Current trend of worsening prognosis of prostate small cell carcinoma: A population-based study.
To determine the accurate age-adjusted incidence of prostate small cell carcinoma (SCC), update the clinical and pathological characteristics, as well as survival data of prostate SCC from Surveillance, Epidemiology, and End Results (SEER) datasets. A total of 260 patients with prostate SCC were selected from the SEER database of the National Cancer Institute between 2004 and 2015. Age-adjusted incidence (AAI) rates, the observed and relative survival rates were evaluated over time by the SEER*Stat Software version 8.3.5. Overall survival (OS) rates that stratified by summary stage and treatment effects were evaluated by Kaplan-Meier method. The significant differences were assessed in a log-rank test. Univariate and multivariate cox hazard regression analysis were performed to determine independent predictors of OS. The incidence of prostate SCC has increased over time. The average age of prostate SCC patients was 70.25 years. More than 90% of tumors were poorly differentiated or undifferentiated. The majority of prostate SCC (77.7%) was at stage IV. 49% of patients had lymph node metastases and 68% of patients presented distant metastases (Compared with 60.5% of patients with distant metastases between 1973-2003). Interestingly only 23.5% patients had high level PSA (>10 ng/mL). 58.8% of patients underwent chemotherapy, 25.4% of patients were treated by surgery, and 31.9% of patients were treated by radiotherapy. The observed survival rates of 1-year, 2-year, and 5-year were 42.1%, 22.1%, and 12.5%, respectively (Compared with 47.9%, 27.5%, and 14.3%, respectively, between 1973 and 2003). Chemotherapy prolonged the OS of patients with regional (distant) metastases from 3 months (2 months) to 12 months (9 months). Multivariate cox regression analysis showed age, race, and stage were independent prognostic factors for prostate SCC patients. Prostate SCC is a highly malignant cancer and our analysis of recent data has shown its incidence is increasing. Incidence rate of metastatic prostate SCC has increased and the survival rates have worsened in recent years. However, chemotherapy shows some survival benefit for prostate SCC patients with regional and distant metastasis over other treatment methods. Further work is needed to understand the reason prognosis of this type prostate cancer is worsening.


Delayed cortical engagement associated with balance dysfunction after stroke.
Cortical resources are typically engaged for balance and mobility in older adults, but these resources are impaired post-stroke. Although slowed balance and mobility after stroke have been well-characterized, the effects of unilateral cortical lesions due to stroke on neuromechanical control of balance is poorly understood. Our central hypothesis is that stroke impairs the ability to rapidly and effectively engage the cerebral cortex during balance and mobility behaviors, resulting in asymmetrical contributions of each limb to balance control. Using electroencephalography (EEG), we assessed cortical N1 responses evoked over fronto-midline regions (Cz) during balance recovery in response to backward support-surface perturbations loading both legs, as well as posterior-lateral directions that preferentially load the paretic or nonparetic leg. Cortical N1 responses were smaller and delayed in the stroke group. While older adults exhibited weak or absent relationships between cortical responses and clinical function, stroke survivors exhibited strong associations between slower N1 latencies and slower walking, lower clinical mobility, and lower balance function. We further assessed kinetics of balance recovery during perturbations using center of pressure rate of rise. During backward support-surface perturbations that loaded the legs bilaterally, balance recovery kinetics were not different between stroke and control groups and were not associated with cortical response latency. However, lateralized perturbations revealed slower kinetic reactions during paretic loading compared to controls, and to non-paretic loading within stroke participants. Individuals post stroke had similar nonparetic-loaded kinetic reactions to controls implicating that they effectively compensate for impaired paretic leg kinetics when relying on the non-paretic leg. In contrast, paretic-loaded balance recovery revealed time-synchronized associations between slower cortical responses and slower kinetic reactions only in the stroke group, potentially reflecting the limits of cortical engagement for balance recovery revealed within the behavioral context of paretic motor capacity. Overall, our results implicate individuals after stroke may be uniquely limited in their balance ability by the slowed speed of their cortical engagement, particularly under challenging balance conditions that rely on the paretic leg. We expect this neuromechanical insight will enable progress toward an individualized framework for the assessment and treatment of balance impairments based on the interaction between neuropathology and behavioral context.


Hallucination induced by paroxetine discontinuation in patients with major depressive disorders.
Discontinuation symptoms can follow the stoppage of almost all classes of antidepressants, including selective serotonin reuptake inhibitors. We report two cases suffering from visual and auditory hallucinations: Case 1 abruptly stopped taking paroxetine (20 mg/day), and Case 2 discontinued paroxetine after reducing the dose from 20 mg/day to 10 mg/day for 5 months. Both cases experienced visual and auditory hallucinations in addition to dizziness, headache, insomnia, and nausea a couple of days after paroxetine discontinuation. These observations suggest that hallucinations are a part of the discontinuation syndrome that results from paroxetine discontinuation. Physicians should be aware of this symptom.


An evaluation of Congo red fluorescence for the diagnosis of amyloidosis.
Congo red stain apple-green birefringence under polarized light is the most popular method for detecting amyloid; however, it has limitations. The goal of this study was to evaluate if examination of Congo red stain by fluorescent microscopy (FM) significantly enhances the diagnostic yield. Congo red-stained tissue sections were retrospectively and prospectively examined by light microscopy (LM) with and without polarizer and by FM using the Texas red filter and results by each method compared. Congo red-stained amyloid recognized by LM was unequivocally and easily identified by FM in each of 48 cases. In 22 of them, FM either confirmed the presence of a small amount of amyloid or lead to a definitive diagnosis, which was otherwise missed. Eight cases with Congo red-negative by LM were also negative by FM. In 8 cases with a false-positive Congo red stain, FM still detected the signal in 5, but it was absent in 3 cases. In conclusion, Congo red fluorescence improves the diagnostic yield of LM for both positive and negative cases.


Genetic Testing for Thrombophilia-Related Genes: Observations of Testing Patterns for Factor V Leiden (G1691A) and Prothrombin Gene "Mutation" (G20210A).
Thrombophilia is a generic term that defines an increased propensity toward thrombosis and associated morbidity. Factor V Leiden (FVL; G1691A) and the prothrombin gene mutation (PGM; G20210A) comprise the most common genetic associations with thrombosis, and thus comprise the most commonly requested genetic thrombophilia investigations. This report describes an audit of local test findings that suggests growing futility in testing for FVL and PGM. Test requests for FVL and PGM were assessed for a recent period of 2.5 years (starting from 2016 to end of June 2018) from a large tertiary-level pathology provider. From a total of more than 10,000 thrombophilia-related test requests over the analysis period, 2,700 and 2,135 were, respectively, for FVL and PGM. The age ranges of patients varied across the full life span spectrum, but the peak investigation age range for the entire cohort was 30 to 39 years. Investigations were more often requested for females (> 70% of requests) than males, and the peak investigation age range for females (30-39 years) was earlier than males (50-59 years). However, proportionally more males than females were identified with FVL (15.4 vs. 6.6%) or PGM (10.4 vs. 4.3%), respectively. The age-related patterns of test ordering were also identified as closely aligned to birth patterns in females and thrombosis patterns in males. There has been a trend to annual reduction in detection of FVL mutation from a peak of more than 25% in 1996 to ∼10% in each year of the past decade, suggesting poorer patient selection. Of test-requesting indications, pregnancy/fetal morbidity was identified in 16.4% of all requests for females, and thromboembolism was identified in 21.4 and 18.0% of all requests for females and males, respectively. In terms of FVL identification, a heterozygous pattern was identified in 4.2% of women tested for pregnancy/fetal morbidity, but 11.7 and 15.1% of females and males, respectively, for thromboembolism. In comparison, the background rate of FVL detection in the general population in our geographical region is approximately 3 to 7%. Overall, better targeted patient selection for testing of FVL and PGM occurred in the male cohort based on higher relative capture of thrombophilia mutations than the female cohort. However, patient selection was not optimal in either the male or female cohorts, since the captured mutation rates were only marginally higher than the expected background population detection rate. Moreover, the decline in relative identification of FVL from overall test requests over time suggests deterioration of patient selection practices by referring physicians. Notably, tests requested in the setting of thromboembolism provided a higher likelihood of FVL detection than pregnancy/fetal morbidity. These data suggest some contemporary futility of genetic testing for FVL and PGM in the real world, and in particular, in females for indications around pregnancy/fetal morbidity, proposed to be related to poor patient selection in most instances.


State dependence of adaptation of force output following movement observation.
Humans readily learn to move through direct physical practice and by watching the movements of others. Some researchers have proposed that action observation can inform subsequent changes in control through the acquisition of a neural representation of the novel dynamics, but to date learning following observation has been described by kinematic metrics. Here we designed an experiment to consider the specificity of adaptation to novel dynamic perturbations at the level of force generation. We measured changes in temporal patterns of force output following either the performance or observation of movements perturbed by either position- or velocity-dependent dynamic environments to 1) establish whether previously described observational motor learning effects were attributable to changes in predictive limb control and 2) determine whether such adaptation reflected a learned dependence on limb states appropriate to the haptic environment. We found that subjects who observed perturbed movements produced significant compensatory changes in their lateral force output, despite never directly experiencing force perturbations firsthand while performing the motor task. The time series of observers' adapted force outputs suggested that the state dependence of observed dynamics shapes adaptation. We conclude that the brain can transform observation of kinematics into state-dependent adaptation of reach dynamics.


