agents compared, beta-L-Fd4C was found to be the most potent antiviral agent.


Modelling marine microplastics accumulation zones through freshwater discharge sources: Simulated release from the Onkaparinga River and Torrens River, South Australia.
Plastic pollution is fast becoming one of the most prominent contamination issues facing the marine environment. Microplastics are a major subset of plastic waste now present in all global oceans, with their numbers standing only to increase. This study applies a coupled hydrodynamic model and Lagrangian particle-tracking model to predict and simulate microplastic transport in South Australian waters. Virtual particles representing microplastics were released daily for 365 days from two major freshwater input sources along the coastline of Adelaide, Australia. These particles entered the Gulf St Vincent and were tracked over two model years using LTRANS software. The model identified general gulf circulation as circular, clockwise, with net southward particle transport from particle release sites. A potential accumulation zone associated with a local eddy was identified. Concentrations of particles that passed through local marine parks were also calculated in response to the potential concerns they pose in vulnerable protected areas.


Anticonvulsant action of thiabendazole.
Thiabendazole was found to be specifically effective against maximal electroshock seizures in albino rats. It produced a significant dose-dependent decrease in the duration of the tonic extensor phase of hind legs. The ED50 was similar for oral or s.c. administration. PTZ-induced convulsions were unaffected by lower doses but aggravated by the higher dose studied.


Reproducibility of intravenous linear pharmacokinetic parameters of ethanol in dogs.
Linear elimination parameters were computed after intravenous administration of the same dose (11 mmol/kg) of intravenous ethanol in anesthetized dogs twice with a period of 7-8 days (group A, n = 10) or 6 hours (group B, n = 8) between the two studies. For rate of elimination, clearance and time of disappearance of half the dose, routine statistical methods (paired t-test, correlation) showed no difference between the first and the second study of either group; however, for each of these three elimination parameters, quantitative analysis showed significant disparities between the first and second studies of each group. For Widmark ratio r, which is a measurement of ethanol distribution rather than elimination, both the routine statistical methods and the quantitative analysis showed no difference between the first and second study of either group. In dogs, the assumption that blood alcohol curve is reproducible in individuals may not be valid.


Acceleration of organic reactions through aqueous solvent effects.
The parallels between organic reactions conducted with water as the solvent and reactions conducted under high pressure can be understood in light of theories of aqueous solvation and hydrophobic effects. Such parallels provide powerful tools for promoting reactions of nonpolar compounds.


Trapezoidal osteotomy of the distal radius for unacceptable articular angulation after Colles' fracture.
Loss of radial palmar tilt in malunion of Colles' fractures alters wrist biomechanics, abnormally loading the tenuous dorsal ligament complex. This can result in midcarpal instability with synovitis, pain, weakness, and possible articular degeneration. An osteotomy to correct radius alignment using a trapezoidal corticocancellous bone graft has been devised. The graft is harvested from the dorsal radius adjacent to the osteotomy and malunion site. When turned 90 degrees, a properly designed trapezoidal graft restores radial length, inclination, and palmar tilt in one step. Functional results in 15 patients at 46 months (range, 18 to 116) were comparable with a series using iliac crest graft and plate- and-screw fixation. This simple technique avoids disruption of the extensor retinaculum and reoperation for hardware removal as Kirschner-wire fixation proved adequate.


Approaches on Generating Optimized Sequences of Items Used in Assessment.
Assessment is a key element in education. Given its multiple methods, assessment contains the aspect of correctness and honesty from both the assessor and the assessed. These methods can be classified and their types are numerous, starting from single questions to tests and practical work. Concerning tests, their vast usage in practice raises problems such as progressing difficulty, concept understanding regardless the test morphology or test sort depending on subject. Generally, we will refer at questions within a test or tests within a group of tests as items. In this paper, we present several approaches for generating items, defining or not some restrictions, in order to obtain optimized sequences of items (OSI). These restrictions consist in connections between items regarding degrees of difficulty or sorting depending on item subject. These cases will be solved using nature-inspired algorithms (genetic algorithms), arborescent structures and lexical usage (keywords).


