MS or not MS: T2-weighted imaging (T2WI)-based radiomic findings distinguish MS from its mimics.
Ischemic vasculopathy, particularly small-vessel disease, may mimic multiple sclerosis (MS) located in the periventricular or subcortical region on magnetic resonance (MR) examinations and should be included in the differential diagnosis of MS-like lesions. To evaluate the performance of a T2-weighted imaging (T2WI)-based radiomic signature to distinguish MS lesions from lesions corresponding to ischemic demyelination, which often mimics MS on MRI. A retrospective study was conducted in 38 patients (627 lesions) with MS and 914 patients (2466 lesions) with lesions mimicking ischemic demyelination in the periventricular or subcortical region. All patients underwent 3 T MRI. A total of 472 radiomic features were extracted from the T2WI data of each patient. Intraclass correlation coefficients were used to select the features with excellent stability and repeatability. Then, we used the minimum-redundancy maximum-relevance (mRMR) and least absolute shrinkage and selection operator (LASSO) algorithms for feature selection. After feature selection, various classifiers (including logistic regression, decision tree, AdaBoost, random forest (RF), or support vector machine (SVM)) were trained. The performance of each classifier was validated in the test set by determining the area under the curve (AUC). Nine features were selected to distinguish MS lesions from the similar lesions of ischemic demyelination. The radiomic signature showed a significant difference between the MS and ischemic demyelination patients (p < 0.01). RF and SVM were overfitted. The LASSO logistic regression model was the best-performing radiomic model,with an AUC, accuracy, sensitivity, and specificity of 0.900 (95% CI: 0.883-0.918), 87.0%, 58.9% and 95.2%, respectively, in the training set and 0.828 (95% CI: 0.791-0.864), 87.7%, 53.6% and 94.4%, respectively, in the validation set. The T2WI-based radiomic signature can effectively differentiate MS patients from patients with MS-like lesions due to ischemic demyelination.


Richter's Transformation.
Richter's transformation (RT) occurs when chronic (CLL) transforms into an aggressive lymphoma. Despite improvements in the treatment of CLL, prognosis for RT remains poor. Here, we review current literature of RT, with a focus on novel treatment options. Efforts are underway to improve outcomes for patients with RT. While small molecule inhibitors have limited efficacy as monotherapy, recent developments combining them with chemo-immunotherapy show promise. Studies exploring the use of cellular therapies including chimeric antigen receptor T-cells and bispecific antibodies are ongoing. The current treatment paradigm for RT is to enroll these patients on a clinical trial when available, together with consultation for a consolidative allogeneic stem cell transplant. Trials investigating novel combinations and cellular therapy are ongoing. Determining predictive variables of transformation is imperative to design studies that allow for early identification and intervention for patients with RT.


Sequence of fimbrial subunit-encoding genes from virulent and benign isolates of Dichelobacter (Bacteroides) nodosus.
Both virulent and benign isolates of the ovine pathogen Dichelobacter (Bacteroides) nodosus produce polar fimbriae which have been implicated in twitching motility. The fimbrial subunit-encoding genes from two virulent and two benign serogroup-B isolates of D. nodosus were cloned and sequenced. Analysis of the deduced amino acid (aa) sequences of these subunits indicated the presence of substitutions that appeared to correlate with the virulence phenotype. However, these aa substitutions were located in variable regions of the protein where they are unlikely to alter the functional properties of the fimbriae. The aa sequences of the serogroup-B subunits had a very high level (91-95%) of similarity, particularly at the N terminus, where the conserved region extended up to aa 61. Specific aa substitutions within the subunit of one isolate may reflect its serotypic variation from the other serogroup-B subunits studied.


Non-invasive treatment for retained common bile duct stones in patients with T tube in situ: saline washout after intravenous ceruletide.
The combination of ceruletide-induced relaxation of the sphincter of Oddi plus flushing with saline has recently been proposed as a novel procedure for the treatment of residual common bile duct (CBD) stones. In this study we have administered intravenous ceruletide (2 ng kg-1 body weight min-1 for 1 h) plus intraductal saline (800-3000 ml, infused at a rate that kept biliary pressure below 30 cmH2O) to a group of 14 patients. The treatment induced the passage of residual stones in 11 subjects (79 per cent) with complete clearance in 7 (50 per cent). The majority of the cleared concretions (11/15) had a diameter less than 10 mm. No severe side-effects were recorded during the treatment. Four of the seven subjects who exhibited incomplete CBD clearance underwent a short cycle of mono-octanoin administration in order to reduce the size of residual radiolucent stones. This course of treatment was followed by another attempt with intravenous ceruletide and saline washout which gave a successful response in an additional three cases. These data indicate that the combination of ceruletide and flushing is a safe and inexpensive method for treatment of residual stones. The procedure is feasible for both radiolucent and radio-opaque stones and is mainly eligible for small concretions of diameter less than 10 mm. Larger (greater than 10 mm) radiolucent stones may be partially dissolved with mono-octanoin and then eliminated by the washout technique.


Gallbladder management in obesity surgery.
In the 1980s, some surgeons recommended routine cholecystectomy for patients undergoing bariatric surgery. This was based on the high prevalence of gallstones in the obese and concern that rapid weight loss would increase the risk of gallbladder disease. Others recommended waiting for a lower weight and a definite need. With increasing prevalence and severity of obesity and increased use of gastric reduction surgery for weight control, it seemed appropriate to review the current standard of care for cholecystectomy. A survey was also made of ursodeoxycholic acid usage for prevention of gallstone formation. Data collected from active contributors for the 28th Report of the International Bariatric Surgery Registry (IBSR) were examined. Two questionnaires were also sent to members of the American Society for Bariatric Surgery (ASBS). The first (Q1) asked about the indications for cholecystectomy. The second (Q2) asked about ursodeoxycholic acid usage for prevention of gallstone formation during rapid weight loss following surgical treatment of obesity. There has been an increase in concurrent cholecystectomy during the last 15 years. Some of this is due to a shift from simple gastric restrictive operations to gastric bypass with gastric restriction. When the most extensive bypass of intestine is used, as in distal Roux-en-Y gastric bypass (RYGBP-X) or biliopancreatic diversion with a duodenal switch (BPD-DS), all patients were reported to have undergone cholecystectomy. Only 30% of surgeons performing standard Roux-en-Y gastric bypass (RYGBP) remove normal-appearing gallbladders. Ursodeoxycholic acid is used to prevent gallstone formation in one-third of patients when a normal-appearing gallbladder is left in place. Prophylactic cholecystectomy is left to the discretion of the surgeon when RYGBP is used. There has been an increase in cholecystectomy and malabsorptive operations during the last 15 years. When most of the small bowel is bypassed, all remaining gallbladders are removed. For patients with simple restriction operations, normal-appearing gallbladders are usually left in place. Urso-deoxycholic acid during rapid weight loss for prevention of gallstone formation is used in one-third of patients with remaining gallbladders.


Radiology-pathology conference: cutaneous angiosarcoma of the leg.
Cutaneous angiosarcoma is a rare aggressive vascular neoplasm with a poor prognosis, seen usually in the elderly population in a background of chronic lymphedema. We present a case of cutaneous angiosarcoma of the leg without any chronic lymphedema with clinicoradiological and histological correlation.


Atopy in children with the enthesitis-related arthritis (ERA) subtype of juvenile idiopathic arthritis is associated with a worse outcome.
We aimed to assess the influence of co-existing atopy on the prognosis of enthesitis-related arthritis (ERA). Patients diagnosed with ERA between March 2006 and August 2012 were enrolled in a prospective cohort study and followed for 2 years. Management of patients was evaluated using the American College of Rheumatology (ACR) pediatric (Pedi) 30/50/70 criteria and laboratory variables. A total of 151 ERA patients were enrolled at diagnosis and were divided into those with atopy (n = 62) and those without (n = 89). When compared with the non-atopic group, atopic patients had significantly more active joints at disease onset (4.72 vs. 3.75), more joints with limitation of motion (LOM) (1.45 vs. 0.87), more painful joints (3.61 vs. 2.80), and more swollen joints (1.02 vs. 0.69) (p < 0.05 for all comparisons). At 3, 6, 12, 18, and 24 months, fewer ERA patients with atopy reached the ACR Pedi 50 and 70 criteria (at 3 months, 25.8 vs. 60.7 % and 11.3 vs. 34.8 %, respectively; at 6 months, 50 vs. 77.5 % and 22.6 vs. 58.4 %, respectively; at 12 months, 53.2 vs. 70.8 % and 33.9 vs. 55.1 %, respectively; at 18 months, 62.9 vs. 86.5 % and 56.5 vs. 78.7 %, respectively; at 24 months, 66.1 vs. 89.9 % and 61.3 vs. 78.7 %, respectively; all p < 0.05). During the 2 years of follow-up, the number of flares was significantly higher in ERA patients with co-existing atopy (1.48 vs. 0.70, p < 0.05). Co-existing atopy in children with ERA may exert an adverse influence on ERA, with atopic patients manifesting more active disease at diagnosis and poorer outcome. \


Temporal trends in the levels of metals, PCDD/Fs and PCBs in the vicinity of a municipal solid waste incinerator. Preliminary assessment of human health risks.
The concentrations of PCDD/Fs, PCBs, and metals were determined in soil and air samples collected near a municipal solid waste incinerator (MSWI) located in Mataró (Catalonia, Spain), being the health risks for the population living in the vicinity of the facility subsequently assessed. We also established the temporal trends with respect to previous surveys performed in the same zone. In general terms, the highest environmental levels of the pollutants were found in the city of Mataró and were independent on the distance to the MSWI. Soil levels of metals did not show temporal variations between the current and previous campaigns. However, the concentrations of metals in air samples collected in 2011 and 2013, were lower than those found in our 2008 survey. Regarding PCDD/Fs and PCBs, no differences were noted between the levels of the current survey and those corresponding to 2008. Anyhow, the concentrations of metals, PCDD/Fs, and PCBs in soils and air did not exceed the reference values established by regulatory organizations, being also in the low range of other similar studies recently reported. Finally, the human non-carcinogenic and carcinogenic risks due to exposure to metals, PCDD/Fs, and PCBs, were, for the population living in the neighborhood of the MSWI, considered as acceptable according to international standards.


Fluctuating dermatoglyphic asymmetry in psychotic twins.
Fluctuating asymmetry of bilateral morphological traits is the result of prenatal developmental instability and has been shown to be greater in organisms having more homozygous genotypes (aabb vs. AaBb, for example). This expected increase in fluctuating asymmetry has been found among individuals having a high degree of liability for schizophrenia, as this disorder appears to have a polygenic basis. We tested the additional prediction that the greater genetic liability for schizophrenia necessary for concordance between twins should be associated with greater fluctuating asymmetry in twin pairs in which both twins are mentally ill compared to twin pairs in which one individual is normal. Our analysis of asymmetry for finger ridge counts from fingerprints of concordant and discordant pairs of twins supports this prediction and provides additional indirect support for the roles of polygenic transmission and prenatal epigenetic vulnerability in schizophrenia.