Design and stability analysis of fuzzy model-based nonlinear controller for nonlinear systems using genetic algorithm.
This paper presents stability analysis of fuzzy model-based nonlinear control systems, and the design of nonlinear gains and feedback gains of the nonlinear controller using a genetic algorithm (GA) with arithmetic crossover and nonuniform mutation. A stability condition is derived based on Lyapunov's stability theory with a smaller number of Lyapunov conditions. A solution of the stability conditions is also determined using GA. An application example of stabilizing a cart-pole typed inverted pendulum system is given to show the stabilizability of the nonlinear controller.


Evaluating the learning curve of experienced laparoscopic surgeons in robot-assisted radical prostatectomy.
Radical prostatectomy is the gold standard surgical treatment for organ-confined prostate cancer. There is no consensus on the impact of previous laparoscopic experience on the learning curve of robot-assisted laparoscopic prostatectomy (RALP). We compared the perioperative complications and early patient outcomes from our initial 100 cases of RALP with laparoscopic prostatectomy (LRP) cases performed well beyond the learning curve. Between July 2011 and January 2012, 110 RALP were performed by one of two surgeons, each with previous experience of more than 1000 LRP. The cases were pair matched from among the last 208 patients who had undergone LRP by the same surgeons at the same time. The clinical parameters, operative details, postoperative complications, and short-term outcomes from these patients, collected prospectively, were compared between the two groups. The prostate-specific antigen (PSA) level and age of the two groups was similar. The operative time (128.4 vs 153.9 min; P=0.01) and blood loss (200 vs 254 mL; P=0.01) was significantly less for the LRP group, but the duration of catheterization was similar (5.89 vs 6.2 days). The complication rate was low. No procedures needed conversions, and no patient had a visceral injury or blood transfusion. Twenty-three patients in the LRP group and 33 patients in the RALP group had extraprostatic disease, and the positive margin rate was 14% and 19% for these respective groups. At 3 months, PSA level was undetectable in 94% of LRP and 92% RALP patients, while 56% and 65% (P=0.062) patients in these groups were using 0 to 2 pads per day. The initial results of the outcome of RALP are at least at par with those of LRP and with those of previously published RALP series. This suggests the lack of a steep learning curve for experienced laparoscopic surgeons in performing RALP.


[Assessment of nutritional status at hospital admission: identification of patients with risk for malnutrition].
Various studies of prevalence in our hospitals have detected large percentages of under-nourished patients in both medical and surgical wards. These groups of patients are not detected in clinical practice and are therefore untreated, leading to nutritional deterioration. The present paper studies the prevalence of the risk of malnutrition, using the Cardona risk assessment sheet as modified by Mager, in 134 patients between the 3rd and 5th day after admission to hospital. A chi-squared test was applied to allow comparison of quantitative and qualitative variables. We found 56.70% of patients risked under-nourishment (60% in medical wards and 50% in surgical wards). The variables which showed the best correlation with the risk of malnutrition were albumen (p < 0.01), weight loss (p < 0.001) and age (p < 0.005). The Hospital's Clinical Nutrition Committee must define the standard to be achieved regarding nutritional risk in order to ensure the quality offered to our patients in this regard.


Parenting and the Serotonin Transporter Gene (5HTTLPR), Is There an Association? A Systematic Review of the Literature.
The current systematic review examines whether there is an association between the genetic 5-HTTPLR polymorphism and parenting, and the mechanisms by which this association operates. The literature was searched in various databases such as PubMed, Scopus, and ScienceDirect. In line with our inclusion criteria, nine articles were eligible out of 22. Most of the studies analysed in this review found an association between 5HTTLPR and parenting. Four studies found a direct association between 5-HTTLPR and parenting with conflicting findings: two studies found that mothers carrying the short variant were more sensitive to their infants, while two studies found that parents carrying the S allele were less sensitive. In addition, several studies found strong interaction between genetic and environmental factors, such as childhood stress and disruptive child behaviour, quality of early care experiences, poor parenting environment, and quality of the environment. Only one study found an association between children's 5HTTLPR and parenting. Parenting can be described as a highly complex construct influenced by multiple factors, including the environment, as well as parent and child characteristics. According to the studies, maternal 5-HTTLPR polymorphism is most likely to be associated with sensitive parenting.


Comprehensive microarray analysis of Hoxa11/Hoxd11 mutant kidney development.
The Hox11 paralogous genes play critical roles in kidney development. They are expressed in the early metanephric mesenchyme and are required for the induction of ureteric bud formation and its subsequent branching morphogenesis. They are also required for the normal nephrogenesis response of the metanephric mesenchyme to inductive signals from the ureteric bud. In this report, we use microarrays to perform a comprehensive gene expression analysis of the Hoxa11/Hoxd11 mutant kidney phenotype. We examined E11.5, E12.5, E13.5 and E16.5 developmental time points. A novel high throughput strategy for validation of microarray data is described, using additional biological replicates and an independent microarray platform. The results identified 13 genes with greater than 3-fold change in expression in early mutant kidneys, including Hoxa11s, GATA6, TGFbeta2, chemokine ligand 12, angiotensin receptor like 1, cytochrome P450, cadherin5, and Lymphocyte antigen 6 complex, Iroquois 3, EST A930038C07Rik, Meox2, Prkcn, and Slc40a1. Of interest, many of these genes, and others showing lower fold expression changes, have been connected to processes that make sense in terms of the mutant phenotype, including TGFbeta signaling, iron transport, protein kinase C function, growth arrest and GDNF regulation. These results identify the multiple molecular pathways downstream of Hox11 function in the developing kidney.


One-pot synthesis of stable Pd@mSiO2 core-shell nanospheres with controlled pore structure and their application to the hydrogenation reaction.
A new type of Pd@mSiO2 composite nanospheres with controlled pore structure, consisting of internal Pd cores and controlled mesoporous silica shells, has been prepared by a facile one-pot method. The thickness and pore size of the shell could be easily tuned by changing the amounts of TEOS and the hydrophobic block length, respectively, during synthesis. In this perspective, the effects of CTAB concentration, pH, and TEOS concentration on the monodisperse sphere morphology of Pd@mSiO2 nanoparticles (NPs) were investigated. In addition, a nucleation mechanism was proposed. Hydrogenation of nitrobenzene to aniline was used as a model reaction to discuss the effect of pore size on the transport rate of the reactants and the product selectivity in metal-catalyzed hydrogenation. The catalysts exhibited a high conversion rate and significantly enhanced stability, leading to a higher recyclability without loss of catalytic activity compared to conventional supported catalysts and commercial catalysts.


[QTL mapping of five agronomic traits in maize].
Agronomic traits have significant influence on stability and adaptability in maize production. In this investigation, using a population with 266 F2:3 families from Yuyu22 (Zong3 x 87-1), two-location field tests were conducted in Wuhan and Xiangfan in 2001, with a randomized complete block design, to characterize five agronomic traits: ear height, tassel branch number, stalk diameter, days to pollen, and days to silk. Correlation analysis of field performance indicated that ear height, tassel branch number and stalk diameter were significantly positive correlative with single-plant yield, days to pollen and days to silk were highly positive correlative with each other, and tassel branch number was significantly positive correlative with stalk diameter too. Utilizing data of field tests and molecular markers, Composite Interval Mapping (CIM) method was used to localize the quantitative trait loci of these traits and 500 times permutation test was conducted to have proper LOD threshold value. As the results, total seven QTL of ear height, nine QTL of tassel branch number, eight QTL of stalk diameter, nine QTL of days to pollen, and seven QTL of days to silk were mapped on 10 chromosomes of maize; all of these QTL distributed unevenly on chromosomes and trended to cluster together. According to analysis of this investigation, the phenotype correlations of quantitative traits may result from the correlations of QTL controlling those traits. Those will be helpful to further understand genetic basis of agronomic traits in maize.


Hypoxia modulates the antioxidant effect of hydroxytyrosol in MCF-7 breast cancer cells.
Although cancer is multifactorial, a strong correlation between this pathology and increased oxidative stress has long been stablished. Hypoxia, inherent to solid tumors, increases reactive oxygen species and should be taken into account when analyzing the response of tumor cells to antioxidants. The Mediterranean diet has been related to a lower incidence of cancer, and particularly of breast cancer. Given that hydroxytyrosol (HT) is largely responsible for the antioxidant properties of olive oil, we have performed a comprehensive and comparative study of its effect on the oxidative stress response of the human breast cancer cell line MCF-7 in hypoxia and normoxia. Our results demonstrate that the antioxidant action of HT is particularly effective in a hypoxic environment. Moreover, we have observed that this polyphenol modulates the transcription and translation of members of the PGC-1α/ERRα and PGC-1α/Nrf2 pathways. However, while the transcriptional effects of HT are similar in normoxic and hypoxic conditions, its translational action is less prominent and partially attenuated in hypoxia, and therefore cannot completely explain the antioxidant effect of HT. Consequently, our results underscore that the hypoxic environment of tumor cells should be considered when analyzing the effect of bioactive compounds. Besides, this study also points to the importance of assessing the regulatory role of HT at both mRNA and protein level to get a complete picture of its effects.