Monocarboxylate Transporter 1 in the Medial Prefrontal Cortex Developmentally Expresses in Oligodendrocytes and Associates with Neuronal Amounts.
Lactate is an energy substrate in adult brain especially when glucose is withdrawn or only lactate is present as main energy source. Besides, the most abundant lactate transporter in brain-monocarboxylate transporter 1 (MCT1)-was recognized recently. Despite this, MCT1 expressions in central nervous system (CNS) have not been clearly understood. Medial prefrontal cortex (mPFC), taking part in many higher executive functions in brain, is chosen here for observing MCT1 expressions in mice in 12 months. As results showed, MCT1 is gradually increased from an initial level at the 1st week to a high level at the 6th week and then gradually decreased to a low level at the 12th month. Besides, neuronal amounts change in a similar trend as MCT1 that neurons at the 6th week are more than that of at the 1st week and the 12th month. Also, MCT1 expressions are highly correlated with neuronal amounts, while MCT1 does not localize within neurons, instead localize around axons. On the other hand, MCT1 does localize to oligodendrocytes (OLs) without localizing to other glial cells (astrocytes and microglias). Importantly, the amounts of OLs change in a similar trend as MCT1, while the amounts of other glial cells do not change obviously in the mPFC in vivo in 12 months. These results demonstrate that the changeable expressions of MCT1 in the mPFC in vivo in 12 months may be mainly contributed by OLs and associate with the neuronal amounts. Above all, it infers that in vivo, MCT1 which is changeably expressed in OLs may further affect neuronal amounts in the mPFC in 12 months.


Integrative analysis of the effects of organic and conventional farming methods on peanut based on transcriptome and metabolomics.
To elucidate the nutritional quality of peanut under different farming methods, we selected two cultivars, "jihua13" and "jihua4", to grow in organic and conventional environments, respectively. After harvest, we measured physiological parameters and differential metabolites. Metabolomics showed that most of the amino acids, carbohydrates, and secondary metabolites in organically grown jihua4 were downregulated, which was completely the opposite in jihua13. Fatty acids associated with heart disease and hypertension are reduced in organically grown peanuts. In particular, the highly statistically significant tryptophan betaine seems to be used as a reference to distinguish between organic and conventional cultivation. Mechanisms leading to differences in crop chemical composition are explained by transcriptome analysis. The results of the transcriptome analysis indicated that organic cultivation largely affects the synthesis of amino acids and carbohydrates in jihua13. Combined analysis of transcriptome and metabolomics found that variety jihua13 is more sensitive to farming methods and produces more unsaturated fatty acids than jihua4.


Are There Therapeutic Benefits of Cannabinoid Products in Adult Mental Illness?
A position statement developed by the Canadian Psychiatric Association's (CPA) Research Committee and approved by the CPA's Board of Directors on May 13, 2020.


Di-tert-butylhydroxylated flavonoids protect endothelial cells against oxidized LDL-induced cytotoxicity.
The protective effect of di-tert-butylhydroxylated flavonoids (chalcones and arylidenes) against minimally oxidized LDL (mO-LDL)-induced cytotoxicity was studied in cultured bovine aortic endothelial cells. Most of the tested compounds decreased aldehydes formation in medium containing mO-LDL, but their capacity to inhibit LDL oxidation in the cellular medium was not sufficient to totally reduce the cellular toxicity of mO-LDL. Most of the tested flavonoids improved the integrity of cells exposed to mO-LDL, whereas butylated hydroxytoluene was ineffective and quercetin worsened the toxicity of mO-LDL. Moreover these flavonoids induced an increase in GSH cellular levels and their protective effects might be because of their inability to reduce metal ion. Arylidene 6 substituted at position 7 by a hydroxyl group was the most potent compound.


On-chip analysis of magnetically labeled cells with integrated cell sorting and counting techniques.
In studies on cell therapies, cells often need to be magnetically labeled and then tracked using magnetic resonance imaging (MRI) techniques. To achieve good imaging performance on infused cells, the analysis of the sorted, labeled cells before infusion is necessary. Herein, we developed a microfluidic chip to quantitatively analyze magnetically labeled cells. The chip was equipped with a magnetophoresis-based cell sorting function and an impedance-based cell counting function. Using RAW264.7 macrophages, we confirmed the two functions of the chip, obtained the number and the magnetic loading distribution of the sorted, labeled cells, and ultimately demonstrated the broad applications of the chip in rapidly selecting a proper flow rate for the buffer solution in the cell sorting process, determining the total average magnetic loading of the labeled cells for the cell labeling process, and offering a necessary reference for the processing of the sorted cells for high performance in vivo imaging. This work provides an integrated lab-on-a-chip design for quantitatively analyzing magnetically labeled cells and thus can promote MRI-based cell-tracking studies.