Deciphering Structure-Activity Relationships in a Series of 2,2-Dimethylchromans Acting as Inhibitors of Insulin Release and Smooth Muscle Relaxants.
4,6-Disubstituted 2,2-dimethylchromans are reported as pharmacologically active compounds that mainly target the ATP-sensitive potassium channels. The present study is an attempt to characterize the impact of the nature of substituents introduced at the 4- and 6-positions of 2,2-dimethylchromans on their capacities to inhibit insulin release from pancreatic β-cells or to relax vascular smooth muscle cells, both biological responses that are supposed to reflect interaction with specific ion channels. From the core structure 4-amino-2,2-dimethylchroman, a progressive increase in the steric hindrance of the chemical functionalities introduced at the 4-position (amino, formamido, acetamido, arylureido/thioureido) and at the 6-position (amino, formamido, acetamido, alkoxycarbonylamino) led to a progressive magnification of the inhibitory effect on the insulin release process and, to a lesser extent, of the vasorelaxant activity. Moreover, the dextrorotatory enantiomer of 2,2-dimethylchroman compound 29 was more potent than its levorotatory counterpart for inhibiting the insulin secretory process. Additional pharmacological investigations suggested, however, that the myorelaxant activity of 11 and 15 resulted from a direct Ca2+ entry blockade.


Global cerebral infarction after aortic arch replacement surgery in a patient with postoperatively revealed factor XII deficiency: a case report.
This case report presents a case of a patient with global cerebral infarction of uncertain etiology following an emergency surgery for acute type A aortic dissection. As a result, factor XII deficiency was revealed postoperatively. To date, there have been several reports of cardiovascular surgery in patients with factor XII deficiency. However, all previous reports were of patients whose factor XII deficiency had been detected preoperatively; therefore, before this, there had been no reports of complications associated with factor XII deficiency following cardiovascular surgery. We report a case of emergency aortic arch replacement surgery for acute type A aortic dissection in a 57-year-old Japanese man. A blood test prior to the surgery showed coagulopathy, a platelet count of 117 × 109/L, a prothrombin time-international normalized ratio of 1.78, an activated partial thromboplastin time of 69.7 seconds, and fibrinogen < 50 mg/dl. A smaller-than-usual dose of heparin (8000 IU) was administered because the patient's activated clotting time was extremely prolonged (> 999 seconds). After the heparin administration, the activated clotting time, measured every 30-60 minutes, remained unchanged (> 999 seconds); therefore, additional heparin was not administered during the surgery, and there was no clinical problem during cardiopulmonary bypass. However, a diagnosis of global cerebral infarction was made on the first postoperative day. An additional blood coagulation test performed on postoperative day 9 revealed factor XII deficiency (8.0%). Regarding the reason that global cerebral infarction occurred in the present case, two reasons were considered: One was factor XII deficiency itself, and the other was low-dose heparin administration during the cardiopulmonary bypass due to excessively prolonged activated clotting time caused by factor XII deficiency. Factor XII deficiency should be considered in patients with prolonged activated clotting time and spontaneous thrombosis in vascular surgeries. Moreover, the present case emphasizes that management of heparin during cardiopulmonary bypass should not be performed on the basis of activated clotting time monitoring alone, especially in a case with prolonged activated clotting time.


Sleep and Cognition: A Narrative Review Focused on Older Adults.
Little is known regarding sleep's association with the traditional developmental course of late-life cognitive functioning. As the number of older adults increases worldwide, an enhanced understanding of age-related changes in sleep and cognition is necessary to slow decline and promote optimal aging. This review synthesizes the extant literature on sleep and cognitive function in healthy older adults, older adults with insomnia, and older adults with sleep apnea, incorporating information on the potential promising effects of treating poor sleep on cognitive outcomes in older adults. Unifying theories of the sleep-cognition association, possible mechanisms of action, and important unanswered questions are identified.


Effects of levosimendan on indocyanine green plasma disappearance rate and the gastric mucosal-arterial pCO2 gradient in abdominal aortic aneurysm surgery.
Levosimendan has a dual mechanism of action: it improves myocardial contractility and causes vasodilatation without increasing myocardial oxygen demand. In a laboratory setting, it selectively increases gastric mucosal oxygenation in particular and splanchnic perfusion in general. The aim of our study was to describe the effects of levosimendan on systemic and splanchnic circulation during and after abdominal aortic surgery. Twenty abdominal aortic aneurysm surgery patients were randomized to receive either levosimendan (n=10) or placebo (n=10) in a double-blinded manner. Both the mode of anaesthesia and the surgical procedures were performed according to the local guidelines. Automatic gas tonometry was used to measure the gastric mucosal partial pressure of carbon dioxide. Systemic indocyanine green clearance plasma disappearance rate (ICG-PDR) was used to estimate the total splanchnic blood flow. The immediate post-operative recovery was uneventful in the two groups with a comparable, overnight length of stay in the intensive care unit. Cumulative doses of additional vasoactive drugs were comparable between the groups, with a tendency towards a higher cumulative dose of noradrenaline in the levosimendan group. After aortic clamping, the cardiac index was higher [4(3.8-4.7) l/min/m(2) vs. 2.6(2.3-3.6) l/min/m(2); P<0.05] and the gastric mucosal-arterial pCO(2) gradient was lower in levosimendan-treated patients [0.9(0.6-1.2) kPa vs. 1.7(1.2-2.1) kPa; (P<0.05)]. However, the total splanchnic blood flow, estimated by ICG-PDR, was comparable [29(21-29)% vs. 20(19-25)%; NS]. Organ dysfunction scores (sequential organ dysfunction assessment) were similar between the groups on the fifth post-operative day. Levosimendan favours gastric perfusion but appears not to have a major effect on total splanchnic perfusion in patients undergoing an elective aortic aneurysm operation.


Xanthogranulomatous orchitis: Review of the published work, and report of one case.
Xanthogranulomatous reaction is rare begin disease affects many different organs, in clinical practice it is well known to affect kidney and gallbladder, but also affect male genital organs including (Testis, epididymis, and spermatic cord), we report a case 70-year old, diabetic patient presented with right scrotal swelling, had history of prior TURP, tumor markers was within normal range, ultrasound shows multiple hypo echoic lesions with moderate hydrocele, exploration done: pus found within tunica vaginalis, and destructed testicular tissue with necrosis, culture revealed (E.Coli), histopathology showed xanthogranulomatous orchitis.


An approach to enhance carbon/polymer interface compatibility for lithium-ion supercapacitors.
Developing high-efficiency and easy machining components, as well as high-performance energy storage components, is a pressing issue on the road to economic and social progress. Optimizing the interface compatibility between composites and promoting the efficient utilization of the electrochemical active sites are crucial factors in improving the electrochemical performance of composite electrode materials. To address this challenge, a carbon-based flexible lithium-ion supercapacitor positive material (Polyaniline @ Carbon Foam-Supercritical carbon dioxide (P@C-SC)) is synthesized using commercial melamine foam and aniline monomer. The synthesis process utilizes supercritical fluid technology, effectively solving the interface compatibility problem between the composite materials. Consequently, the electrochemical performance of the composite electrode materials is significantly improved. The supercapacitive properties of this material are investigated in 1 mol/L sulfuric acid (H2SO4) and lithium sulfate (Li2SO4) electrolytes using a three-electrode system. In H2SO4 electrolyte, the material exhibits a working voltage of up to 2.2 V and a specific capacitance of 898F/g (at 1 A/g), resulting in a maximum energy density of 50.8 Wh kg-1. Furthermore, this electrode demonstrates superior lithium storage performance, with a specific capacity of approximately 900 mAh/g (at 1 A/g) and a retention of about 400 mAh/g after 200 cycles, along with a coulomb efficiency of 100%. This work offers insights into the integrated design of composite materials with improved electrochemical properties and interface compatibility, thus providing potential applicability of supercritical fluids in the field of lithium-ion supercapacitors.


The burden of kidney cancer and its attributable risk factors in 195 countries and territories, 1990-2017.
Kidney cancer globally accounts for more than 131,000 deaths each year and has been found to place a large economic burden on society. However, there are no recent articles on the burden of kidney cancer across the world. The aim of this study was to present a status report on the incidence, mortality and disability-adjusted life years (DALYs) associated with kidney cancer in 195 countries, from 1990 to 2017. Vital registration and cancer registry data (total of 23,660 site-years) were used to generate the estimates. Mortality was estimated first and the incidence and DALYs were calculated based on the estimated mortality values. All estimates were presented as counts and age-standardised rates per 100,000 population. The estimated rates were calculated by age, sex and according to the Socio-Demographic Index (SDI). In 2017, kidney cancer accounted for 393.0 thousand (95% UI: 371.0-404.6) incident cases, 138.5 thousand (95% UI: 128.7-142.5) deaths and 3.3 million (95% UI: 3.1-3.4) DALYs globally. The global age-standardised rates for the incidence, deaths and DALY were 4.9 (95% UI: 4.7-5.1), 1.7 (95% UI: 1.6-1.8) and 41.1 (95% UI: 38.7-42.5), respectively. Uruguay [15.8 (95% UI: 13.6-19.0)] and Bangladesh [1.5 (95% UI: 1.0-1.8)] had highest and lowest age-standardised incidence rates, respectively. The age-standardised death rates varied substantially from 0.47 (95% UI: 0.34-0.58) in Bangladesh to 5.6 (95% UI: 4.6-6.1) in the Czech Republic. Incidence and mortality rates were higher among males, than females, across all age groups, with the highest rates for both sexes being observed in the 95+ age group. Generally, positive associations were found between each country's age-standardised DALY rate and their corresponding SDI. The considerable burden of kidney cancer was attributable to high body mass index (18.5%) and smoking (16.6%) in both sexes. There are large inter-country differences in the burden of kidney cancer and it is generally higher in countries with a high SDI. The findings from this study provide much needed information for those in each country that are making health-related decisions about priority areas, resource allocation, and the effectiveness of prevention programmes. The results of our study also highlight the need for renewed efforts to reduce exposure to the kidney cancer risk factors and to improve the prevention and the early detection of this disease.