Strontium in the bone-implant interface.
Total hip replacement surgery is being performed on an increasingly large part of the population and at increasingly younger age. Because we live and stay physically active longer, and since hip replacement surgery has become quite successful, the treatment is being offered to progressively more patients. Unfortunately, about 17% of hip replacement surgeries currently involve revisions. Consequently, the longevity of both the primary and revision implant is an issue and warrants further investigation. Implants undergoing early instability or even subsidence correlate with an increased risk of aseptic loosening, subsequently requiring revision. Thus, the goal is early fixation by osseointegration of the implant. For revision implants, this is an even greater challenge since an allograft is often needed during surgery to obtain immediate stability of the implant. Bone grafts are rapidly resorbed. Thus, instability of the prosthesis may develop before new bone formation is well established and can mechanically secure the prosthesis. Strontium is a dual action drug; being both bone anabolic and anti-catabolic. In the form of strontiumranelate, it is used in the treatment of osteoporosis. Strontium may potentially improve the early osseointegration and fixation of implants. This dissertation consists of three studies investigating the effect of strontium at the bone-implant interface. The questions were firstly, what is the optimal delivery method for strontium to the interface, and secondly, can strontium exercise its dual action at the interface? The studies were performed in a cementless, experimental gap model in canine. The effects of strontium were evaluated by histomorphometrical analysis of the osseointegration and mechanical push-out test of implant fixation. Different stereological methods were used for the histomorphometrical analysis of each study. The methods used were reviewed critically and found valid. Study I compared a 5% strontium-substituted hydroxyapatite (HA) coating with an HA coating after 4 weeks and 12 weeks observation time. We examined whether fixation of the implant was improved by the strontium substitution. It was found that fixation of the implant was not improved by the strontium substituted HA coating at any of the two time points. Study II compared a 5% strontium-doped HA bone graft extender with an HA bone graft extender. The bone graft extender was mixed with allograft and impacted around a titanium implant. The objective of this study was to determine whether strontium doping of the bone graft extender could protect the allograft from fast resorption and increase gap healing, leading to the improved fixation of the implant. We found that the strontium doping increased gap healing and protected the allograft, however, results of the mechanical test were inconclusive. The reason might have been that the increased gap healing had not yet reached the implant during the 4 weeks observation time, so ongrowth onto the implant was not improved. Study III investigated the effects of bioactive glass coating with a 0%, 10% or 50% strontium-substitution versus HA coating of grit-blasted titanium alloy implants. The goal was to determine whether fixation of the implant would be improved by the bioactive glass coating, and then further improved by the strontium-substitution of the coating in a dose-dependent manner. Unfortunately, the bioactive glass coating failed, presumably due to aluminum contamination originating from the grit-blasting powder. The HA coated implants were superior in all parameters of osseointegration and the mechanical fixation of the implants. These studies show the importance of performing further experimental investigation. Even when investigating a known agent for use in a new application. Strontium delivered as doping of an HA bone graft extender showed potential as a dual acting agent in the interface. However, delivery methods of strontium to the bone-implant interface clearly need further investigation.


ATM orchestrates the DNA-damage response to counter toxic non-homologous end-joining at broken replication forks.
Mutations in the ATM tumor suppressor gene confer hypersensitivity to DNA-damaging chemotherapeutic agents. To explore genetic resistance mechanisms, we performed genome-wide CRISPR-Cas9 screens in cells treated with the DNA topoisomerase I inhibitor topotecan. Thus, we here establish that inactivating terminal components of the non-homologous end-joining (NHEJ) machinery or of the BRCA1-A complex specifically confer topotecan resistance to ATM-deficient cells. We show that hypersensitivity of ATM-mutant cells to topotecan or the poly-(ADP-ribose) polymerase (PARP) inhibitor olaparib reflects delayed engagement of homologous recombination at DNA-replication-fork associated single-ended double-strand breaks (DSBs), allowing some to be subject to toxic NHEJ. Preventing DSB ligation by NHEJ, or enhancing homologous recombination by BRCA1-A complex disruption, suppresses this toxicity, highlighting a crucial role for ATM in preventing toxic LIG4-mediated chromosome fusions. Notably, suppressor mutations in ATM-mutant backgrounds are different to those in BRCA1-mutant scenarios, suggesting new opportunities for patient stratification and additional therapeutic vulnerabilities for clinical exploitation.


Playing God: Testing, Modeling, and Imitating Blood Miracles in Eighteenth-Century Europe.
In the late Middle Ages, rumors began to spread throughout Europe regarding blood miracles associated with the relics of martyrs. Centuries-old blood, pulverized or solidified and black in color, was said to return to its original bright red color, or else to liquefy or bubble under certain circumstances or on certain dates in the liturgical calendar. With the Reformation, in Protestant countries most of these relics were either destroyed or forgotten. In Catholic countries, on the contrary, blood miracles multiplied, reaching a peak between the seventeenth and eighteenth centuries. This article reconstructs the debate that sprang up in eighteenth-century Europe over the blood of Saint Januarius and the attempts made to disprove its miraculous properties, often not in written works, but by staging highly theatrical demonstrations. It examines the way in which, with phenomena as complex as miracles, the activities of testing alleged facts, creating elucidative models, and staging imitations intertwined over the centuries, often overlapping and becoming confused.


Central blood pressure measurement may improve risk stratification.
Central systolic blood pressure (SBP) may differ between individuals with similar brachial SBP, which may have implications for risk assessment. This study aimed to determine the variation and potential clinical value of central SBP between patients with similar brachial SBP. Brachial SBP was measured by sphygmomanometer and central SBP by radial tonometry in 675 people (430 men), comprising healthy individuals (n = 222), patients with known or suspected coronary artery disease (n = 229) and diabetes (n = 224). Individuals were stratified by brachial SBP in accordance with European Society of Hypertension guidelines (optimal, normal, high-normal, grades 1, 2 and 3 hypertension). The potential clinical value of central SBP was determined from the percentage of patients re-classified into different brachial SBP groups due to the difference between brachial and aortic SBP (defined as brachial SBP-central SBP). Central SBP increased with each brachial SBP level (optimal to grade 3 hypertension; P < 0.001 for all). However, large variation in brachial-aortic SBP difference occurred within each brachial SBP group (range 2-33 mm Hg), resulting in sizeable overlap of central SBP between brachial SBP groups. For patients with normal brachial SBP, 96% had central SBP within the range of patients with high-normal brachial SBP, as well as 64% within the range of patients with grade 1 hypertension. We conclude that wide variation in brachial-aortic SBP difference occurs between patients with similar brachial SBP. This results in a significant overlap of central SBP scores between brachial SBP risk groups. This is likely to have treatment implications but remains to be tested.


Sunitinib for Taiwanese patients with gastrointestinal stromal tumor after imatinib treatment failure or intolerance.
To report preliminary results of the efficacy and safety of sunitinib in the management of Taiwanese gastrointestinal stromal tumors (GIST) patients facing imatinib mesylate (IM) intolerance or failure. Between 2001 and May 2010, 199 Taiwanese patients with metastatic GIST were treated at Chang Gung Memorial Hospital. Among them, 23 (11.6%) patients receiving sunitinib were investigated. Sixteen male and 7 female patients with a median age of 59 years (range: 24-83 years) received sunitinib. Twenty-two GIST patients changed to sunitinib because of IM failure and 1 because of intolerance. The median duration of sunitinib administration was 6.0 mo (range: 2-29 mo). The clinical benefit was 65.2% [2 complete response (CR), 4 partial response (PR), and 9 stationary disease (SD); 15/23]. In 12 patients harboring mutations of the kit gene at exon 11, the clinical benefit rate (CR, PR, and SD) was 75.0% and 6 patients with tumors containing kit exon 9 mutations had a clinical benefit of 50.0% (not significant, P = 0.344). The progression free survival (PFS) and overall survival (OS) did not differ between patients whose GISTs had wild type, KIT exon 9, or KIT exon 11 mutations. Hand-foot syndrome was the most common cause of grade III adverse effect (26.1%), followed by anemia (17.4%), and neutropenia (13.0%). During the median 7.5-mo follow-up after sunitinib use, the median PFS and OS of these 23 GIST patients after sunitinib treatment were 8.4 and 14.1 mo, respectively. Sunitinib appears to be an effective treatment for Taiwanese with IM-resistant/intolerant GISTs and induced a sustained clinical benefit in more than 50% of Taiwanese advanced GIST patients.