Homeostatic expansion versus antigen-driven proliferation: common ends by different means?
The requirements for T-cell proliferation driven by "space-filling" (homeostatic expansion) differ significantly from those for antigen-driven responses. Here we review these differences and discuss their implications for regulation of T-cell responses and the size of the T-cell compartment.


Nanolipid-loaded Preyssler polyoxometalate: Synthesis, characterization and invitro inhibitory effects on HepG2 tumor cells.
Polyoxometalate-based drugs have been selected by some researchers as alternative antitumor substances with promising results in suppression of tumor growth because of low toxicity towards the human body and high activity. In this research, for the first time, nanolipid-loaded Preyssler polyoxometalate with diameters of 230-250 nm was synthesized and characterized by the Transmission Electron Microscopy (TEM), Scanning Electron Microscopy (SEM), Energy Dispersive X-Ray Analysis (EDAX), Atomic Force Microscopy (AFM), and Infrared (IR) spectroscopy. The nanoliposomes were found to be nearly spherical, without any agglomeration with the Entrapment Efficiency of 53.8%. In -vitro antitumor activity of the synthesized nanoliposomes was investigated using the MTT method on HepG2 tumor cells. Our findings showed enhanced anticancer activity for the nanolipid-loaded Preyssler (NLP) compared to the Sorafenib as a commercially drug at 72 h. Selectivity of the synthesized NLP and Sorafenib for cancer cells versus primary HFF cells was obtained as 4.2 and 2.2, respectively. The IC50 value of the loaded nanoliposomes for cancer cells and normal cells was equal to 470 and 2000 μg/mL, respectively at 72 h, which was much better compared to that of the Sorafenib (7 and 16 μg/mL, respectively).


Implementing a protocol to prevent incisional hernia in high-risk patients: a mesh is a powerful tool.
The small bites (SB) technique for closure of elective midline laparotomies (EMLs) and a prophylactic mesh (PM) in high-risk patients are suggested by the guidelines to prevent incisional hernias (IHs) and fascial dehiscence (FD). Our aim was to implement a protocol combining both the techniques and to analyze its outcomes. Prospective data of all EMLs were collected for 2 years. Results were analyzed at 1 month and during follow-up. The incidence of HI and FD was compared by groups (M = Mesh vs. S = suture) and by subgroups depending on using SB. A lower number of FD appeared in the M group (OR 0.0692; 95% CI 0.008-0.56; P = 0.01) in 197 operations. After a mean follow-up of 29.23 months (N = 163; min. 6 months), with a lower frequency of IH in M group (OR 0.769; 95% CI 0.65-0.91; P < 0.0001). (33) The observed differences persisted after a propensity matching score: FD (OR 0.355; 95% CI 0.255-0.494; P < 0.0001) and IH (OR 0.394; 95% CI 0.24-0.61; P < 0.0001). On comparing suturing techniques by subgroups, both mesh subgroups had better outcomes. PM was the main factor related to the reduction of IH (HR 11.794; 95% CI 4.29-32.39; P < 0.0001). Following the protocol using PM and SB showed a lower rate of FD and HI. A PM is safe and effective for the prevention of both HI and FD after MLE, regardless of the closure technique used.


Comparison of neutrophil-to-lymphocyte ratio between myelin oligodendrocyte glycoprotein antibody-associated disease and aquaporin-4 antibody-positive neuromyelitis optica spectrum disorders in adults.
The neutrophil-to-lymphocyte ratio (NLR) is a biomarker for evaluating disease activity in systemic autoimmune diseases. However, few studies have discussed NLR changes in myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD). This study aimed to explore the NLR difference between MOGAD, aquaporin-4 antibody (AQP4-Ab)-positive neuromyelitis optica spectrum disorders (NMOSD), and healthy controls (HCs) and evaluate the clinical value of NLR in the differential diagnosis. We included 15 patients with MOGAD, 28 patients with AQP4-Ab-positive NMOSD, and 68 HCs. Their NLRs were calculated, and statistical analysis was performed, with statistical significance set at P < 0.05. In pairwise comparisons between three groups, P < 0.017 was considered statistically significant under Bonferroni correction. NLR was higher during the acute attack in MOGAD patients than HCs but lower than in AQP4-Ab-positive NMOSD patients. NLR was correlated with Expanded Disability Status Scale (EDSS) in MOGAD and AQP4-Ab-positive NMOSD patients. Also, there were no statistical differences in intracranial pressure between MOGAD and AQP4-Ab-positive NMOSD patients and HCs. The cut-off value was 2.86, and the sensitivity and specificity were 0.750 and 0.867, respectively. In conclusion, our results suggest that NLR may be a helpful marker to evaluate disease severity and differentiate between both diseases at a cut-off value of > 2.86 when patients have clinical symptoms like optic neuritis or myelitis.