Neuropsychiatric outcome in subgroups of Intensive Care Unit survivors: Implications for after-care.
Poor neuropsychiatric outcomes are common in survivors of critical illness but it is unclear what patient groups to target for interventions to improve mental health. We compared anxiety, depression, and post-traumatic stress disorder (PTSD) symptoms and health-related quality of life (HrQoL) across different subgroups of Intensive Care Unit (ICU) survivors. A single-center cohort study was conducted in a mixed-ICU in the Netherlands among survivors of an ICU admission ≥48 h (n = 1730). Survivors received a survey one year after discharge, containing the Hospital Anxiety and Depression Scale (HADS), Impact of Event Scale (IES/IES-R), and EQ-5D (response rate of 67%). Neuropsychiatric symptoms and quality of life were evaluated in a priori defined subgroups, by chi-square tests and Mann-Whitney U tests. Symptoms of anxiety (HADS anxiety ≥8), depression (HADS depression ≥8), and PTSD (IES ≥35; IES-R ≥ 1.6) were reported by 34%, 33%, and 19% of ICU survivors, with a median HrQoL utility score of 0.81 (IQR:0.65-1.00). These figures were similar for survivors of ARDS, sepsis, severe multiple organ failure (SOFA>11), or ICU stay ≥7 days. This underlines the importance of prevention and treatment for neuropsychiatric symptoms in ICU survivors in general, not only in specific patient groups.


Activation of phospholipase A2 and beta-thromboglobulin release in human platelets: comparative effects of thrombin and fluoroaluminate stimulation.
Several reports have suggested that the activity of platelet phospholipase A2 is modulated by GTP-binding protein(s) whose nature and properties need to be defined. Fluoroaluminate is known to activate G-proteins and this leads to a number of cellular responses including the activation of phospholipases. This paper demonstrates that human platelets, prelabelled with [3H]arachidonic acid, produce free arachidonic acid when stimulated with fluoroaluminate and this effect is time- and dose-dependent. The production of arachidonic acid is not inhibited by neomycin, a PI-cycle inhibitor, but is completely abolished by mepacrine, an inhibitor of both phospholipase A2 and C. At low concentration of fluoroaluminate (10 mM NaF) phospholipase A2 but not phospholipase C is activated. In addition, fluoroaluminate treatment releases beta-thromboglobulin (beta-TG) and this effect is not inhibited by acetylsalicylic acid. Under identical conditions both neomycin and mepacrine suppress the release of arachidonic acid and beta-TG induced by thrombin. Sodium nitroprusside, which increases cGMP levels in platelets, inhibits arachidonic acid liberation and beta-TG release in thrombin-stimulated platelets but has no effect in fluoroaluminate-treated platelets; cGMP was reported to suppress phospholipase C activation. These results are consistent with the hypothesis that, in thrombin-stimulated platelets, the liberation of arachidonic acid and beta-TG are strictly dependent on the activation of phospholipase C. We have also provided evidence for the existence of a phospholipase A2 activated by a G-protein which is independent from the degradation of phosphoinositides and, contrary to phospholipase C, it is not down regulated by cGMP.


Pharmacogenetics of immunosuppressants: State of the art and clinical implementation - recommendations from the French National Network of Pharmacogenetics (RNPGx).
Therapeutic drug monitoring is already widely used for immunosuppressive drugs due to their narrow therapeutic index. This article summarizes evidence reported in the literature regarding the pharmacogenetics of (i) immunosuppressive drugs used in transplantation and (ii) azathioprine used in chronic inflammatory bowel disease. The conditions of use of currently available major pharmacogenetic tests are detailed and recommendations are provided based on a scale established by the RNPGx scoring tests as "essential", "advisable" and "potentially useful". Other applications for which the level of evidence is still debated are also discussed.


Fecal indicator bacteria and Salmonella in ponds managed as bird habitat, San Francisco Bay, California, USA.
Throughout the world, coastal resource managers are encouraging the restoration of previously modified coastal habitats back into wetlands and managed ponds for their ecosystem value. Because many coastal wetlands are adjacent to urban centers and waters used for human recreation, it is important to understand how wildlife can affect water quality. We measured fecal indicator bacteria (FIB) concentrations, presence/absence of Salmonella, bird abundance, and physico-chemical parameters in two coastal, managed ponds and adjacent sloughs for 4 weeks during the summer and winter in 2006. We characterized the microbial water quality in these waters relative to state water-quality standards and examined the relationship between FIB, bird abundance, and physico-chemical parameters. A box model approach was utilized to determine the net source or sink of FIB in the ponds during the study periods. FIB concentrations often exceeded state standards, particularly in the summer, and microbial water quality in the sloughs was generally lower than in ponds during both seasons. Specifically, the inflow of water from the sloughs to the ponds during the summer, more so than waterfowl use, appeared to increase the FIB concentrations in the ponds. The box model results suggested that the ponds served as net wetland sources and sinks for FIB, and high bird abundances in the winter likely contributed to net winter source terms for two of the three FIB in both ponds. Eight serovars of the human pathogen Salmonella were isolated from slough and pond waters, although the source of the pathogen to these wetlands was not identified. Thus, it appeared that factors other than bird abundance were most important in modulating FIB concentrations in these ponds.


Monitoring prevention or emergence of HIV drug resistance: results of a population-based foundational survey of early warning indicators in mainland Tanzania.
In Tanzania, routine individual-level testing for HIV drug resistance (HIVDR) using laboratory genotyping and phenotyping is not feasible due to resource constraints. To monitor the prevention or emergence of HIVDR at a population level, WHO developed generic strategies to be adapted by countries, which include a set of early warning indicators (EWIs). To establish a baseline of EWIs, we conducted a retrospective longitudinal survey of 35 purposively sampled care and treatment clinics in 17 regions of mainland Tanzania. We extracted data relevant for four EWIs (ART prescribing practices, patients lost to follow-up 12 months after ART initiation, retention on first-line ART at 12 months, and ART clinic appointment keeping in the first 12 months) from the patient monitoring system on patients who initiated ART at each respective facility in 2010. We uploaded patient information into WHO HIVResNet excel-based tool to compute national and facility averages of the EWIs and tested for associations between various programmatic factors and EWI performance using Fisher's Exact Test. All sampled facilities met the WHO EWI target (100%) for ART prescribing practices. However, the national averages for patients lost to follow-up 12 months after ART initiation, retention on first-line ART at 12 months, and ART clinic appointment keeping in the first 12 months fell short, at 26%, 54% and 38%, respectively, compared to the WHO targets ≤ 20%, ≥ 70%, and ≥ 80%. Clinics with fewer patients lost to follow-up 12 months after ART initiation and more patients retained on first-line-ART at 12 months were more likely to have their patients spend the longest time in the facility (including wait-time and time with providers), (p = 0.011 and 0.007, respectively). Tanzania performed very well in EWI 1a, ART prescribing practices. However, its performance in other three EWIs was far below the WHO targets. This study provides a baseline for future monitoring of EWIs in Tanzania and highlights areas for improvement in the management of ART patients in order not only to prevent emergence of HIVDR due to programmatic factors, but also to improve the quality of life for ART patients.


Mapping Risk of Nipah Virus Transmission from Bats to Humans in Thailand.
Nipah virus (NiV) is a zoonotic virus that can pose a serious threat to human and livestock health. Old-world fruit bats (Pteropus spp.) are the natural reservoir hosts for NiV, and Pteropus lylei, Lyle's flying fox, is an important host of NiV in mainland Southeast Asia. NiV can be transmitted from bats to humans directly via bat-contaminated foods (i.e., date palm sap or fruit) or indirectly via livestock or other intermediate animal hosts. Here we construct risk maps for NiV spillover and transmission by combining ecological niche models for the P. lylei bat reservoir with other spatial data related to direct or indirect NiV transmission (livestock density, foodborne sources including fruit production, and human population). We predict the current and future (2050 and 2070) distribution of P. lylei across Thailand, Cambodia, and Vietnam. Our best-fit model predicted that central and western regions of Thailand and small areas in Cambodia are currently the most suitable habitats for P. lylei. However, due to climate change, the species range is predicted to expand to include lower northern, northeastern, eastern, and upper southern Thailand and almost all of Cambodia and lower southern Vietnam. This expansion will create additional risk areas for human infection from P. lylei in Thailand. Our combined predictive risk maps showed that central Thailand, inhabited by 2.3 million people, is considered highly suitable for the zoonotic transmission of NiV from P. lylei. These current and future NiV transmission risk maps can be used to prioritize sites for active virus surveillance and developing awareness and prevention programs to reduce the risk of NiV spillover and spread in Thailand.


Experimental therapy of human endometrial cancers with a targeted cytotoxic bombesin analog AN-215: low induction of multidrug resistance proteins.
In this study we have investigated the efficacy and toxicity of targeted cytotoxic bombesin (BN) analog AN-215 and its effects on the expression of three multidrug resistance proteins in experimental human endometrial cancers. Nude mice bearing HEC-1A, RL-95-2 and AN3CA tumours were treated with AN-215 and its cytotoxic radical (AN-201). The BN receptor expression in tumours was followed by RT-PCR analysis and radioligand binding assays. Expression of drug resistance proteins MDR-1, MRP-1 and BCRP were measured by realtime PCR. AN-215 significantly (P<0.05) inhibited the growth of HEC-1A, RL-95-2 and AN3CA tumours while AN-201 was ineffective. The expression of BN receptors was demonstrated in all three tumour models. AN-215 caused a lower induction of MDR-1 in HEC-1A and RL-95-2 cancers than AN-201. MRP-1 and BCRP were not induced by AN-215 or AN-201. Thus, targeted chemotherapy with AN-215 powerfully inhibits the growth of human BN receptor-positive endometrial cancers.


First report of Rhodnius montenegrensis (Hemiptera: Reduviidae: Triatominae) infection by Trypanosoma rangeli.
This study reports for the first time the infection of Rhodnius montenegrensis by Trypanosoma rangeli. The triatomines were manually collected in Attalea speciosa in the municipality of Buritis, Rondônia. The identification of the trypanosomatid species was confirmed by multiplex PCR. All of the collected triatomines were R. montenegrensis. The analysis confirmed that all of the adults were infected with the epimastigote form of T. rangeli. This report of a new vector of T. rangeli raises a warning for the State of Rondônia because the simultaneous presence of T. rangeli with T. cruzi in the same geographic region enables the occurrence of mixed infections in hosts and vectors, which complicates the differential diagnosis.


Perineal wound healing after proctectomy for inflammatory bowel disease.
One hundred fifty-one cases of patients who underwent proctectomy for inflammatory bowel disease at the Lahey Clinic were analyzed with respect to the factors that predispose to delay in perineal wound healing. Significantly poorer healing took place in patients with Crohn's colitis, in men with ulcerative colitis, and in patients with ulcerative colitis who underwent one-stage operations. Factors that were not statistically significant but that appeared to contribute to delay in healing were younger age of patients and presence of anal fistula. A comparison is made with the results of other series, and recommendations for treatment and prevention are presented.