Injuries among talented young dancers: findings from the U.K. Centres for Advanced Training.
The aim of the present study was to characterize the injuries of young dancers attending Centres for Advanced Training. 806 dancers, ages 10-18 years responded to surveys regarding their biological profile, dance experience and injury history, and were examined for their anthropometric profile. Of the 806 dancers, 347 reported an injury. Based on 4 age groups, the total hours of practice per week increased significantly with increasing age. Incidence of injuries per 1000 h of dance practice for dancers ages 11-12 were found to be significantly higher compared to the incidence for dancers ages 13-18 (p<0.05). Foot and ankle and other lower extremities were the most common injury location, and muscle injuries were the most common type of injury. Total months in CAT training (OR=1.044, 95% CI=1.014-1.075) and hours per week in creative style practice (OR=1.282, 95% CI=1.068-1.539) were found to be significantly associated with injuries. In conclusion, both young and mature dancers are exposed to extensive risk of injury. The intensity of training (such as number of months and number of hours of training per week) is important factor that should be taken into account in order to decrease future injuries among young dancers.


Influence of COVID-19 pandemic on quality of life in patients with epilepsy - Follow-up study.
To perform a follow-up study of the quality of life in patients with epilepsy in the era of the COVID-19 crisis. Two months before the first case of the COVID-19 in Serbia, we obtained the Serbian Version of Quality of Life Inventory for Epilepsy 31 (SVQOLIE-31) and Neurological Disorders Depression Inventory for Epilepsy scores (SVNDDI-E) for another study. We retested the same patients one year after in COVID-19 pandemic. In addition to SVQOLIE-31, and SVNDDI-E we used a generic questionnaire compiled from items related to the COVID-19. We retested 97 out of 118 patients (82.2%) for the follow-up analysis. The average age was 36.1 ± 12.2 (range: 18-69), and 49 were women (50.5%). The median duration of epilepsy was 13 years (range: 1.5-48). The structural etiology of epilepsy was noted in 41 (42.3%), unknown etiology in 41 (42.3%), and genetic etiology in 15 (15.4%) patients. Fewer patients (27.8%) experienced at least one seizure three months before follow-up testing when compared to patients who experienced at least one seizure three months in initial testing (36.0%) (p = 0.15). All patients reported full compliance with anti-seizure medication in the follow-up. The SVQOLIE-31 score during the COVID-19 pandemic visit (64.5 ± 14.6) was significantly lower than the SVQOLIE-31 score before the pandemic (p < 0.001). The SVNDDI-E score during the COVID-19 pandemic (10.5 ± 3.5) was significantly higher than the SVNDDI-E score before it (p < 0.001). Multiple linear regression analyses revealed fear of seizures, and fear of a reduction in household income, significantly associated with SVQOLIE-31 and SVNDDI-E overall score. These variables accounted for 66% and 27% of the variance of SVQOLIE-31 and SVNDDI-E overall score. Lower quality of life, higher prevalence of depression, healthcare availability issues, and perceived fears during pandemic all suggest COVID-19 has negatively impacted lives of patients with epilepsy.


How Lewis acidity of the cationic framework affects KNaNbOF(5) polymorphism.
The valence matching principle is used to explain the loss of inversion symmetry in the noncentrosymmetric (NCS) polymorph of KNaNbOF5 in comparison to its centrosymmetric (CS) polymorph. The [NbOF5](2-) anion has five contacts to both potassium and sodium in the NCS polymorph, whereas in the CS polymorph there are only four contacts to potassium and six contacts to sodium. The lower average Lewis acidity of the cationic framework in the NCS polymorph relative to the CS polymorph reflects the loss of inversion symmetry. This lower average Lewis acidity is achieved during hydrothermal synthesis with a potassium-rich solution when the K:Na ratio in the reaction is greater than 1:1, as the Lewis acidity of potassium is lower than that of sodium. The contrasting coordination environments are manifested in secondary distortions that weaken the primary Nb═O interaction and lengthen the Nb═O bond in the NCS polymorph. An unusual heat-induced phase transition from the CS to the NCS polymorph was studied with in situ powder X-ray diffraction. The transition to the NCS polymorph upon cooling occurs through an intermediate phase(s).


The psychosocial M & M: a tool in reinterpreting problematic medical situations.
This article explores the concept of a psychosocial morbidity and mortality (M & M) conference as a useful adjunct to the traditional M & M in physician education. It argues that understanding significantly unexpected and disturbing patient outcomes often requires a shift in the analytic paradigm used and offers an interpretive and relational perspective as a way to deepen the understanding of physicians-in-training. In particular, it is argued that the psychosocial M & M can highlight previously missed or trivialized dimensions of patient, family, and physician interactions which affect care and, simultaneously, can help address the affective distress of the physician-in-training which results from a difficult and painful case. Definition, goals, and a theoretical formulation are provided, as well as a detailed description of how a psychosocial M & M might be conducted. A discussion of potential difficulties and anecdotal positive outcomes are also included.


Effects of the 2-Substituted Adenosine-1,3-diazaphenoxazine 5'-Triphosphate Derivatives on the Single Nucleotide Primer Extension Reaction by DNA Polymerase.
The adenosine triphosphate derivatives of 2-oxo-1,3-diazaphenoxazine (dAdapTP) showed a significant discrimination ability for the template strand including that between 8-oxo-2'-deoxyguanosine (8-oxodG) and 2'-deoxyguanosine (dG) by the single nucleotide primer extension reaction using the Klenow Fragment. In this study, we synthesized new dAdapTP derivatives, i.e., 2-amino-dAdapTP, 2-chloro-dAdapTP and 2-iodo-dAdapTP, to investigate the effect on the selectivity and efficiency of incorporation for the primer extension reaction using a variety of DNA polymerases. In contrast to the previously tested dAdapTP, the selectivity and efficiency of the 2-halo-dAdapTP incorporation were dramatically decreased using the Klenow Fragment. Moreover, the efficiency of the 2-amino-dAdapTP incorporation into the T-containing template was almost the same with that of dAdapTP. In the case of the Bsu DNA polymerase, the efficiency of all the dAdapTP derivatives decreased compared to that using the Klenow Fragment. However, the incorporation selectivity of dAdapTP had improved against the oxodG-containing template for all the template sequences including the T-containing template. Moreover, 2-amino-dAdapTP showed a better efficiency than dAdapTP using the Bsu DNA polymerase. The 2-amino group of the adenosine unit may interact with syn-oxodG at the active site of the Bsu DNA polymerase during the single primer extension reaction.


Regulation of aromatic amino acid transport by tRNA: role of 2-methylthio-N6-(delta2-isopentenyl)-adenosine.
E. coli growing rapidly in media where ferric iron is not freely available contain a population of specifically undermodified tRNAs. These tRNAs contain isopentenyl adenosine instead of the usual methylthioisopentenyl adenosine adjacent to the 3' end of the anticodon. Iron restricted E. coli also show an enhanced capacity to transport aromatic amino acids into the cell. Our work shows that undermodified tRNAs for phe, tyr and trp can function as positive regulatory elements of the aromatic amino acid transport system in E. coli. This iron related metabolic control, mediated through a specific post-transcriptional modification of the tRNAs, may be an important mechanism for adapting E. coli for growth in an iron restricted environment.


Mammographic patterns as a predictive biomarker of breast cancer risk: effect of tamoxifen.
Mammographic breast density has been shown to be associated with up to a 4- to 6-fold increase in risk of breast cancer, whereas tamoxifen therapy increases disease-free survival and reduces mortality. We have therefore investigated whether these effects are related. To determine the effects of tamoxifen on mammographic density, mammograms from 94 women who had received tamoxifen for breast cancer and 188 women (without breast cancer) who had not received tamoxifen were visually classified according to the criteria of Wolfe. Two controls were age-matched to each case. All of the women were postmenopausal (ages, 50-64 years), neither group was taking hormone replacement therapy, and none of the cases had received chemotherapy. There were significant differences in breast density between cases and controls at the initial mammogram (P = 0.0001) but no significant differences at the follow-up mammogram (P = 0.51). A significant change to a more lucent pattern had occurred among the case group (P = 0.0001). The odds ratio for cancer that was associated with the more dense (P2 and DY) patterns with respect to the more lucent (N1 and P1) patterns was 3.6 (95% confidence interval, 2.11-6.18) at the initial mammogram. This was significantly reduced to 1.5 (95% confidence interval, 1.32-1.70) after treatment with tamoxifen (P = 0.019; chi2 = 5.52). The substantial reduction in breast density with tamoxifen provides evidence that tamoxifen has the capacity to favorably alter postmenopausal breast density toward a more lucent pattern, which is associated with reduced risk of breast cancer. Mammographic pattern is, thus, a potential biomarker of breast cancer risk.