Ontogeny of the transplantation immunity of mice for rejecting ascitic allogeneic tumors.
Ontogeny of the murine transplantation immunity for rejecting ascitic allogeneic tumors (chemically-induced RG lymphoma and L1210 leukemia) as a model of in vivo cytotoxic T cell immunity was studied. Challenge by 10(6) to 10(7) allogeneic tumor cells per 20 g body weight (b.w.) of the mouse was fatal to 1-3 day-old mice, whereas 7-30 day-old mice rejected the tumor. In newborn mice however some yet undetermined mechanism worked to temporally depress the initial tumor growth. Injection of low (10(6) cells per 20 g b.w.) to moderate (10(7)) doses of semiallogeneic spleen cells into newborn mice prepared for second set rejection of the tumor carrying the same alloantigens as the spleen cells, although injection of high dose (3 X 10(8)) cells reduced the tumor rejecting immunity. This second set rejection occurred even against the allogeneic tumor inoculated as early as 3 days old, if the mice had been primed with the alloantigens at birth. It appears therefore that newborn and early suckling mice are protected from tumor invasion by cytotoxic immunity more powerfully than expected from earlier in vitro works.


Facilitated transport of basic and acidic drugs in solutions through snakeskin by a new enhancer--dodecyl N,N-dimethylamino acetate.
The permeation characteristics of two model drugs, clonidine (basic) and indomethacin (acidic), were studied by determining their penetration fluxes through hydrated shed snakeskins (Elaphe obsoleta) at 32 degrees C. The drugs were formulated in buffers of different pH's, ranging from 3 to 7. The total penetration fluxes at pH 7.0 for both compounds using skins pretreated with dodecyl N,N-dimethylamino acetate were at least 11 times higher than those of the control runs without enhancer treatment. Equations were derived to calculate the permeability coefficients (Ki) and fluxes (Ji) for the ionized and the nonionized species to allow for comparison of their penetration ability through the model membrane. The permeability coefficient of clonidine is 2.50 x 10(-3) cm/hr for the nonionized form and 2.41 x 10(-4) cm/hr for the protonated form. This result indicates that the nonionized form penetrates the skins better than the ionized form. Both permeability coefficient values are 11 times larger than the corresponding values obtained from the control skins. The total flux of clonidine is dependent on its initial concentration in the donor cell but is independent of the ionic strength of the solution formulations. The penetration characteristics of indomethacin are similar to those of clonidine, with a higher permeability coefficient of the nonionized form (3.90 x 10(-3) cm/hr) than of the ionized form (7.97 x 10(-4) cm/hr) using pretreated skins. While the enhancer shows 24 times penetration enhancement of the ionized form of indomethacin, it does not enhance the penetration of the nonionized species.


MetaboLights: a resource evolving in response to the needs of its scientific community.
MetaboLights is a database for metabolomics studies, their raw experimental data and associated metadata. The database is cross-species and cross-technique and it covers metabolite structures and their reference spectra as well as their biological roles and locations. MetaboLights is the recommended metabolomics repository for a number of leading journals and ELIXIR, the European infrastructure for life science information. In this article, we describe the significant updates that we have made over the last two years to the resource to respond to the increasing amount and diversity of data being submitted by the metabolomics community. We refreshed the website and most importantly, our submission process was completely overhauled to enable us to deliver a far more user-friendly submission process and to facilitate the growing demand for reproducibility and integration with other 'omics. Metabolomics resources and data are available under the EMBL-EBI's Terms of Use via the web at https://www.ebi.ac.uk/metabolights and under Apache 2.0 at Github (https://github.com/EBI-Metabolights/).