Nomimicin, a new spirotetronate-class polyketide from an actinomycete of the genus Actinomadura.
Nomimicin (1), a new spirotetronate-class polyketide, was isolated from the culture broth of an actinomycete of the genus Actinomadura. Its structure was established by spectroscopic methods, and the absolute configuration was determined by a combination of NOESY experiment, J-based configuration analysis and the modified Mosher method. Nomimicin (1) showed antimicrobial activity against Micrococcus luteus, Candida albicans and Kluyveromyces fragilis.


Rational development of capecitabine.
Capecitabine is a fluoropyrimidine carbamate that was rationally designed as an oral drug capable of mimicking continuous infusion 5-fluorouracil (5-FU) and delivering 5-FU preferentially to tumour tissue. Following extensive absorption, capecitabine is rapidly converted to 5-FU via a three-step enzymatic pathway. The final step depends on thymidine phosphorylase, an enzyme present at higher concentrations in malignant compared with normal tissue. This results in the delivery of 5-FU preferentially to the tumour site. Capecitabine has demonstrated high activity in preclinical xenograft models for a wide range of human solid tumours, including those resistant to 5-FU. Phase I studies have determined the maximum tolerated dose (MTD) of capecitabine and identified a number of dosage regimens, which were subsequently evaluated in a randomised, phase II study as first-line treatment for metastatic colorectal cancer. This established an intermittent regimen of capecitabine 1250 mg/m2 twice daily for 14 days followed by a 7-day rest period as the most appropriate regimen for further clinical development.


Genome-wide association study reveals 14 new SNPs and confirms two structural variants highly associated with the horned/polled phenotype in goats.
There is a long-term interest in investigating the genetic basis of the horned/polled phenotype in domestic goats. Here, we report a genome-wide association study (GWAS) to detect the genetic loci affecting the polled phenotype in goats. We obtained a total of 13,980,209 biallelic SNPs, using the genotyping-by-sequencing data from 45 Jintang Black (JT) goats, which included 32 female and nine male goats, and four individuals with the polled intersex syndrome (PIS). Using a mixed-model based GWAS, we identified two association signals, which were located at 150,334,857-150,817,260 bp (P = 5.15 × 10- 119) and 128,286,704-131,306,537 bp (P = 2.74 × 10- 15) on chromosome 1. The genotype distributions of the 14 most significantly associated SNPs were completely correlated with horn status in goats, based on the whole-genome sequencing (WGS) data from JT and two other Chinese horned breeds. However, variant annotation suggested that none of the detected SNPs within the associated regions were plausible causal mutations. Via additional read-depth analyses and visual inspections of WGS data, we found a 10.1-kb deletion (CHI1:g. 129424781_129434939del) and a 480-kb duplication (CHI1:150,334,286-150,818,098 bp) encompassing two genes KCNJ15 and ERG in the associated regions of polled and PIS-affected goats. Notably, the 10.1-kb deletion also served as the insertion site for the 480-kb duplication, as validated by PCR and Sanger sequencing. Our WGS genotyping showed that all horned goats were homozygous for the reference alleles without either the structural variants (SVs), whereas the PIS-affected goats were homozygous for both the SVs. We also demonstrated that horned, polled, and PIS-affected individuals among 333 goats from JT and three other Chinese horned breeds can be accurately classified via PCR amplification and agarose gel electrophoresis of two fragments in both SVs. Our results revealed that two genomic regions on chromosome 1 are major loci affecting the polled phenotypes in goats. We provided a diagnostic PCR to accurately classify horned, polled, and PIS-affected goats, which will enable a reliable genetic test for the early-in-life prediction of horn status in goats.


Association Between Circulating Plasmacytoid Dendritic Cell Percentage and Blood Lead Levels in Children.
Lead (Pb) exposure is known to cause T helper 1 (Th1) to T helper 2 (Th2) shift in the immune response. The mechanism responsible for these effects is unclear. Plasmacytoid dendritic cells (pDCs) are known as the principal secretor of type 1 interferons (IFNs), which have a stimulatory effect on Th1 differentiation. However, no previous study has explored the effect of Pb on pDCs. Thus, the present study was conducted to explore the correlation between circulating pDC count, serum IFNα (pan) levels, and blood lead levels (BLLs) in children environmentally exposed to Pb. A total of 82 school-going children were recruited from government and private schools in Jodhpur. BLL, pDC percentages, and serum IFNα (pan) levels were estimated by atomic absorption spectrometry, flow cytometry, and ELISA, respectively, in 82 samples. The participants were divided as per BLL quartiles into 4 groups: (A) BLL < 3 μg/dL (n = 21), (B) BLL = 3-4.08 μg/dL (n = 20), (C) BLL = 4.08-6.17 μg/dL (n = 20), and (D) BLL > 6.17 μg/dL (n = 21). Only in category D, pDC percentages showed a significant positive correlation with BLL (Spearman's R = 0.5). Therefore, this preliminary data suggests that BLL might modulate pDC levels in a dose-dependent manner.


Antenna-coupled photon emission from hexagonal boron nitride tunnel junctions.
The ultrafast conversion of electrical signals to optical signals at the nanoscale is of fundamental interest for data processing, telecommunication and optical interconnects. However, the modulation bandwidths of semiconductor light-emitting diodes are limited by the spontaneous recombination rate of electron-hole pairs, and the footprint of electrically driven ultrafast lasers is too large for practical on-chip integration. A metal-insulator-metal tunnel junction approaches the ultimate size limit of electronic devices and its operating speed is fundamentally limited only by the tunnelling time. Here, we study the conversion of electrons (localized in vertical gold-hexagonal boron nitride-gold tunnel junctions) to free-space photons, mediated by resonant slot antennas. Optical antennas efficiently bridge the size mismatch between nanoscale volumes and far-field radiation and strongly enhance the electron-photon conversion efficiency. We achieve polarized, directional and resonantly enhanced light emission from inelastic electron tunnelling and establish a novel platform for studying the interaction of electrons with strongly localized electromagnetic fields.


Possible role of Lipoptena fortisetosa (Diptera: Hippoboscidae) as a potential vector for Theileria spp. in captive Eld's deer in Khao Kheow open zoo, Thailand.
Eld's deer (Rucervus eldii thamin) is an endangered species endemic to South Asia. Various ectoparasites (hematophagous insects and ticks) and blood parasites (e.g., piroplasms such as Babesia and Theileria) have been reported in this deer. Deer keds of the genus Lipoptena (L.) are wingless hematophagous insects acting as ectoparasites and potential vectors, thereby transmitting diseases to animals and humans. Many Lipoptena species have been reported, including L. fortisetosa; the latter may be a potential vector of several pathogens such as Babesia spp. and Theileria spp. However, the available data regarding Lipoptena in domestic animals and wildlife in Thailand is limited. The aim of this study was to investigate the presence of L. fortisetosa in Eld's deer as well as the role of this insect as a disease vector in Thailand by employing molecular analysis. A total of 91 wingless insects were collected and morphologically identified as L. fortisetosa. A partial fragment of the cytochrome c oxidase subunit I gene (COI) was amplified and successfully sequenced from twelve insects, and the COI nucleotide Basic Local Alignment Search Tool results revealed a 94.28%-94.45% identity to L. fortisetosa (accession number: OL850869/China). The undertaken phylogenetic analysis revealed that the L. fortisetosa samples from Thailand belong to a clade that is distinct from the previously deposited (in GenBank®) L. fortisetosa. As far as the pathogen detection is concerned, 46.2% (42/91) of the deer keds were positive for Theileria, while no Lipoptena was found to be positive for Babesia. Twenty-one sequences of Theileria were obtained and exhibited a 98.84%-100% identity to the Theileria sp. from several hosts. The phylogenetic analysis of Theileria revealed that Theileria capreoli and Theileria cervi were present in our L. fortisetosa samples. It can be implied that L. fortisetosa may serve as a vector of Theileria spp. in the Eld's deers of Thailand. We believe that the particular open zoo (from where the sampling took place) should implement preventive and control strategies for deer keds, other vectors, and vector-borne diseases.


Migraine and risk of rheumatoid arthritis: A systematic review and meta-analysis of observational studies.
Exposure to Migraine may be one of the risk factors for the onset of rheumatoid arthritis (RA), while the relationship between the two is debatable. In this study, the connection between migraine and the risk of RA was investigated using a systematic review and meta-analysis of the pertinent literature. Up to July 2022, the PubMed, EMBASE, Web of Science (WOS), and scopus databases were employed to search for observational studies on the risk of RA in migraineurs. The effect sizes were pooled using a random-effects model or a fixed-effects model. Out of 2345 records, 5 studies (3 case and control studies and 2 cohort studies) were identified and included in the meta-analysis. According to a pooled analysis, migraine sufferers had a higher chance of developing RA (pooled adjusted effect estimate: 1.94, 95% confidence interval: 1.74-2.17; p < 0.01). Migraine can be legitimately regarded as a risk factor for RA since this study demonstrated a relationship between migraine and RA. This conclusion should be treated with caution due to low power and precision. Rigorous design and larger sample sizes of studies are needed to verify the findings.


Association between virus variants, vaccination, previous infections, and post-COVID-19 risk.
The SARS-CoV-2 Omicron variant has spread rapidly and has been the dominant variant since 2022. The course of acute infection, in a vaccinated population, with Omicron is milder compared with earlier variants. However, little is known about how the occurrence of long-term symptoms after Omicron infection compared with other variants is modulated by previous infections and/or vaccinations. Participants of the DigiHero study provided information about their SARS-CoV-2 infections, vaccinations, and symptoms 12 or more weeks after infection (post-COVID-19 condition - PCC). Participants infected with wildtype SARS-CoV-2 had the highest PCC risk (adjusted odds ratio [aOR] 6.44, 95% confidence interval (CI): 5.49; 7.56), followed by participants infected with Alpha and Delta compared with the reference group (individuals infected with Omicron having received three or more vaccinations). Among those infected with a specific variant, the number of preceding vaccinations was not associated with a risk reduction for PCC, whereas previous infection was strongly associated with a lower PCC risk (aOR 0.14, 95% CI 0.07; 0.25). While infection with Omicron is less likely to result in PCC compared with previous variants, lack of protection by vaccination suggests a substantial challenge for the healthcare system during the early endemic period. In the midterm, the protective effects of previous infections can reduce the burden of PCC.


Discrepancies between the California Verbal Learning Test: Children's Version and the Children's Category Test after pediatric traumatic brain injury.
One hundred 9-16-year-old children with traumatic brain injury (TBI) completed the California Verbal Learning Test-Children's Version (CVLT-C) and the Children's Category Test (CCT) within 1 year after injury. Performance contrasts between these two instruments that were unusually large (> 16 T score points) were about as common in this clinical sample as in the standardization sample of both instruments. However, relatively poor performance on the CVLT-C as compared to the CCT was associated with prolonged coma and lower scores on the Processing Speed index of the Wechsler Intelligence Scale for Children-Third Edition. It is concluded that a relative weakness on the CVLT-C is more likely to reflect cerebral compromise after pediatric TBI than is a relative weakness on the CCT.