Thiomicrorhabdus sediminis sp. nov. and Thiomicrorhabdus xiamenensis sp. nov., novel sulfur-oxidizing bacteria isolated from coastal sediments and an emended description of the genus Thiomicrorhabdus.
Two novel Gram-strain-negative and rod-shaped bacteria, designated strain G1T and G2T, were isolated from sediment samples collected from the coast of Xiamen, PR China. The cells were motile by a single polar flagellum. Growth of strain G1T occurred at 10-40 °C (optimum, 30 °C), at pH 6.0-9.0 (optimum, pH 7.5) and with 5-1530 mM NaCl (optimum, 510 mM), while the temperature, pH and NaCl concentration ranges for G2T were 4-45 °C (optimum, 28 °C), pH 5.5-8.0 (optimum, pH 6.5) and 85-1530 mM NaCl (optimum, 340 mM). The two isolates were obligate chemolithoautotrophs capable of using thiosulfate, sulfide, elemental sulphur or tetrathionate as an energy source. Strain G1T used molecular oxygen or nitrite as an electron acceptor, while strain G2T used molecular oxygen as the sole electron acceptor. The dominant fatty acids of G1T and G2T were summed feature 3 (C16:1 ω7c and/or C16:1 ω6c), C16 : 0 and summed feature 8 (C18:1 ω7c and/or C18:1 ω6c). The DNA G+C content of G1T and G2T were 45.1 and 48.3 mol%, respectively. Phylogenetic analysis based on 16S rRNA gene sequences indicated that strain G1T and G2T were members of the genus Thiomicrorhabdus, and most closely related to Thiomicrorhabdus hydrogeniphila MAS2T (96.0 %) and Thiomicrorhabdus indica 13-15AT (95.4 %), respectively. The 16S rRNA gene sequence similarity between strains G1T and G2T was 95.8 %. Based on the phylogenetic, genomic and phenotypic data presented here, the isolate strains represent novel species of the genus Thiomicrorhabdus, for which the names Thiomicrorhabdus sediminis sp. nov. (type strain G1T=MCCC 1A14511T=KCTC 15841T) and Thiomicrorhabdus xiamenensis sp. nov. (type strain G2T=MCCC 1A14512T=KCTC 15842T) are proposed.


Human parainfluenza virus type 2 phosphoprotein: mapping of monoclonal antibody epitopes and location of the multimerization domain.
The epitopes recognized by 42 monoclonal antibodies directed against the human parainfluenza virus type 2 (hPIV-2) phosphoprotein (P) were mapped on the primary structure of the P protein by testing their reactivities with deletion mutants. By Western Immunoblotting with these monoclonal antibodies and P protein deletion mutants the region essential for P-P interactions was determined. The P protein region encompassing amino acids 211-248 was required for proper folding and oligomerization which is mediated by predicted coiled-coils in this region. The oligomer was shown to be a homotrimer by chemical cross-linking experiments.


Isolation of dermal adipocytes from mouse skin for biochemical analysis.
The role of dermal white adipose tissue in regulating skin homeostasis and self-renewal processes has recently attracted interest. However, the isolation of proteins from dermal adipocytes for biochemical analysis is challenging. Here, we provide a protocol for the isolation of murine dermal adipocytes. We describe steps for inducing adipocyte-specific gene deletion, adipocyte isolation, protein purification, and western blot analysis. The reliability of the protocol is demonstrated by verifying efficient adipocyte-specific Atgl gene deletion in a tamoxifen-inducible Cre/loxP-based mouse model. For complete details on the use and execution of this protocol, please refer to Zhang et al. (2019).1.


Comparative Genome Analysis and Phenotypic Characterization of Clostridium gasigenes CGAS001 Isolated From Chilled Vacuum-Packed Lamb Meat.
Genomic data for psychrophilic bacteria causing blown pack spoilage (BPS) are limited. This study characterizes the genome of a novel Clostridium gasigenes strain CGAS001 isolated from meat juice sample (MJS) of vacuum-packed lamb meat by comparing it with the type strain C. gasigenes DSM 12272 and five strains representing four other BPS-causing Clostridium sensu stricto species. Phenotypic characteristics of the strain, which include biochemical characteristics, antimicrobial resistance and production of putative polyketide, have been determined. The size of its draft genome is 4.1 Mb with 3,845 coding sequences, 28.7% GC content and 95 RNA genes that include 75 tRNAs, 17 rRNAs, and 3 ncRNAs. Average Nucleotide Identity (ANI) and digital DNA-DNA Hybridization (dDDH) predict that C. gasigenes CGAS001 and DSM 12272 constitute a single species (ANI and dDDH = 98.3% for speciation) but two distinct subspecies (dDDH = 73.3% for subspeciation). The genome is characterized by saccharolytic, lipolytic and proteolytic genes as well as hemolysins and phospholipases, which are consistent with its phenotype. The genome also reveals the ability of C. gasigenes to synthesize polyketides which is demonstrated by the antimicrobial activity of a crude polyketide extract against Listeria monocytogenes and Enterococcus devriesei. The strain is resistant to polymyxin B and streptomycin. The genetic and phenotypic analyses suggest that CGAS001 constitutes a novel subspecies of C. gasigenes adapted to a saprophytic lifestyle and can synthesize narrow spectrum antimicrobial compounds.


Coexistent bullous pemphigoid and systemic lupus erythematosus.
A case of coexistent bullous pemphigoid and systemic lupus erythematosus is reported. Evidence for an immunologic pathogenesis is reviewed for both disorders. It is suggested that the coexistence of bullous pemphigoid and systemic lupus erythematosus may represent a similar pathomechanism.


Electric Field Effect on Phospholipid Monolayers at an Aqueous-Organic Liquid-Liquid Interface.
The electric potential difference across cell membranes, known as the membrane potential, plays an important role in the activation of many biological processes. To investigate the effect of the membrane potential on the molecular ordering of lipids within a biomimetic membrane, a self-assembled monolayer of 1-stearoyl-2-oleoyl-sn-glycero-3-phosphocholine (SOPC) lipids at an electrified 1,2-dichloroethane/water interface is studied with X-ray reflectivity and interfacial tension. Measurements over a range of electric potential differences, -150 to +130 mV, that encompass the range of typical biomembrane potentials demonstrate a nearly constant and stable structure whose lipid interfacial density is comparable to that found in other biomimetic membrane systems. Measurements at higher positive potentials, up to 330 mV, illustrate a monotonic decrease in the lipid interfacial density and accompanying variations in the interfacial configuration of the lipid. Molecular dynamics simulations, designed to mimic the experimental conditions, show that the measured changes in lipid configuration are due primarily to the variation in area per lipid with increasing applied electric field. Rotation of the SOPC dipole moment by the torque from the applied electric field appears to be negligible, except at the highest measured potentials. The simulations confirm in atomistic detail the measured potential-dependent characteristics of SOPC monolayers. Our hybrid study sheds light on phospholipid monolayer stability under different membrane potentials, which is important for understanding membrane processes. This study also illustrates the use of X-ray surface scattering to probe the ordering of surfactant monolayers at an electrified aqueous-organic liquid-liquid interface.


A convolutional neural network for bleeding detection in capsule endoscopy using real clinical data.
The goal of the present study was to develop a convolutional neural network for the detection of bleedings in capsule endoscopy videos using realistic clinical data from one single-centre. Capsule endoscopy videos from all 133 patients (79 male, 54 female; meanage = 53.73 years, SDage = 26.13) who underwent capsule endoscopy at our institution between January 2014 and August 2018 were screened for pathology. All videos were screened for pathology by two independent capsule experts and confirmed findings were checked again by a third capsule expert. From these videos, 125 pathological findings (individual episodes of bleeding spanning a total of 5696 images) and 103 non-pathological findings (sections of normal mucosal tissue without pathologies spanning a total of 7420 images) were used to develop and validate a neural network (Inception V3) using transfer learning. The overall accuracy of the model for the detection of bleedings was 90.6% [95%CI: 89.4%-91.7%], with a sensitivity of 89.4% [95%CI: 87.6%-91.2%] and a specificity of 91.7% [95%CI: 90.1%-93.2%]. Our results show that neural networks can detect bleedings in capsule endoscopy videos under realistic, clinical conditions with an accuracy of 90.6%, potentially reducing reading time per capsule and helping to improve diagnostic accuracy.


The provision of home-based palliative care for those with advanced heart failure.
Although widely recognized as best practice for advanced heart failure patients, palliative care is underused by this population. The purpose of this brief review is to highlight recent findings related to home-based palliative care among patients with advanced heart failure. This review considers new models of home-based palliative care and reports recent evidence on the effectiveness, and burden of these models for patients with advanced heart failure and their caregivers. New models currently under investigation and gaps in current research are presented. New models integrating home-based palliative care and standard heart failure care have shown to be effective in reducing both physical and psychological symptoms in patients. Recent evidence suggests that home-based palliative care reduces hospitalizations and decrease the probability of 30-day re-admissions in patients with advanced heart failure; thus, potentially reducing costs of care and increasing likelihood of dying at home. However, caregiver burden for families of those with heart failure remains an issue. Research that addresses caregiver burden and the challenges of providing palliative care to patients with the uncertain disease trajectory seen in advanced heart failure require further research.