[Update on vascular dementias].
The concept of vascular dementia greatly evolved since Hachinski's description of multi-infarct dementia. Vascular dementias are reviewed with emphasis on current diagnostic criteria, elusive natural history, neuroradiological aspects, difficult epidemiological features and intriguing links with Alzheimer's disease. The recent proposed shift from vascular dementias to a broader definition of "vascular cognitive disorders", including non demented subjects with "vascular cognitive impairment", is described, followed by a brief review of current treatments.


Use of an 125I-labelled DNA ligand to probe DNA structure.
It no longer seems likely that DNA molecules in situ have a uniform conformation, represented by the classical B-form helix. For example, recent structural studies have shown that in certain conditions DNA can have a left-handed (so-called Z-form) helix, and have revealed extensive sequence-dependent variations of B-DNA helical parameters. Such sequence-dependent variations in DNA structure can be investigated in solution with reagents that bind to DNA in a conformation-dependent manner, and cut one or both strands of the double-helix at the site of binding, as, for example, has been shown for the endonuclease DNase I3. We describe here a simple way to endow a DNA-binding ligand with the ability to cleave DNA--labelling with 125I. The radiochemical damage associated with 125I decay induces a double-stranded DNA break. Using this technique we have shown that a sequence of four consecutive A X T base pairs is a necessary, but not sufficient, condition for strong binding to DNA of the bis-benzamide Hoechst 33258--presumably the other important factor is the conformation of the double-helix at the site of the (A/T)4 sequence. We suggest 125I-Hoechst 33258 may be a useful new probe of DNA structure.


A unique role of p53 haploinsufficiency or loss in the development of acute myeloid leukemia with FLT3-ITD mutation.
With an incidence of ~50%, the absence or reduced protein level of p53 is much more common than TP53 mutations in acute myeloid leukemia (AML). AML with FLT3-ITD (internal tandem duplication) mutations has an unfavorable prognosis and is highly associated with wt-p53 dysfunction. While TP53 mutation in the presence of FLT3-ITD does not induce AML in mice, it is not clear whether p53 haploinsufficiency or loss cooperates with FLT3-ITD in the induction of AML. Here, we generated FLT3-ITD knock-in; p53 knockout (heterozygous and homozygous) double-transgenic mice and found that both alterations strongly cooperated in the induction of cytogenetically normal AML without increasing the self-renewal potential. At the molecular level, we found the strong upregulation of Htra3 and the downregulation of Lin28a, leading to enhanced proliferation and the inhibition of apoptosis and differentiation. The co-occurrence of Htra3 overexpression and Lin28a knockdown, in the presence of FLT3-ITD, induced AML with similar morphology as leukemic cells from double-transgenic mice. These leukemic cells were highly sensitive to the proteasome inhibitor carfilzomib. Carfilzomib strongly enhanced the activity of targeting AXL (upstream of FLT3) against murine and human leukemic cells. Our results unravel a unique role of p53 haploinsufficiency or loss in the development of FLT3-ITD + AML.


Social self-value intervention for empowerment of HIV infected people using antiretroviral treatment: a randomized controlled trial.
Prevention and antiretroviral therapy (ART) management for human immunodeficiency virus (HIV) infected people need to have long-term health care. An empowerment focused intervention is a procedure by which HIV infected people obtain combined possession of programs to attain mainly cost-effective HIV outcomes and deal with social and structural difficulties related to their universal health access and human rights. Empowerment is a key approach for addressing HIV related issues that focuses on addressing a broader context. However, the practices of empowerment based approaches are sparse. We assessed the effect of an intervention to empower HIV infected people receiving ART. In this open-label randomized controlled trial, HIV infected people from Nepal who were using ART from 6 to 24 months and were aged 18 years and above were randomly assigned to receive either the intervention or routine care. The intervention was led by two counselors for a period lasting six weeks. Participants were followed up at three and six months after the baseline. The primary outcome was change in empowerment scores, analyzed by using Difference-in-Difference (DiD). Between September and November 2014, 1447 HIV infected people were screened, of whom 132 were randomly assigned to the intervention (n = 66) or control (n = 66) group. All the participants completed the 3- and 6- months follow up. A significant difference in mean empowerment score was found between the groups at 3- (46.77, p-value <0.001) and 6- (49.71, p-value <0.001) months follow up. The average treatment effect (after matching intervention and control individuals) showed that the participants who received the intervention increased their mean empowerment scores from baseline by 47.05 (p-value <0.001, at three months) and 49.87 (p-value <0.001, at six months) than those who did not receive the intervention. No adverse events were reported. Social self-value intervention provided to HIV infected people during ART increased their empowerment. This intervention can be expanded to be utilized in routine services. Thai Clinical Trials Registry, number TCTR20140814002 .