SH3-dependent stimulation of Src-family kinase autophosphorylation without tail release from the SH2 domain in vivo.
Src family protein-tyrosine kinase activity is suppressed by two intramolecular interactions. These involve binding of the SH2 domain to the phosphorylated C-terminal tail and association of the SH3 domain with a polyproline type II helix formed by the SH2-kinase linker. Here we show that SH3-dependent activation of the Src family member Hck by HIV-1 Nef binding or by SH2-kinase linker mutation does not affect tail tyrosine phosphorylation in fibroblasts. Surprisingly, replacement of the wild type Hck tail with a high-affinity SH2 domain-binding sequence did not affect Hck activation or downstream signaling by these SH3-dependent mechanisms, suggesting that activation through SH3 occurs without SH2-tail dissociation. These results identify SH3-linker interaction as an independent mode of Hck kinase regulation in vivo and suggest that different mechanisms of Src kinase activation may generate distinct output signals because of differences in SH2 or SH3 domain accessibility.


Slight rate acceleration in permanent rechargeable nickel-cadmium pacemakers: a possible marker of battery failure.
Thirty-seven rechargeable pacemakers were implanted in 33 patients between 1972 and 1976. Average follow-up has been 4.9 years. Six patients have had these pacers for an average of 7.8 years. Slight rate acceleration of 3 to 5 beats per minute was demonstrated in 46% of the units; rate acceleration to greater than 80 beats per minute was present in three pacemakers, two of which failed within three months. Although rechargeable pacemakers have performed well, frequent surveillance or replacement is warranted if the pacing rate increases to greater than 80 beats per minute.


High Fe and Mn groundwater in the Nanchang, Poyang Lake Basin of China: hydrochemical characteristics and genesis mechanisms.
Based on the water quality test data of 257 groups of phreatic groundwater and 165 groups of confined groundwater in the Nanchang area and the redox conditions, acid-base conditions and the organic matter content in groundwater, we identified hydrochemical characteristics and genesis of groundwater with high Fe and Mn contents in Nanchang. The results showed that Fe and Mn exceeded the standard in both phreatic and confined groundwater. The over-standard rates of Fe and Mn in groundwater were 8.56-11.52% and 33.07-36.36%, respectively. The degree of pollution Fe and Mn in the confined groundwater is higher than that in the phreatic groundwater, and the degree of pollution caused by Mn is higher than that caused by Fe. The high Fe and Mn contents in groundwater were caused by the release of Fe and Mn minerals from the native environment due to changes in the groundwater environment of the study area. A mild redox environment (Eh < 100) and low pH value are favorable for Fe and Mn enrichment in groundwater. The presence of organic matter accelerates microbial activity and promotes the release of Fe and Mn from aquifer sediments. Therefore, the change in the native environment played an important role in the increase in Fe and Mn content in the study area.


Duration of untreated psychosis and cognitive deterioration in first-episode schizophrenia.
Cognitive impairment is an important clinical feature in many individuals with schizophrenia. Factors associated with cognitive deficit are not well established. Duration of untreated psychosis (DUP) has recently gained interest as a prognostic factor in schizophrenia. This study reports on the association between DUP and cognitive function. Subjects comprised 42 individuals (30 males, 12 females) who experienced a first-episode of DSM-III-R schizophrenia or schizophreniform disorder. Cognitive function was determined at clinical stabilization using the WAIS-R. An estimate of cognitive deterioration was based on the WAIS-R subtest profile. Longer DUP, male gender, higher premorbid IQ and younger age at admission independently predicted cognitive deterioration. Poorer performance on Digit Symbol and Comprehension subtests was associated with longer DUP. The findings suggest that untreated psychosis compromises some aspects of cognitive function. Studies investigating the association between DUP and outcome should control for potentially confounding variables. Early treatment of psychosis could help to reduce the prominent cognitive deficit in first-episode schizophrenia.


The secondary metabolites produced by Lactobacillus plantarum downregulate BCL-2 and BUFFY genes on breast cancer cell line and model organism Drosophila melanogaster: molecular docking approach.
The current study was designed to evaluate the toxicity of the secondary metabolites of Lactobacillus plantarum against the human breast cancer cell line (MCF-7) and the Drosophila melanogaster. In this study, toxicity analyses of secondary metabolites of Lactobacillus plantarum were analyzed on breast cancer cells, and the Drosophila melanogaster. After application, in the MCF-7 cell line, expression levels of RRAS-2, TP53, BCL-2, APAF-1, CASP-3, FADD, CASP-7, BOK genes; in D. melanogaster; expression levels of RAS64B P53, BUFFY, DARK, DECAY, FADD, DRICE, and DEBCL genes were determined by RT-PCR. In addition, analysis of L. plantarum secondary metabolite was performed by GC-MS method and molecular binding poses of secondary metabolites and human enzymes were investigated in silico. Drosophila melanogaster being used as a model organism where some of the human genes were preserved. The IC50 value of the secondary metabolite in the MCF-7 cell line was determined to be 0.0011 mg/ml. Lethal concentration 50 (LC50) and 99 (LC99) values of secondary metabolites against fruit fly adults were 0.24 mg/ml and 0.54 mg/ml, respectively. The expression levels of BCL-2 and BUFFY genes which are anti-apoptotic in human and fruit flies have been reduced, and at the same time, increased expression of DECAY, FADD, RAS64B apoptotic genes in D. melanogaster. The substance detected in the secondary metabolite content and encoded as L13 (3-phenyl-1, 2, 4-benzotriazine) has been observed to have high binding affinity in the studied genes.


Effects of rimegepant 75 mg daily on the pharmacokinetics of a combined oral contraceptive containing ethinyl estradiol and norgestimate in healthy female participants.
To assess the effect of single and multiple doses of rimegepant 75 mg dose on the pharmacokinetics of an oral contraceptive containing ethinyl estradiol (EE)/norgestimate (NGM) in healthy females of childbearing potential or non-menopausal females with tubal ligation. Females of childbearing age experience the highest prevalence of migraine and frequently inquire about the concomitant use of anti-migraine medications and contraceptives. Rimegepant, a calcitonin gene-related peptide receptor antagonist, demonstrated efficacy and safety for treating an acute migraine attack and preventing migraine. This open-label, single-center, phase 1, drug-drug interaction study explored the effects of rimegepant 75 mg daily dose on the pharmacokinetics of an oral contraceptive containing EE/NGM 0.035 mg/0.25 mg in healthy females of childbearing potential or non-menopausal females with tubal ligation. During cycles 1 and 2, participants received EE/NGM once daily for 21 days followed by placebo tablets with inactive ingredients for 7 days. Rimegepant was administered during only cycle 2 for 8 days, from days 12 through 19. The primary endpoint was the effect of single and multiple doses of rimegepant on the pharmacokinetics of EE and norelgestromin (NGMN), an active metabolite of NGM, at steady state, including area under the concentration-time curve for 1 dosing interval (AUC0-τ,ss ) and maximum observed concentration (Css[max] ). The study enrolled 25 participants, with pharmacokinetic data assessed for 20 participants. A single 75 mg dose of rimegepant co-administered with EE/NGM increased exposures of EE and NGMN by ≤16% (geometric mean ratio [GMR], 1.03; 90% confidence interval [CI], 1.01-1.06; and GMR, 1.16; 90% CI, 1.13-1.20, respectively). After 8 days of co-administering EE/NGM with rimegepant, EE pharmacokinetic parameters, AUC0-τ,ss and Css(max) , increased by 20% (GMR, 1.20; 90% CI, 1.16-1.25) and 34% (GMR, 1.34; 90% CI, 1.23-1.46), respectively, and NGMN pharmacokinetic parameters increased by 46% (GMR, 1.46; 90% CI, 1.39-1.52) and 40% (GMR, 1.40; 90% CI, 1.30-1.51), respectively. The study identified modest elevations in overall EE and NGMN exposures after multiple doses of rimegepant, but these elevations are unlikely to be clinically relevant in healthy females with migraine.


Functional genomic delineation of TLR-induced transcriptional networks.
The innate immune system is the first line of defense mechanisms protecting the host from invading pathogens such as bacteria and viruses. The innate immunity responses are triggered by recognition of prototypical pathogen components by cellular receptors. Prominent among these pathogen sensors are Toll-like receptors (TLRs). We sought global delineation of transcriptional networks induced by TLRs, analyzing four genome-wide expression datasets in mouse and human macrophages stimulated with pathogen-mimetic agents that engage various TLRs. Combining computational analysis of expression profiles and cis-regulatory promoter sequences, we dissected the TLR-induced transcriptional program into two major components: the first is universally activated by all examined TLRs, and the second is specific to activated TLR3 and TLR4. Our results point to NF-kappaB and ISRE-binding transcription factors as the key regulators of the universal and the TLR3/4-specific responses, respectively, and identify novel putative positive and negative feedback loops in these transcriptional programs. Analysis of the kinetics of the induced network showed that while NF-kappaB regulates mainly an early-induced and sustained response, the ISRE element functions primarily in the induction of a delayed wave. We further demonstrate that co-occurrence of the NF-kappaB and ISRE elements in the same promoter endows its targets with enhanced responsiveness. Our results enhance system-level understanding of the networks induced by TLRs and demonstrate the power of genomics approaches to delineate intricate transcriptional webs in mammalian systems. Such systems-level knowledge of the TLR network can be useful for designing ways to pharmacologically manipulate the activity of the innate immunity in pathological conditions in which either enhancement or repression of this branch of the immune system is desired.


The effect of colchicine on mortality outcome and duration of hospital stay in patients with COVID-19: A meta-analysis of randomized trials.
Overactivation of the NLR family pyrin domain containing 3 (NLRP3) inflammasome can lead to severe illness in patients with coronavirus disease-2019 (COVID-19). The NLRP3 inhibitor, colchicine, therefore, appears to be promising for the treatment of COVID-19. We aimed to perform a meta-analysis of randomized trials investigating the effect of colchicine in patients with COVID-19. We systematically searched electronic databases and clinical trial registries (up to October 17, 2021) for eligible studies. The outcomes of interest were all-cause mortality and duration of hospital stay. Meta-analysis with the random-effects model was used to estimate the pooled odds ratio (OR) of mortality and 95% confidence interval (CI). The pooled standardized mean difference of duration of hospital stay with 95% CI between colchicine users and non-colchicine users was estimated using Cohen's d index. The meta-analyses revealed no significant difference in the odds of mortality (pooled OR = 0.76; 95% CI: 0.53-1.07), but a significant reduction in the duration of hospital stay with the use of colchicine (pooled standardized mean difference = -0.59; 95% CI: -1.06 to -0.13). The ability of colchicine to reduce the length of stay in hospitalized patients with COVID-19 is consistent with its potential to prevent clinical deterioration via inhibition of NLRP3 inflammasome. Nevertheless, such beneficial effects of colchicine did not translate into mortality benefits in patients with COVID-19.