Myosin and actin expression and oxidation in aging muscle.
While the age-related loss in muscle mass partially explains the decline in strength, other yet undefined mechanisms contribute. This study investigates whether changes in myosin-actin stoichiometry and oxidative modification could help explain the decrement in muscle strength with aging. Protein expression and oxidation were evaluated in myosin and actin isolated from the soleus and semimembranosus muscles from young adult, old, and very old Fischer 344 rats. In the soleus muscle, actin and myosin content did not change with aging. In the semimembranosus, actin content was stable, but myosin exhibited decreased content in muscles from very old rats, resulting in a decrease in the myosin-to-actin ratio. 3-Nitrotyrosine and 4-hydroxy-2-nonenal were used as markers of protein oxidative damage. Although myosin and actin are modified with 3-nitrotyrosine and 4-hydroxy-2-nonenal, the extent of chemical modification does not increase with age. The results suggest that the decline in force production with age is not due to the accumulation of these two specific markers of protein oxidation on the myofibrillar proteins. Additionally, age-dependent changes in myofibrillar stoichiometry do not contribute to the decline in force production in the soleus, but may play a role in the semimembranosus with advanced age.


Elucidating the microbial community associated with the protein preference of sludge-degrading worms.
Sludge predation by aquatic worms results in an increased sludge reduction rate, which is mainly due to the specific removal of a protein fraction from the sludge. As microorganisms play an essential role in sludge hydrolysis a better understanding of the microbial community involved in the worm predation process will provide more insight into the relations between the aquatic worms, their associated microbiome and the efficient sludge reduction. In this study, the microbial community associated with predation by the Tubifex tubifex was investigated. The microbial diversity in the samples of the worm faeces (WF), predated activated sludge and protein-rich substrates were compared. The results indicated that predation on sludge resulted in a microbial change from Actinobacteria (44%) in the sludge, to Proteobacteria (64%) and Bacteriodites (36%) in the WF. Interestingly, the faecal microbial community was more related to the community in (predated) protein-rich substrates than to the community in predated or endogenously respirated activated sludge samples. This similar microbial community could be due to microbial utilisation of protein hydrolysis products. Alternatively, conditions in the worm gut could facilitate a protein hydrolysing community which assists in protein hydrolysis. The genera Burkholderiales, Chryseobacterium and Flavobacterium were found to be associated with predation by T. tubifex.


Single-neuron activity in the human supplementary motor area underlying preparation for action.
The supplementary motor area (SMA) is considered critical in the planning, initiation, and execution of motor acts. Despite decades of research, including electrical stimulation mapping in patients undergoing neurosurgery, the contribution of this region to the generation of motor behavior has remained enigmatic. This is a study of single-neuron responses at various stages of a motor task during depth electrode recording in the SMA, pre-SMA, and medial temporal lobe of humans, with the goal of elucidating the disparate roles of neurons in these regions during movements. The patients were undergoing evaluation for epilepsy surgery requiring implantation of intracranial depth electrodes. Single-unit recordings were made during both the execution and mental imagery of finger apposition sequences. Only medial frontal neurons responded selectively to specific features of the motor plan, such as which hand performed the motor activity or the complexity of the sequence. Neuron activity progressively increased before the patient was given a "go" cue for the execution of movements; this activity peaked earlier in the pre-SMA than in the SMA proper. We observed similar patterns of activation during motor imagery and actual movement, but only neurons in the SMA differentiated between imagined and real movements. These results provide support at the single-neuron level for the role of the medial frontal cortex in the temporal organization and planning of movements in humans.


Responding to the needs of the homeless mentally ill.
The homeless mentally ill represent a pivotal and urgent challenge to the mental health field in the 1980s. Those homeless who have extended histories of psychiatric hospitalization stand as harsh reminders of the failures of deinstitutionalization, while young mentally ill homeless adults who never have been treated as inpatients testify to the gaps and unrealized promises of community-based care under deinstitutionalization. Homelessness and mental illness are social and clinical problems, respectively, distinct in some ways but intertwined in others. Some of the factors that contribute to homelessness--such as economic deprivations, a dearth of low-cost housing, discontinuities in social service systems, and radical changes in the composition of American families--are felt particularly keenly by many persons who are mentally ill. And symptoms of mental disorders, in turn, frequently impede an individual's capacities to cope with those, as well as other, stressors. Developing appropriate and effective responses to the needs of homeless people who are mentally ill requires precise definition and identification of the target population, innovations in the mental health service system, encouragement of those who staff it to work with homeless mentally ill patients, and public education. Ultimately, however, fundamental answers will be found in an improved understanding of severe mental illness, enhanced treatment capacities, and greater attention to the rehabilitative needs of mentally ill persons.


Increased DNA vaccine delivery and immunogenicity by electroporation in vivo.
DNA vaccines have been demonstrated to be potent in small animals but are less effective in primates. One limiting factor may be inefficient uptake of DNA by cells in situ. In this study, we evaluated whether cellular uptake of DNA was a significant barrier to efficient transfection in vivo and subsequent induction of immune responses. For this purpose, we used the technique of electroporation to facilitate DNA delivery in vivo. This technology was shown to substantially increase delivery of DNA to cells, resulting in increased expression and elevated immune responses. The potency of a weakly immunogenic hepatitis B surface Ag DNA vaccine was increased in mice, as seen by a more rapid onset and higher magnitude of anti-hepatitis B Abs. In addition, the immunogenicity of a potent HIV gag DNA vaccine was increased in mice, as seen by higher Ab titers, a substantial reduction in the dose of DNA required to induce an Ab response, and an increase in CD8+ T cell responses. Finally, Ab responses were enhanced by electroporation against both components of a combination HIV gag and env DNA vaccine in guinea pigs and rabbits. Therefore, cellular uptake of DNA is a significant barrier to transfection in vivo, and electroporation appears able to overcome this barrier.


Integrative functional genomic analysis of human brain development and neuropsychiatric risks.
To broaden our understanding of human neurodevelopment, we profiled transcriptomic and epigenomic landscapes across brain regions and/or cell types for the entire span of prenatal and postnatal development. Integrative analysis revealed temporal, regional, sex, and cell type-specific dynamics. We observed a global transcriptomic cup-shaped pattern, characterized by a late fetal transition associated with sharply decreased regional differences and changes in cellular composition and maturation, followed by a reversal in childhood-adolescence, and accompanied by epigenomic reorganizations. Analysis of gene coexpression modules revealed relationships with epigenomic regulation and neurodevelopmental processes. Genes with genetic associations to brain-based traits and neuropsychiatric disorders (including MEF2C, SATB2, SOX5, TCF4, and TSHZ3) converged in a small number of modules and distinct cell types, revealing insights into neurodevelopment and the genomic basis of neuropsychiatric risks.


Sensory deprivation differentially impacts the dendritic development of pyramidal versus non-pyramidal neurons in layer 6 of mouse barrel cortex.
Early postnatal sensory experience can have profound impacts on the structure and function of cortical circuits affecting behavior. Using the mouse whisker-to-barrel system we chronically deprived animals of normal sensory experience by bilaterally trimming their whiskers every other day from birth for the first postnatal month. Brain tissue was then processed for Golgi staining and neurons in layer 6 of barrel cortex were reconstructed in three dimensions. Dendritic and somatic parameters were compared between sensory-deprived and normal sensory experience groups. Results demonstrated that layer 6 non-pyramidal neurons in the chronically deprived group showed an expansion of their dendritic arbors. The pyramidal cells responded to sensory deprivation with increased somatic size and basilar dendritic arborization but overall decreased apical dendritic parameters. In sum, sensory deprivation impacted on the neuronal architecture of pyramidal and non-pyramidal neurons in layer 6, which may provide a substrate for observed physiological and behavioral changes resulting from whisker trimming.


The effects of electroacupuncture on peripheral nerve regeneration in rats.
This study was designed to examine the effects of electroacupuncture with direct current (DC) on peripheral nerve regeneration. The left sciatic nerve of 55 7-month-old rats was crushed at the thigh. They were ramdomly allocated to four groups: distal cathode DC group (n = 15), distal anode DC group (n = 14), sham operated group (n = 13), and control group (n = 13). In the distal cathode DC group, a cathode electrode was connected to an insulated acupuncture needle inserted at 1 cm distal to the injured site, while an anode electrode was connected to a needle inserted at 1 cm proximal to the lesion. In the distal anode DC group, the anode and the cathode electrode were connected to the needle at 1 cm distal and proximal to the lesion respectively. In the sham operated group, no electrical stimulation was given to the insulated needle inserted at the same site, and in the control group, no treatment was given. Regeneration of the sciatic nerve was evaluated by the number of evoked EMGs recorded at 12 sites in the plantar region, by their latency, and by the weight ratio of the tibialis anterior at four weeks after the crush injury. Regeneration of the peripheral nerve was faster and more accelerated in the distal cathode DC group than in the other groups, while in the distal anode DC group the regeneration was delayed. This result suggested electroacupuncture with cathode distal orientation might be a useful treatment having the advantage of enabling deeper insertion with minimal tissue damage.