The characteristics of [3H]-clonidine binding to an alpha-adrenoceptor in membranes from guinea-pig kidney.
1. [3H]-clonidine binds to membranes prepared from guinea-pig kidney. 2. At 25 degrees C the binding is rapid and saturable. 3. Scatchard analysis of the binding data showed that the Kd for [3H]-clonidine binding in kidney membranes is 8.54 nM and the density of binding sites 12.5 pmol/g wet wt. tissue. 4. Hill plots of the binding data showed that there were no cooperative site interactions associated with binding. 5. [3H]-clonidine binding could be displaced by drugs, the most potent being drugs with a high affinity for the alpha-adrenoceptor. The neuroleptic drugs (+)-butaclamol, cis-clopenthixol and cis-flupenthixol at high concentration also displaced [3H]-clonidine binding. 6. Drugs acting as agonists or antagonists of beta-adrenoceptors, histamine receptors, acetylcholine receptors as well as prostaglandins E1, E2, F1alpha and F2alpha, angiotensin II, arginine vasopressin, naloxone, nalorphine and pargyline had little effect on binding. 7. It is likely that the binding site labelled by [3H]-clonidine in guinea-pig kidney membranes is an alpha-adrenoceptor similar in some pharmacological aspects to an alpha2-adrenoceptor.


Polycystic ovary syndrome and epilepsy--a gynaecological perspective.
The prevalence of polycystic ovaries (PCO) and polycystic ovary syndrome (PCOS) in the general population is approximately 20 and 10%, respectively, and published studies suggest a similar prevalence in women with epilepsy. These data do not suggest that epilepsy is associated with a higher prevalence of the condition, and it would appear that the background prevalence of PCO and PCOS is the same as in the general population.


Effect of the naturally occurring prostaglandins E2 and F2 alpha on the human myometrium in vivo during pregnancy.
Hysterometry has been used to evaluate the effect on the human myometrium in vivo during early pregnancy of the naturally occurring prostaglandins E2 and F2 alpha. The hystermetric technique is based upon the fact that mechanical distension of smooth muscle induces contraction. According to the analysis of the contractile responses, the effects of the agents have been determined quantitatively. The drug effects have been characterized by changes in myometrial response between registrations under basic conditions and during the infusion of the active agent, respectively. It was found that when these drugs were given in the doses usually employed in clinical practice, the effect on contractility of the PGF2 alpha compound was more pronounced than that of the PGE2. However, when describing the results on a microgram basis, the PGE2 was confirmed to be more potent than the PGF2 alpha by a factor of up to 7-8.


Development of the Occupational Safety and Health Administration's proposed standard to protect workers from contracting bloodborne diseases in the workplace.
The Occupational Safety and Health Administration (OSHA) is in the process of developing a health standard to protect workers by reducing occupational exposure to hepatitis B virus, human immunodeficiency virus, and other bloodborne pathogens. This article reviews the history of the standard, the steps involved in OSHA standard development, and--most specifically--how the dental professional can participate in this process.


Opioid Initiation Within One Year After Starting a Digital Musculoskeletal (MSK) Program: An Observational, Longitudinal Study with Comparison Group.
In-person, conservative care may decrease opioid use for chronic musculoskeletal (MSK) pain, but the impact of digitally delivered conservative care on opioid use is unknown. This study examines associations between a digital MSK program and opioid initiation and prescriptions among opioid naive adults with chronic MSK pain. This observational study used commercial medical and pharmacy claims data to compare digital MSK program members to matched physical therapy (PT) patients. Outcomes were any opioid prescriptions and opioid prescriptions per 100 participants within the 12-months after starting a digital MSK program. After propensity-score matching, we conducted multivariate regression models that controlled for demographic, comorbidity, and baseline MSK healthcare use. The study included 4195 members and 4195 matched PT patients. For opioid initiation, 7.89% (95% Confidence Interval [CI]: 7.07%, 8.71%) of members had opioid prescriptions within 12 months after starting the digital MSK program versus 13.64% (95% CI: 12.60%, 14.67%) of matched PT patients (p < 0.001). Members had significantly fewer opioid prescriptions (16.73 per 100 participants; 95% CI: 14.11, 19.36) versus PT patients (22.36 per 100 participants; 95% CI: 19.99, 24.73). Members had lower odds (OR: 0.52, 95% CI: 0.45, 0.60) of initiating opioids and significantly fewer prescriptions per 100 participants (beta: -6.40, 95% CI: -9.88, -2.93) versus PT patients after controlling for available confounding factors. An MSK program that delivers conservative care digitally may be a promising approach for decreasing opioid initiation among individuals with chronic MSK pain given the limitations of the observational design and matching on only available covariates.