Relationship between the nicotinamide adenine dinucleotide redox potential and the 2,3-diphosphoglycerate content in the erythrocyte in sickle cell disease.
The percentage of nicotinamide adenine dinucleotide (NAD) in the oxidized form [NAD+/(NAD+ and NADH); i.e. the NAD+/NADT ratio] is increased in the red cell (RBC) in sickle cell disease. We tested the hypothesis that the increased NAD+/NADT ratio was a determinant of the increased 2,3-diphosphoglycerate (DPG) content of the SCD RBC. Using normal subjects and individuals with sickle cell disease or autoimmune haemolytic anaemia (AIHA), we observed an inverse relationship between the packed cell volume (PCV) and the RBC DPG concentration (r = -0.69) and a direct relationship between the RBC NAD+/NADT ratio and the DPG concentration (r = 0.74). When the effect of the PCV on DPG was removed using analysis of covariance [DPGady(PCV)], the NAD+/NADT ratio had a significant relationship with the DPGadj(PCV) (r = 0.50, P less than 0.001). In in vitro incubation studies, increasing the NAD+/NADT ratio significantly increased the DPG content of both normal and AIHA RBC. Conversely, decreasing the NAD+/NADT ratio decreased the DPG content of normal, AIHA and SCD RBC. Thus, the increased DPG content in the SCD RBC appears to be due, in part, to the increased NAD+/NADT ratio and is not purely a physiologic response to decreased oxygen carrying capacity.


The Effect of Emotional Intelligence on Caring Behaviors Among Psychiatric Nurses in Greece : Emotional Intelligence and Caring Behaviors in Mental Healthcare.
The effect of emotional intelligence in the field of mental health is of particular interest, as it is an intensely emotional field. The nursing staff has as an object the healthcare of people with mental problems, where emotions and their management are key factors. The purpose of this study was to investigate the levels of emotional intelligence and caring behaviors among mental health nurses as well as the correlation between these variables. In this cross-sectional study, 191 nurses completed the tools Trait Emotional Intelligence Questionnaire-Short Form (TEIQue-SF) and the Caring Behaviors Inventory-24 scale (CBI-24) for assessing the degree of emotional intelligence and caring behaviors, respectively. Demographic and job characteristics were recorded. Results: The results showed that the majority of participants were female and the average age was 44.69 years. According to the total but also the individual scoring of the TEIQue-SF, emotional intelligence was found to be at a relatively high level (total mean: 4.92) and was associated directly (r = 0.448, p < 0.001) with the frequency of caring behaviors of the CBI-24 which was found to be at a fairly high level (total mean 5.08). The study findings showed that as the overall emotional intelligence increased, the frequency of occurrence and the importance of behavioral behaviors increased.


Cumulative pregnancy rates after sequential treatment with modified natural cycle IVF followed by IVF with controlled ovarian stimulation.
In modified natural cycle IVF (MNC-IVF), treatment is aimed at using the one follicle that spontaneously develops to dominance, using a GnRH-antagonist together with gonadotrophins in the late follicular phase only. The MNC-IVF is of interest because of its low-risk and patient-friendly profile. The effect of application of MNC-IVF preceding standard IVF with ovarian stimulation on overall results is unknown. This single-center cohort study provides follow-up of an earlier study in which nine cycles of MNC-IVF were offered to 268 patients. Ongoing pregnancy rates and live birth rates, as well as time-to-pregnancy after controlled ovarian stimulation-IVF (COS-IVF) following MNC-IVF, were evaluated. Actual observed cumulative ongoing pregnancy rates and live birth rates after sequential treatment with MNC-IVF followed by COS-IVF were 51.5 (95% CI: 45.4-57.6) and 50.0% (95% CI: 43.9-56.1) per patient, of which 8.0 and 6.7% were twins. Median time to ongoing pregnancy was 28.8 weeks. Including treatment-independent pregnancies, cumulative ongoing pregnancy rate was 56.7% (95% CI: 50.7-62.8). Sequential treatment with MNC-IVF followed by COS-IVF does not appear to compromise overall success rates, while twin pregnancy rate is low. Because of its patient-friendly and low-risk profile, it seems appropriate to perform MNC-IVF preceding COS-IVF.


Intake of volatile nitrosamines by Chinese residents in different provinces via food and drinking water.
N-nitrosamines are potent carcinogens, particularly N-nitrosodimethylamine (NDMA) and N-nitrosodiethylamine (NDEA), which are commonly found in a variety of foods and drinking water. We calculated the food and drinking water intakes of NDMA, NDEA, and total volatile nitrosamines (TVNA) by Chinese residents in different provinces by multiplying the reported total diet study results by the nitrosamine contents in food and drinking water. The weighted content of nitrosamines in each category of foods and the concentration of nitrosamines in drinking water was obtained through literature review. The exogenous NDMA, NDEA and TVNA intakes of adult residents in 20 provinces ranged from 171 to 425 ng/d, 41 to 140 ng/d and 373 to 1028 ng/d, respectively. The main contributors to NDMA and TVNA intakes were vegetables, cereals, aquatic products, and meats while the main sources of NDEA intake were vegetables and cereals. The average total NDMA intake per capita in China (251 ng/d) was similar to that in Germany in 1991 (231 ng/d) but higher than that in the United States (136 ng/d), Canada (87.6 ng/d) and France (188 ng/d). Large differences in nitrosamine intakes were observed between the coastal provinces and inland provinces. Drinking water was estimated to contribute 13.1%, 1.3% and 10.8% of the exogenous intakes of NDMA, NDEA and TVNA, respectively. Based on our results, we recommend setting the NDMA drinking water criterion of 40 ng/L. Overall, this study presents basic information regarding nitrosamines intake via food and drinking water in China that will facilitate risk assessment, generation of health advisories and policy making.


Assessing the Plant Growth Promoting and Arsenic Tolerance Potential of Bradyrhizobium japonicum CB1809.
Accumulation of heavy metals in soil is of concern to the agricultural production sector, because of the potential threat to food quality and quantity. Inoculation with plant growth-promoting bacteria (PGPR) has previously been shown to alleviate heavy metal stress but the mechanisms are unclear. Potential mechanisms by which inoculation with Bradyrhizobium japonicum CB1809 affected the legume soybean (Glycine max cv. Zeus) and the non-legume sunflower (Helianthus annus cv. Hyoleic 41) were investigated in solution culture under 5 μM As stress. Adding As resulted in As tissue concentrations of up to 5 mg kg-1 (shoots) and 250 mg kg-1 (roots) in both species but did not reduce shoot or root biomass. Inoculation increased root biomass but only in the legume (soybean) and only with As. Inoculation resulted in large (up to 100%) increases in siderophore concentration but relatively small changes (±10-15%) in auxin concentration in the rhizosphere. However, the increase in siderophore concentration in the rhizosphere did not result in the expected increases in tissue N or Fe, especially in soybean, suggesting that their function was different. In conclusion, siderophores and auxins may be some of the mechanisms by which both soybean and sunflower maintained plant growth in As-contaminated media.


Production of radioactive particles for endovascular therapeutic interventions.
Recanalization is a common phenomenon that decreases the efficacy of embolization procedures. It can be inhibited by beta-radiation. Two novel ways of producing radioactive particles are described, by neutron beam irradiation of gold-containing microspheres, or by using the 32P binding capacity of zirconium-containing microspheres. Particles were tested in vivo, to assess their ability to deliver radioactivity locally, using canine renal artery, porcine rete mirabile, and rabbit ear embolization models. Both radioactive microspheres (198Au and 32P) showed no detectable activity outside the target territory. 32P microspheres demonstrated typical radiation changes in a porcine rete mirabile arteriovenous malformation model.


Biosynthesis of folate polyglutamate in the rat with different tracers.
1. The recent suggestions that folate polyglutamate biosynthesis demonstrated in vivo with [3'5'9(n)-3H]folic acid is due to exchange and cannot be achieved with [2(-14)C]folic acid has been demonstrated to be untrue. 2. The compounds formed with both types of radioactive tracer have been shown to be folate polyglutamates from their elution position from precalibrated ion-exchange columns and their susceptibility to hydrolysis by a gamma-carboxypeptidase (conjugase) from human sera. 3. By the use of the methods involving [2(-14)C]folic acid, reported by others to give only folate monoglutamates, we have been able to demonstrate clearly the presence of folate polyglutamates.


Autocrine signaling of platelet-derived growth factor regulates disabled-2 expression during megakaryocytic differentiation of K562 cells.
Platelet-derived growth factor (PDGF) is involved in megakaryocytopoiesis and is secreted into the culture medium during megakaryocytic differentiation of human leukemic cells. We investigate whether PDGF plays a role in the regulation of the adapter protein Disabled-2 (DAB2) that expresses abundantly in platelets and megakaryocytes. Western blot analysis revealed that conditioned medium from 12-O-tetradecanoylphorbol-13-acetate (TPA)-treated, megakaryocytic differentiating K562 cells upregulated DAB2 expression. DAB2 induction and megakaryocytic differentiation was abrogated when cells were co-treated with the PDGF receptor inhibitor STI571 or when the conditioned medium was derived from TPA-plus STI571-treated cells. Although the level of PDGF mRNA was not altered by STI571, an approximate 44% decrease in PDGF in the conditioned medium was observed. Consistent with these findings, interfering PDGF signaling by PDGF neutralization antibody or dominant negative PDGF receptors attenuated DAB2 expression. Accordingly, transfection of an expression plasmid encoding secreted PDGF upregulated DAB2. This study shows for the first time that PDGF autocrine signaling regulates DAB2 expression during megakaryocytic differentiation.


On the definition of noise.
Urbanization has exposed people to extreme sound levels. Although researchers have investigated the ability of people to listen, analyze, and distinguish sound, the concept of noise has not been clearly articulated from a human perspective. The lack of knowledge on how people perceive noise limits our capacity to control it in a targeted manner. This study aimed to interpret the definition of noise from the public perspective based on a grounded theory approach. Seventy-eight participants were interviewed about noise, and four categories of perceived understanding of noise were identified: challenges, definitions of noise, opportunities, and action. As one of the challenges, urbanization is associated with increased noise levels around the human environment. In terms of definition, perceiving sound as noise is considered to be a result of the complex and dynamic process that includes sound, the environment, and humans. Sound and humans interact with the environment. In terms of opportunities, noise may have positive roles on certain occasions, dispelling the misconception that noise is exclusively negative. In addition, we found that noise perception has gradually shifted from noise control to noise utilization. In terms of action, noise can be controlled at the sound sources, susceptible target groups, susceptible behaviors and states, locations, and times where noise is perceived with high frequency. In this study, we investigated several aspects of noise, ranging from noise control, soundscape definition, and 'soundscape indices' (SSID) integration and application. Our findings provide an additional basis for developing better definitions, control, and utilization strategies of noise in the future, thereby improving the quality of the sound environment.