Highly Similar Tetramerization Domains from the p53 Protein of Different Mammalian Species Possess Varying Biophysical, Functional and Structural Properties.
The p53 protein is a transcriptional regulatory factor and many of its functions require that it forms a tetrameric structure. Although the tetramerization domain of mammalian p53 proteins (p53TD) share significant sequence similarities, it was recently shown that the tree shrew p53TD is considerably more thermostable than the human p53TD. To determine whether other mammalian species display differences in this domain, we used biophysical, functional, and structural studies to compare the properties of the p53TDs from six mammalian model organisms (human, tree shrew, guinea pig, Chinese hamster, sheep, and opossum). The results indicate that the p53TD from the opossum and tree shrew are significantly more stable than the human p53TD, and there is a correlation between the thermostability of the p53TDs and their ability to activate transcription. Structural analysis of the tree shrew and opossum p53TDs indicated that amino acid substitutions within two distinct regions of their p53TDs can dramatically alter hydrophobic packing of the tetramer, and in particular substitutions at positions corresponding to F341 and Q354 of the human p53TD. Together, the results suggest that subtle changes in the sequence of the p53TD can dramatically alter the stability, and potentially lead to important changes in the functional activity, of the p53 protein.


The protective effect of glucose on soluble rat lens hexokinase in the presence of oxidative stress.
An in vitro animal model was used to characterize the protective effect of glucose on lenses subjected to oxidative stress. Paired rat lenses were incubated in TC-199 medium for six hours in the presence of an oxidant (0.06 mM H2O2, superoxide produced from 5 mM purine, or hydroxyl radical) and 2 mM glucose (control) or no glucose (experimental). Soluble hexokinase (HK) specific activity and lactate production were measured. 0.06 mM H2O2 inactivates 48% of the hexokinase in the absence of glucose; with glucose present hexokinase activity is reduced only 26%. Control experiments without oxidants show a statistically insignificant difference between hexokinase activities in the 0 and 2 mM groups, suggesting that the changes observed are not simply due to the presence or absence of glucose. Hexosemonophosphate shunt activity increases nearly 2.5-fold in the presence of 0.06 mM H2O2 and 2.0, 4.0 or 5.5 mM glucose. This suggests that the loss of hexokinase (a -SH enzyme) in the presence of H2O2 and 0 mM glucose is due to NADPH production inadequate to offset the oxidative stress on enzyme -SH groups. FPLC analysis suggests that type II HK is more susceptible to oxidative inactivation than type I, and further studies have shown that this inactivation is localized to the capsule/epithelium. Lactate levels were measured and controls (without oxidants) were run, to obtain a baseline value for fresh lenses and assess the contribution of endogenous glucose to lactate production. H2O2 levels in superoxide and hydroxyl radical media were measured, and the protective effects of mannitol and catalase were also determined.


Submicroscopic fibres in industrial atmospheres.
Evidence obtained from a large number of samples of airborne dust from a number of different asbestos-using industries suggests that it would be possible to use gravimetric sampling to estimate the respirable fibre concentration of the atmosphere around specific operations. The precision of this method of estimating airborne fibre concentration is shown to be approximately the same as the variation between different counters using existing counting techniques. Tables are included showing the fibre content of industrial dusts in millions of fibres/mg of dust and the factors (with 95% confidence limits) by which light microscope counts should be multiplied to give the true counts of fibres longer than 5 micrometers.


Comparative evaluation of turmeric gel with 2% chlorhexidine gluconate gel for treatment of plaque induced gingivitis: A randomized controlled clinical trial.
Ayurveda is regarded as most ancient traditional system of medicine originated in India having its root back in the Vedas. Medicinal herbs have been long employed to improve the oral health by means of frequently used therapeutic procedures Kavala (gargling) and Gandusha (holding of medicated liquids in the mouth). Gingivitis is most common ailment that results in bleeding gums and halitosis. To evaluate the efficacy of turmeric gel as an anti-plaque and anti-gingivitis agent compared to chlorhexidine gel. Sixty patients with plaque-induced gingivitis were divided into two groups, Group A was given turmeric gel and Group B was given chlorhexidine gel for 21 days in vaccupress trays. Plaque and gingival index were taken at baseline, 14 days and 21 days. Subjective and objective criteria were evaluated at 14 and 21 days. On comparison of Group A and Group B, statistically insignificant difference was observed at 14 and 21 days. Reduction in plaque index at 0 and 21 days was 60.81% and 60.21% for turmeric and chlorhexidine group, respectively. Reduction in the gingival index at 0 and 21 days was 71.79% and 71.20% for turmeric and chlorhexidine group, respectively. Both groups reported a comparable reduction in plaque and gingival index. Turmeric gel reported better acceptance due to pleasant odor and no staining of teeth in comparison to chlorhexidine gel that reported a bitter taste and staining of teeth.


Review. EGFR mutations in non-small cell lung cancer--clinical implications.
The epidermal growth factor receptor (EGFR) family members seem to play a critical role in lung tumourigenesis and are overexpressed in 40-80% of non-small cell lung carcinoma (NSCLC) tumours. EGFR activation results in a series of downstream signaling events that mediate cancer cell growth, proliferation, motility, adhesion, invasion, apoptosis inhibition and metastasis as well as resistance to chemotherapy. Therefore, EGFR inhibitors seem to be an effective therapy for some patients with previously treated NSCLC. A thorough investigation of EGFR, its major signaling pathways, its identification and biology in NSCLC and the responsiveness to gefitinib, erlotinib and cetuximab in connection to EGFR mutations as well as the possible mechanisms of resistance to tyrosine kinase inhibitors is the scope of this review.


Modification of gelation kinetics in bioactive peptide amphiphiles.
Peptide amphiphiles (PAs) previously designed in our laboratory are known to self-assemble into nanofibers that exhibit bioactivity both in vitro and in vivo. Self-assembly can be triggered by charge neutralization or salt-mediated screening of charged residues in their peptide sequences, and the resulting nanofibers can form macroscopic gels at concentrations as low as 0.5% by weight. Controlling the kinetics of gelation while retaining the bioactivity of nanofibers could be critical in tailoring these materials for specific clinical applications. We report here on a series of PAs with different rates of gelation resulting from changes in their peptide sequence without changing the bioactive segment. The pre-existence of hydrogen-bonded aggregates in the solution state of more hydrophobic PAs appears to accelerate gelation kinetics. Mutation of the peptide sequence to include more hydrophilic and bulky amino acids suppresses formation of these nuclei and effectively slows down gelation through self-assembly of the nanofiber network. The ability to modify gelation kinetics in self-assembling systems without disrupting bioactivity could be important for injectable therapies in regenerative medicine.


Novel Risk Assessment Tool for Immunoglobulin Resistance in Kawasaki Disease: Application Using a Random Forest Classifier.
Resistance to intravenous immunoglobulin (IVIG) therapy is a risk factor for coronary lesions in patients with Kawasaki disease (KD). Risk-adjusted initial therapy may improve coronary outcome in KD, but identification of high risk patients remains a challenge. This study aimed to develop a new risk assessment tool for IVIG resistance using advanced statistical techniques. Data were retrospectively collected from KD patients receiving IVIG therapy, including demographic characteristics, signs and symptoms of KD and laboratory results. A random forest (RF) classifier, a tree-based machine learning technique, was applied to these data. The correlation between each variable and risk of IVIG resistance was estimated. Data were obtained from 767 patients with KD, including 170 (22.1%) who were refractory to initial IVIG therapy. The predictive tool based on the RF algorithm had an area under the receiver operating characteristic curve of 0.916, a sensitivity of 79.7% and a specificity of 87.3%. Its misclassification rate in the general patient population was estimated to be 15.5%. RF also identified markers related to IVIG resistance such as abnormal liver markers and percentage neutrophils, displaying relationships between these markers and predicted risk. The RF classifier reliably identified KD patients at high risk for IVIG resistance, presenting clinical markers relevant to treatment failure. Evaluation in other patient populations is required to determine whether this risk assessment tool relying on RF has clinical value.


Regulation of lipolysis during pregnancy and lactation in sheep. Response to noradrenaline and adenosine.
The effects of pregnancy and lactation on lipolysis in sheep adipose tissue in vitro were investigated. Neither pregnancy nor lactation altered the basal rate of lipolysis. The rate of noradrenaline-stimulated lipolysis was directly proportional to adipocyte mean cell volume. Lactation, but not pregnancy, increased the response to noradrenaline, but had no effect on the ED50 of noradrenaline. The adenosine analogue N6-phenylisopropyladenosine decreased the rate of lipolysis in the presence of noradrenaline; the effect was greater with adipose tissue from lactating than from control, unmated, sheep. Results are discussed in relation to the need of sheep to mobilize lipid during early lactation to support milk production.