Increased platelet transfusion requirement is associated with multiple organ dysfunctions in patients undergoing hematopoietic stem cell transplantation.
Organ dysfunction following hematopoietic stem cell transplantation (HSCT) may be a manifestation of a systemic inflammatory response. We speculate that part of the platelet transfusion requirement in HSCT patients results from this systemic inflammatory response, and increased transfusion requirement would be associated with, or precede, organ dysfunction. We studied 199 adults undergoing autologous (n=173) or allogeneic (n=26) HSCT. Patients with CNS (P=0.008) or pulmonary (P=0.002) dysfunction, or with VOD (P=0.05) received a higher mean number of platelet transfusions per week than patients who did not have these dysfunctions. Furthermore, a higher number of platelet transfusions during any 1 week period was significantly associated with development of pulmonary (P=0.0002) or renal (P < 0.0001) dysfunction in the following week. This predictive value was strongest early in the HSCT course, but remained significant over all 4 weeks. In multivariate analysis the number of platelet transfusions during the previous week was independently predictive for development of pulmonary dysfunction in week 2 (P=0.01) and week 3 (P=0.055). We believe that occurrence of increased platelet transfusion requirement prior to onset of dysfunction is consistent with the concept that an antecedent inflammatory response results in both platelet consumption and various organ dysfunctions. Increased platelet transfusion requirement may act as an early marker of subsequent organ dysfunction. Additionally, there may be a direct role of platelets in the development and progression of organ dysfunction in HSCT patients.


Recovery of emulsifying and gelling protein from waste chicken exudate by using a sustainable pH-shifting treatment.
The inevitably generated chicken exudate was usually unconsciously discarded, leading to protein waste and environmental pollution. The study is performed to reveal the loss and constitute of different sourced exudate (purge exudate/defrozen exudate, PE/DE), investigate the efficiency of various pH-shifting strategies (Method I: NaOH-HCl, Method II: Ca(OH)2-Critric acid, and Method III: Ca(OH)2-Glucono δ-lactone) in recovering selected exudate, and evaluate the functionality of these recovered protein isolates. Accordingly, PE and DE shared greatly similar (P > 0.05) lipid and ash content. Despite sarcoplasmic protein, there are a small amount of functional myofibrillar protein in the exudate samples. During extraction, Method III had higher recovery yield (85.5%) than other two groups, but the isolates contained higher level of moisture. The protein isolates treated with Method II exhibited highest emulsion ability, while the Method III treated group obtained best gelation properties. Overall, pH-shifting could recover functional protein from chicken exudate for industrial application.


Angiopoietin-2 concentration in serum is associated with severe asthma phenotype.
Several proangiogenic molecules have been implicated in the pathogenies of asthmatic inflammation and remodeling. The aim of the study was to compare the concentration of proangiogenic factors in the sera of asthmatic patients and in healthy subjects (HS), and to refer the concentrations to both clinical and inflammatory markers of the disease severity. Serum was collected from 45 patients with severe/refractory asthma (SRA) and 51 patients with non-severe asthma (nSA). The control group included 30 HS. Serum concentrations of Angiopoietin-1, Angiopoietin-2, vascular endothelial growth factor (VEGF) and osteopontin were assessed by the enzyme-linked immunosorbent assay. The levels of Angiopoietin-1 (68.8 ± 2.7 vs 56.4 ± 9.3 ng/ml; p < 0.05), Angiopoietin-2 (4.9 ± 0.35 vs 1.38 ± 0.14 ng/ml; p < 0.0001) and VEGF were significantly higher in asthmatic patients (n = 94) as compared to HS (255 ± 45.4 vs 424.5 ± 27.8 pg/ml; p < 0.01). The mean serum level of Angiopoietin-2 was found to be significantly higher in patients with SRA as compared to nSA patients (6.04 ± 0.46 vs 3.84 ± 0.43; p < 0.001). Angiopoietin-2 serum level correlated with respiratory function and with parameters of asthma severity: the mean number of asthma exacerbations in the preceding 12 months (R = 0.21; p < 0.05), mean number of emergency visits due to severe asthma exacerbation (R = 0.24; p < 0.04) and mean number of hospitalizations (R = 0.21; p < 0.05) or dose of inhaled glucocorticosteroids taken by the patients (R = 0.36; p < 0.001). Angiopoietin-2 seems to be a crucial proangiogenic cytokine overproduced in patients with SRA characterized by repeated exacerbations and Angiopoietin-2 serum levels can serve as a biomarker of severe asthma.