Cystic degeneration in cemento-ossifying fibroma: Diagnosis challenge and conservative management - Case report.
Cemento ossifying fibroma (COF) is an encapsulated lesion that is often found in the mandible of middle-aged females. Cystic degeneration may be associated to several osseous lesion. This particular presentation is not well documented in the jaws. Patient presented was referred to oral surgery department for abnormal radiolucency in the right mandible on panoramic X-ray. The patient did not have any specific medical history and reported painful areas in right mandibular region. During diagnosis assessment, ameloblastoma was first considered due to the presence of cystic lesion clusters. But the mixed image in previous X-ray pointed to a fibro-osseous with a change in pathogenesis pathway. Diagnosis buildup was based on previous radiographs, incisional biopsy was proposed to identify the histopathological feature of the lesion before proceeding to further investigation (CBCT) or treatments (decompression or enucleation). COF of the jaws associated to non-specific cystic changes was the histopathological diagnosis. Delay in treatment showed an unexpected outcome with good clinical and bone healing. This case shows the importance of previous radiographs, when available, in diagnosis buildup. The fibro-osseous lesion with cystic change may show a good biological response with conservative management. A clinical and radiological surveillance after a conservative treatment may be a better option in treatment of these lesions.


Use of Popular Opinion Leader Models to Disseminate Information About Clinical Trials to Black Individuals With Lupus in Two US Cities.
Clinical trials for systemic lupus erythematosus ("lupus") under enroll Black individuals despite higher disease prevalence, morbidity, and mortality among Black compared to White individuals. To begin to address this disparity, we leveraged community-academic partnerships in 2 US cities (Boston and Chicago) to train popular opinion leaders (POLs) to disseminate information about clinical trials in predominantly Black communities. The team of community and academic partners collaboratively developed a 5-module curriculum about clinical trials, barriers, facilitators, and structural racism in research. We enrolled POLs in Boston and Chicago to participate virtually in the curriculum and assessed knowledge gained by comparing pre- and post-test scores. We described the POLs' ability to disseminate information about clinical trials through their communities. We enrolled 19 POLs in Boston and 16 in Chicago; overall, 71% reported a lupus diagnosis, 94% were female, and 80% self-identified as Black or African American. The program was adapted to virtual formats due to the COVID-19 pandemic. POLs demonstrated significant improvement comparing pre/post scores for the conduct of clinical trials and history of racism in clinical research. Fifteen POLs (43%) reported their dissemination of information about clinical trials. Information reached 425 community members in Boston (90% virtually) and 1,887 in Chicago (95% virtually). By leveraging community-academic partnerships, we developed and implemented a curriculum to promote familiarity with clinical trials, leading to information dissemination by POLs in predominantly Black communities that are underrepresented in lupus clinical trials. The program successfully transitioned to a virtual model during the COVID-19 pandemic.


Therapeutic orchids: traditional uses and recent advances--an overview.
Orchids have been used as a source of medicine for millennia to treat different diseases and ailments including tuberculosis, paralysis, stomach disorders, chest pain, arthritis, syphilis, jaundice, cholera, acidity, eczema, tumour, piles, boils, inflammations, menstrual disorder, spermatorrhea, leucoderma, diahorrhea, muscular pain, blood dysentery, hepatitis, dyspepsia, bone fractures, rheumatism, asthma, malaria, earache, sexually transmitted diseases, wounds and sores. Besides, many orchidaceous preparations are used as emetic, purgative, aphrodisiac, vermifuge, bronchodilator, sex stimulator, contraceptive, cooling agent and remedies in scorpion sting and snake bite. Some of the preparations are supposed to have miraculous curative properties but rare scientific demonstration available which is a primary requirement for clinical implementations. Incredible diversity, high alkaloids and glycosides content, research on orchids is full of potential. Meanwhile, some novel compounds and drugs, both in phytochemical and pharmacological point of view have been reported from orchids. Linking of the indigenous knowledge to the modern research activities will help to discover new drugs much more effective than contemporary synthetic medicines. The present study reviews the traditional therapeutic uses of orchids with its recent advances in pharmacological investigations that would be a useful reference for plant drug researches, especially in orchids.


A multivariate analysis on spatiotemporal evolution of Covid-19 in Brazil.
This data-driven work aims to analyze and classify the spatiotemporal distribution of all Brazilian states considering data so diverse as the number of Covid-19 cases, deaths, confirmed cases per 100 k inhabitants, mortality per 100 k inhabitants and case fatality rates as health indicators. We also considered population, area and population density as geographic indicators. Finally, GDP and HDI were taken into account as economic and social criteria. For this task data were collected from April 3rd until August 8th, 2020, corresponding to epidemiological weeks 14-32, reaching three million cases and a hundred thousand deaths. With this data it was possible to classify Brazilian states using multivariate methods into possible groups by means of non-hierarchical (k-means) cluster as well as factor analysis. It was possible to group all states plus the Federal District into five clusters, taking into account these 10 variables over the first five months of the epidemic. Group changes between states were observed over time and clusters, and between three and four factors were found. However, even with great difference on health indicators during days, the number of clusters remains fixed. Also, São Paulo and Rio de Janeiro states were ranked at top list taking into account all epidemiological weeks. Correlations were observed between variables, such as the number of Covid cases and deaths with GDP for most of epidemiological weeks. Some clusters were more critical due to specific variables, including cities that are main hotspots. These multivariate findings would provide a comprehensive description of the ongoing Covid-19 epidemic and may help to guide subsequent studies to understand and control virus transmission.


Clinical and imaging diagnosis for heredodegenerative diseases.
Clinical features (progressive psychomotor retardation, seizures, movement disorders and motor signs in both central and peripheral systems, sensorineural defects, and psychiatric symptoms) and brain imaging are the keys to diagnosis. CT is indicated for the detection of calcifications and blood, and for angiography. MRI in all three axes requires T1, T2, FLAIR (from 1 year on), eventually T2* or contrast administration, and diffusion in any acute condition. MR spectroscopy allows the dectection of lactate and creatine deficiency, elevated choline in high membrane turnover, and low NAA in neuronal death. The normal sequence of myelination needs to be taken into account. Pre- and neonatal anomalies include cystic and basal ganglia lesions, gyral and myelin anomalies, callosal agenesis, and large subdural spaces. Anomalies disclosed after 3 months of age include basal ganglia appearing hyper- or hypointense on T2, hypointense on T2*, or calcified white matter anomalies mainly periventricular or subcortical, or with contrast enhancement, associated with macrocephaly and/or large or very small cysts, and hypomyelination; there may be "vascular" or pseudostroke disorders, cortical atrophy, hypoplasia, or abnormal signal of the brainstem and/or cerebellum. Spectroscopy should investigate basal ganglia, white matter, and the cerebellum. MRI may reveal typical alterations of the brain at the preclinical stage in siblings of affected children.


Primary endometrioid stromal sarcomas of the ovary: a clinicopathological study of 14 cases with a review of the literature.
Primary endometrioid stromal sarcomas (ESS) of the ovary are rare mesenchymal tumors with scarce data on their behavior and optimal treatment. We aimed to describe the clinicopathologic features and outcome among patients with primary ovarian ESS. The age of the patients ranged from 34 to 61 years (mean: 49.1 years, median: 51.5 years). The most common symptoms were abdominal distention or pain or both. Nine (64.3%) and five patients (35.7%) had low-grade and high-grade disease, respectively. The median duration of follow-up was 65 months (range, 8-311 months). All 9 patients with low-grade ESS were alive, of these, 3 (33.3%) of them developed recurrence after surgery. Only 1 patient (20%) with high-grade ESS was alive with no evidence of disease in a short-term follow-up visit; the remaining 4 (80%) developed recurrence after surgery, and 2 (40%) died of progressive disease. Medical records of 14 patients with primary ovarian ESS in our institution were collected and analyzed. The behavior of primary ovarian ESS is similar to that of their uterine counterparts. Low-grade ESS is an indolent tumor with a propensity for late recurrences. The prognosis of high-grade ESS is poor.


Culturing partial-denitrification (PD) granules in continuous flow reactor with waste sludge as inoculum: performance, granular sludge characteristics and microbial community.
Partial denitrification granular sludge (PDGS) can provide long-term stable nitrite for anaerobic ammonia oxidation (anammox). The cultivation of ordinary activated sludge from wastewater treatment plants into PDGS can further promote the application of PD in practical engineering. In this study, the feasibility of fast start-up of PDGS was explored by inoculating waste sludge in up-flow anaerobic sludge blanket (UASB) reactor with synergistic control of nitrogen load rate (NLR, 0.05-0.65 kg N/m3/d) and electron donor starvation (EDS) (240-168 mg L-1), and system performance, particle characteristics and microbial structure were studied. The results showed that PD-UASB started successfully within 48 days, the average nitrite accumulation rate (NTR) and nitrate removal ratio (NRR) reached 79.6% and 82.5% after successful initiation, accompanied by high abundance of PD bacteria (Thauera, Pseudomonas, unclassflied commamonadaceae and Limnobacter) (25.3%). The increase of PD activity, and the difference between nitrate reductase (NAR) and nitrite reductase (NIR) contributed to nitrite production. Besides, the sludge shifted from flocculated (≤0.5 mm, 95.37%) to granulated state (0.5-2 mm, 64.74%), which could be due to the increase of extracellular polymers (EPS) (especially T-EPS) and metabolism of specific microorganisms (Bacteroidota and Chloroflexi, 19.92%). Good sludge granulation promoted the settleability of PD (the SVI5 was 47.248 mL/ g. ss after successful start-up). In summary, good PD sludge granulation process could be achieved in a short time by synergistically controlling NLR and EDS.


Multiple complex odontoma of the maxilla and the mandible.
The aim of this study was to present a literature review and case report of multiple odontoma. A case of multiple odontoma is presented with a review of the English-language literature. The clinical and radiologic features are summarized. In total, 12 cases of multiple odontoma were retrieved from the literature for analysis. The multiple odontomas were localized or extensive and involved two to four quadrants of the jaws. The histologic types were compound or complex. Odontomas can be multiple and involve multiple quadrants of the jaws.


Plasma noradrenalin and dopamine-beta-hydroxylase during behavioral testine of sexually deviant XYY and XXY males.
In a behavior study of a sexually deviant XYY and XXY male, who were both murderers, plasma noradrenaline (NAA), dopamine-beta-hydroxylase (DBH) were determined radioenzymatically under resting conditions and during exertional and emotional stress. Under a physical sork load on the bicycle ergometer both had normal plasma NA and DBH levels. During emotional stress both had NA increases of the same magnitude. During an arithmetic test NA values did not increase more than expected for the sitting position.