Germline sequencing for presumed germline pathogenic variants via tumor-only comprehensive genomic profiling.
The European Society for Medical Oncology Precision Medicine Working Group (ESMO-PMWG) published recommendations regarding confirmatory germline testing for presumed germline pathogenic variants (PGPVs) in tumor-only comprehensive genomic profiling (CGP). However, the clinical validity of these recommendations has not been investigated in a real-world practice. Medical records of 180 consecutive patients who obtained the results of a tumor-only CGP (FoundationOne® CDx, Foundation Medicine, Inc, Cambridge, MA, USA) between October 2018 and March 2020, were retrospectively reviewed. After excluding patients with no reported variants in 45 actionable genes (n = 6), or no archived germline DNA samples (n = 31), 143 patients were investigated. The PGPVs were selected from the CGP report and germline sequencing were performed using DNA samples archived in Clinical Bioresource Center in Kyoto University Hospital (Kyoto, Japan). A total of 195 variants were classified as PGPV based on the conventional criteria. Germline sequencing disclosed that 12 variants (6.2%) were of germline origin. In contrast, after filtering these 195 variants through the ESMO-PMWG recommendation criteria for confirmatory germline testing, following seven PGPVs, BRCA2 (n = 2), BRIP1 (n = 1), BAP1 (n = 1), PMS2 (n = 1), MSH2 (n = 1), and SDHB (n = 1) remained and six variants (85.7%) were confirmed to be of germline origin. Our current data suggested that the application of ESMO-PMWG criteria is helpful in selecting PGPVs with a high likelihood of germline origin in a tumor-only CGP in daily clinical practice.


Prenatal development of individual retinogeniculate axons during the period of segregation.
When connections are first formed during the development of the vertebrate nervous system, inputs from different sources are frequently intermixed and the specific adult pattern then emerges as the different inputs segregate from each other. During the prenatal development of connections between retina and lateral geniculate nucleus (LGN) in the cat, the projections from the two eyes initially overlap with each other within the LGN. Over the next 3 weeks a reduction in the amount of overlap occurs so that by birth, a segregated pattern similar to the adult is present. We report here that during the period of overlap, individual retinogeniculate axons are simple in shape and restricted in extent without any widespread branches. Further, the appearance of the segregated pattern of eye input is accompanied by the elaboration of extensive new axonal arbors within appropriate LGN territory accompanied by retraction of only a limited number of minor branches. This developmental strategy contrasts with that in other regions of the vertebrate central nervous system in which the orderly adult pattern of connections within a target is achieved by a relative reduction in the overall extent of the axon arbor.


Anti-VEGF-Induced Hypertension: a Review of Pathophysiology and Treatment Options.
Abnormal intracellular signaling has been implicated in the development of many different types of cancer. Therapies targeting these abnormal pathways have revolutionized the treatment of many malignancies leading to significantly improved outcomes and survival. Despite these advances, cardiovascular toxicity is a frequently reported complication. Angiogenesis is the physiologic process of new blood vessel development and can be dysregulated in some forms of cancer. VEGF inhibitors are the pharmaceutical agents targeting this pathway; however hypertension is a commonly observed toxicity which can have significant adverse consequences including premature cessation of therapy if adequate blood pressure control cannot be achieved. This review will provide a comprehensive discussion about hypertension due to VEGF inhibition, focusing on pathophysiology, frequently used agents, and available treatment options for VEGF-induced hypertension.