Enhancements to the multiple sleep latency test.
The utility of multiple sleep latency tests (MSLTs) is limited to determining sleep onset latency (SOL) and rapid eye movement sleep latency. The odds ratio product (ORP) is a continuous index of sleep depth with values of 0, 1.0, and 2.5 reflecting very deep sleep, light sleep, and full wakefulness, respectively. We determined the time course of sleep depth during MSLT naps expecting that this would enhance the test's clinical utility. Thirty MSLTs (150 naps) were performed for excessive somnolence. Patients indicated whether they slept (yes/no) after each nap. SOL was scored by two experienced technologists. Time course of ORP was determined with a commercial system. We determined ORP at SOL (ORPSOL), times ORP decreased <2.0, <1.5, <1.0 and <0.5 during the entire nap duration, and the integral of decrease in ORP over nap duration (ΔORPINT). SOL occurred almost invariably when ORP was between 1.0 and 2.0. Of 47 naps (21 patients) with SOL <5 minutes, ORP decreased <1.0 (light sleep) in <5 minutes in only 13 naps (nine patients) and <0.5 (deep sleep) in only two naps in one patient. The relation between ORPINT and frequency of sleep perception was well defined, allowing determination of a threshold for sleep perception. This threshold ranged widely (5-50 ΔORP*epoch). As currently identified, SOL reflects transition into a highly unstable state between wakefulness and sleep. Reporting the times of attaining different sleep depths may help better identify patients at high risk of vigilance loss. Furthermore, an ORPSOL outside the range 1.0-2.0 can help identify scoring errors.


Reconstruction of 3D stacked hepatocyte tissues using degradable, microporous poly(d,l-lactide-co-glycolide) membranes.
There is great demand for constructing well-organized three-dimensional (3D) tissues in vitro. Here, we developed a 3D stacked culture method using biodegradable poly(d,l-lactide-co- glycolide) (PLGA) membranes with defined topography. Pore size and porosity of the membranes can be controlled by changing the moisture content during fabrication. The optimized membrane served as a scaffold to manipulate small hepatocyte (SH) layers when they were stacked, while it degraded after stacking, resulting in the reorganization of the cells into a 3D stacked structure. Immunofluorescent staining for domain markers of cell polarity and electron microscopy confirmed that the cells in the 3D stacked structures recovered polarity. Furthermore, the cells exhibited improved liver-specific function as compared with cells in a monolayer. This 3D stacked culture may enable reconstruction of multilayered hepatic tissues with highly differentiated functions in vitro.


Effect of albumin distribution. A simulation analysis of the effect of altered albumin distribution on the apparent volume of distribution and apparent elimination rate constant of drugs.
The effects of altered albumin distribution on the apparent volume of distribution (V) and the apparent elimination rate constant (kappa) of drugs were investigated by a simulation analysis. The Equations derived by Oie et al. were modified for this purpose. Within the range observed in normal healthy subjects and patients, the change in albumin distribution significantly affected V of drugs but, in general, not kappa. For drugs with more than 90% plasma-protein binding, V changed by more than 100%. The change in plasma-protein binding caused by an altered albumin distribution produced a greater effect on V than that caused by an altered albumin amount. These results suggest that albumin distribution is an important factor in controlling the kinetics of drugs which are highly bound to plasma protein. This is illustrated using midazolam as an example.


Water-soluble extract of Coleus barbatus modulates weight gain, energy utilization and lipid metabolism in secondary biliary cirrhosis: an experimental study in young rats.
To test if a water extract of Coleus barbatus (WEB) has any effect on weight gain, food energy utilization and lipid metabolism in young rats with obstructive cholestasis. Forty 21 day old (P21) Wistar rats, in groups of 10, were submitted to one of the following treatments: a sham operation with daily water or WEB administration, double ligature and resection of the bile duct with daily water or WEB administration. At P49 they were submitted for euthanasia when the following were determined: ingested feed (IF), energy utilization (EU) and weight gain (WG) from P29 to P49, together with total serum cholesterol (TC) and triacylglycerol (TG) concentrations, liver wet weight (LWW) and fat content (LFC). Two Way ANOVA and the S.N.K. test for paired comparisons were employed to study the effects of cholestasis and those of WEB and their interactions (p < or = 0.05). Cholestasis, independently of WEB, and WEB, independently of cholestasis both reduced IF, EU, and WG but there was no significant interaction between the two factors. Cholestasis, independently of WEB, increased LWW, LFC, the TC and TG The WEB, independently of cholestasis, reduced these values, and there was a significant interaction between the two factors; such that these effects were more accentuated in animals with cholestasis. The WEB reduced IF, WG, and EU, both in the presence and absence of cholestasis in the same proportion. It also partially inhibited the increase in LWW, LFC, TC and TG caused by cholestasis.


Effects of Prepubertal Exposure to Aroclor-1221 on Reproductive Development and Transcriptional Gene Expression in Female Rats.
Polychlorinated biphenyls (PCBs), as persistent organic pollutants, are environmental endocrine-disrupting chemicals (EDCs). We aim to investigate the effects of prepubertal exposure to PCBs on the reproductive development and expression and regulation of related genes in rats. Female rats were treated with Aroclor-1221 (A-1221) (4 mg/kg/day, 0.4 mg/kg/day) or castor oil daily from postnatal day (PND) 28 for 2 weeks by gavage. Morphological, histological, hormonal, and biochemical parameters were studied. Lower weight and relative weight of hypothalamus, earlier puberty onset, a longer length of the estrous cycle, lower serum estradiol and progesterone levels, accelerated ovarian folliculogenesis, and higher apoptotic index in the ovary were found. The in vitro fertilization study showed a lower fertilization rate and cleavage rate. The genetic study revealed higher expression of Kiss-1 mRNA and lower expression of GnRH mRNA in the hypothalamus and higher expression of AMH mRNA and lower expression of C-myc mRNA in the ovary. These confirmed the reproductive damage of A-1221 in rats.


Delayed mandibular reconstruction following removal of a mesenchymal chondrosarcoma. Report of a case.
An unusual case of mesenchymal chondrosarcoma is presented. Initially seen when the patient was 8 years old, the lesion was repeatedly biopsied and curetted with a diagnosis of odontogenic fibroma. In 1971 a diagnosis of osteosarcoma of the chondroblastic type was made. At that time, the patient underwent a partial mandibulectomy with immediate graft. The patient did well until 1981, when a recurrence of the lesion was noted. The microscopic diagnosis at this time was mesenchymal chondrosarcoma. The treatment of this lesion as a staged procedure with initial resection of the mandible and placement of a silicone rubber mandibular prosthesis is discussed. The second stage of the procedure was definitive mandibular reconstruction, with an allogeneic mandible as a crib for autologous particulate cancellous bone from the iliac crest. Although the prognosis of mesenchymal chondrosarcoma is usually grave, this case is unusual because of its long history of multiple procedures performed prior to the definitive treatment of the lesion 14 years after its discovery. Two-year follow-up since the definitive mandibular reconstruction shows adequate range of motion, excellent healing, and no recurrence.


Chaos analysis and explicit series solutions to the seasonally forced SIR epidemic model.
Despite numerous studies of epidemiological systems, the role of seasonality in the recurrent epidemics is not entirely understood. During certain periods of the year incidence rates of a number of endemic infectious diseases may fluctuate dramatically. This influences the dynamics of mathematical models describing the spread of infection and often leads to chaotic oscillations. In this paper, we are concerned with a generalization of a classical Susceptible-Infected-Recovered epidemic model which accounts for seasonal effects. Combining numerical and analytic techniques, we gain new insights into the complex dynamics of a recurrent disease influenced by the seasonality. Computation of the Lyapunov spectrum allows us to identify different chaotic regimes, determine the fractal dimension and estimate the predictability of the appearance of attractors in the system. Applying the homotopy analysis method, we obtain series solutions to the original nonautonomous SIR model with a high level of accuracy and use these approximations to analyze the dynamics of the system. The efficiency of the method is guaranteed by the optimal choice of an auxiliary control parameter which ensures the rapid convergence of the series to the exact solution of the forced SIR epidemic model.


Phosphoenolpyruvate hydrolase activity of rabbit muscle pyruvate kinase.
Rabbit muscle pyruvate kinase catalyzes the hydrolysis of P-enolpyruvate at the same active site which catalyzes the physiologically important kinase reaction. The hydrolase activity is lower than the kinase activity by a factor of at least 10(3). There are specific monovalent cation and divalent cation requirements. No other cofactors are required. The relative activation of the pyruvate kinase for the hydrolase reaction is: Ni(II) greater than Co(II) greater than Mg(II) greater than Mn(II). This parallels the rates of nonenzymatic hydrolysis of P-enolpyruvate (Benkovic, S.J., and Schray, K.J. (1968) Biochemistry 7, 4097-4102). The pH rate profiles of the hydrolase and kinase reactions activated by Ni(II) and Co(II) are similar, suggesting common features in their mechanisms. In contrast to the kinase reaction, the reaction velocity of the hydrolase increases at high Co(II) concentrations indicating a second mode for hydrolysis.


The Need for Accurate Risk Assessment in a High-Risk Patient Population: A NSQIP Study Evaluating Outcomes of Cholecystectomy in the Patient With Cancer.
Cholecystectomy is considered a low-risk procedure with proven safety in many high-risk patient populations. However, the risk of cholecystectomy in patients with active cancer has not been established. The American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP) database was queried to identify all patients with disseminated cancer who underwent cholecystectomy from 2005 to 2016. Postcholecystectomy outcomes were defined for patients with cancer and those without by comparing several outcomes measures. A multivariate model was used to estimate the odds of 30-d mortality. We compared outcomes in 3097 patients with disseminated cancer to a matched cohort of patients without cancer. Patients with cancer had more comorbidities at baseline: dyspnea (10.5% versus 7.0%, P < 0.0001), steroid use (10.1% versus 3.0%, P < 0.0001), and loss of >10% body weight in 6-mo prior (9.3% versus 1.6%, P < 0.0001). Patients with cancer sustained higher rates of wound (2.3% versus 5.6%, P < 0.0001), respiratory (1.4% versus 3.9%, P < 0.0001), and cardiovascular (2.0% versus 6.8%, P < 0.0001) complications. In addition, patients with disseminated cancer experienced a longer length of stay and higher 30-d mortality. Multivariate modeling showed that the odds of 30-d mortality was 3.3 times greater in patients with cancer. Compared to patients without cancer, those with disseminated cancer are at higher risk of complication and mortality following cholecystectomy. Traditional treatment algorithms should be used with caution and care decisions individualized based on the patient's disease status and treatment goals.