Dynamic in vitro measurement of patellar movement after total knee arthroplasty: an in vitro study.
Changing the kinematic behaviour of patellar movement could be one of the reasons for anterior knee pain after implantation of a total knee arthroplasty (TKA). The aim of the current study was to measure the potential influence on patellar kinematics of patellar resurfacing during TKA. Patellar movement before and after TKA with and without patellar resurfacing was measured under dynamic conditions in an in vitro cadaver simulation. Physiologic Musculus quadriceps forces were applied to five physiologic human knee specimens undergoing simulated isokinetic extension motions, patellar movement was measured using an ultrasonic measurement system. Thereafter, the Interax I.S.A.-prosthesis system was implanted without and with resurfacing the patella, and patellar movement was again measured. The physiologic patella center moved on a semilunar path up to 6.4 mm (SD 6.4 mm) medially during extension. After TKA, the unresurfaced patella showed significantly less medial translation (p = 0.04) than the resurfaced patella. Subsequent resurfacing of the patella then resulted in a return to mediolateral positioning of the patella similar to the physiological case, whereas the resurfaced patella tilted up to twice as much as physiologic. The results of this study suggest that resurfacing of the patella during TKA can result in a restoration of the physiologic mediolateral shift of the patellofemoral joint while angulation of the patella remains unphysiologic.


Advances in biomaterials for the treatment of retinoblastoma.
Retinoblastoma is the most common primary intraocular malignancy in children. Although traditional chemotherapy has shown some success in retinoblastoma management, there are several shortcomings to this approach, including inadequate pharmacokinetic parameters, multidrug resistance, low therapeutic efficiency, nonspecific targeting, and the need for adjuvant therapy, among others. The revolutionary developments in biomaterials for drug delivery have enabled breakthroughs in cancer management. Today, biomaterials are playing a crucial role in developing more efficacious retinoblastoma treatments. The key goal in the evolution of drug delivery biomaterials for retinoblastoma therapy is to resolve delivery-associated obstacles and lower nonlocal exposure while ameliorating certain adverse effects. In this review, we will first delve into the historical perspective of retinoblastoma with a focus on the classical treatments currently used in clinics to enhance patients' quality of life and survival rate. As we move along, we will discuss biomaterials for drug delivery applications. Various aspects of biomaterials for drug delivery will be dissected, including their features and recent advances. In accordance with the current advances in biomaterials, we will deliver a synopsis on the novel chemotherapeutic drug delivery strategies and evaluate these approaches to gain new insights into retinoblastoma treatment.


Pretreatment of astrocytes with interferon-alpha/beta prevents neuronal mitochondrial respiratory chain damage.
Excessive nitric oxide/peroxynitrite generation has been implicated in the pathogenesis of multiple sclerosis, and the demonstration of increased astrocytic nitric oxide synthase activity in the postmortem brain of multiple sclerosis patients supports this hypothesis. Interferon-beta is used for the treatment of multiple sclerosis, but currently little is known regarding its mode of action. Exposure of astrocytes in culture to interferon-gamma plus lipopolysaccharide results in stimulation of nitric oxide release. Using a coculture system, we have been able to use astrocytes as a source of nitric oxide/peroxynitrite in an attempt to "model" the effects of raised cytokine levels observed in multiple sclerosis and to monitor the effect on neurones. Our results indicate that stimulation of astrocytic nitric oxide synthase activity causes significant damage to the mitochondrial activities of complexes II/III and IV of neighbouring neurones. This damage was prevented by a nitric oxide synthase inhibitor, suggesting that the damage was nitric oxide-mediated. Furthermore, interferon-alpha/beta also prevented this damage. In view of these results, we suggest that a possible mechanism of action of interferon-beta in the treatment of multiple sclerosis is that it prevents astrocytic nitric oxide production, thereby limiting damage to neighbouring cells, such as neurones.


Investigating the Effects of the POPC-POPG Lipid Bilayer Composition on PAP248-286 Binding Using CG Molecular Dynamics Simulations.
PAP248-286 is a fusogenic peptide derived from prostatic acid phosphatase, commonly found in human semen, and is known to mediate HIV fusion with cell membranes. In this study, we performed 120 independent coarse-grained molecular dynamics simulations to investigate the spontaneous binding of PAP248-286 monomers, considering both charged and neutral histidine (His) residues, to membrane bilayers composed of different lipid compositions: 100% POPC, 70% POPC-30% POPG, and 50% POPC-50% POPG. Our simulations revealed that PAP248-286 displayed spontaneous binding to the membrane, with increased binding observed in the presence of anionic lipid POPG. Specifically, in systems containing 30% and 50% POPG lipids, monomer residues, particularly in the systems containing charged histidine (His) residues, exhibited prolonged binding with the membrane. Furthermore, our simulations indicated that PAP248-286 adopted a parallel orientation with the membrane, exposing its positively charged residues to the lipid bilayer. Interestingly, systems containing charged His residues showed a higher lipid occupancy around the peptide. These findings are consistent with previous experimental data, suggesting that PAP248-286 binding is enhanced in membranes with charged His residues, resembling the conditions found in the acidic vaginal pH environment. The results of our study provide further insights into the molecular mechanisms underlying the membrane binding of PAP248-286, contributing to our understanding of its potential role in HIV fusion and infection.


[Pattern of HIV/AIDS infection in Manaus, State of Amazonas, between 1986 and 2000].
The objective of this study was to describe HIV infection in Manaus, Amazonas, between 1986 and 2000. This was a descriptive study on confirmed cases of HIV/AIDS among adults, from the medical records of the State Reference Service. To delineate the spatial epidemiological profile and historical trends, the following periods were considered: 1986-1990, 1991-1995 and 1996-2000. The behavioral, social and clinical variables were analyzed by means of descriptive statistics. The spatial trends and patterns and the incidence rates were presented according to residential district using thematic maps. Among the 1,400 cases studied, the mortality rate decreased from 61.3% to 17.8% and the gender ratio (four men/one woman) decreased over the study period. The main exposure route was sexual: bisexual (31%) and heterosexual (19.3%). There was a high rate of late diagnosis, made during the symptomatic phase of AIDS (50.8%). This study showed that HIV/AIDS infection in Manaus has spread slowly and progressively from the central area of the city towards the south, north, east and west.


Fractionation of membrane proteins by temperature-induced phase separation in Triton X-114. Application to subcellular fractions of the adrenal medulla.
After solubilization with the detergent Triton X-114, membrane proteins may be separated into three groups: if the membrane is sufficiently lipid-rich, one family of hydrophobic constituents separates spontaneously at low temperature; warming at 30 degrees C leads to separation of a detergent-rich phase and an aqueous phase. Using the chromaffin-granule membrane as a model, we found that many intrinsic membrane glycoproteins are found in the latter phase, probably maintained in solution by adherent detergent. They precipitate, however, when this is removed by dialysis, leaving in solution those truly hydrophilic proteins that were originally adhering to the membranes. We have used this method with mitochondria, and with Golgi- and rough-endoplasmic-reticulum-enriched microsomal fractions: it has proved to be a rapid and convenient method for effecting a partial separation of proteins from a variety of different membranes.


Effects of vibration therapy for post-stroke spasticity: a systematic review and meta-analysis of randomized controlled trials.
The efficacy of vibration therapy (VT) in people with post-stroke spasticity (PSS) remains uncertain. This study aims to conduct a comprehensive meta-analysis to assess the effectiveness of VT in PSS. PubMed, Embase, Cochrane Library, Physiotherapy Evidence Database, and Web of Science were searched from inception to October 2022 for randomized controlled trials (RCTs) of VT in people with PSS. The primary outcome was spasticity, and secondary outcomes included pain, motor function, gait performance, and adverse events. A meta‑analysis was performed by pooling the standardized mean difference (SMD) with 95% confidence intervals (CI). A total of 12 studies met the inclusion criteria. Overall, VT had significant effects on reducing spasticity (SMD = - 0.77, 95% CI - 1.17 to - 0.36, P < 0.01) and pain (SMD = - 1.09, 95% CI - 1.74 to - 0.45, P < 0.01), and improving motor function (SMD = 0.42, 95% CI 0.21 to 0.64, P < 0.01) in people with PSS. However, VT had no significant effect on gait performance (SMD = - 0.23, 95% CI - 0.56-0.10). In addition, subgroup differences in short-term anti-spasticity effects between different vibration subtypes, vibration frequencies, vibration durations, frequency of sessions, control therapy, spasticity distribution, and population classification were not significant. We found that VT significantly alleviated spasticity and pain in people with PSS and improved motor function, but its effect on gait performance was unclear. However, further studies are needed to validate these findings.


Novel risk genes and mechanisms implicated by exome sequencing of 2572 individuals with pulmonary arterial hypertension.
Group 1 pulmonary arterial hypertension (PAH) is a rare disease with high mortality despite recent therapeutic advances. Pathogenic remodeling of pulmonary arterioles leads to increased pulmonary pressures, right ventricular hypertrophy, and heart failure. Mutations in bone morphogenetic protein receptor type 2 and other risk genes predispose to disease, but the vast majority of non-familial cases remain genetically undefined. To identify new risk genes, we performed exome sequencing in a large cohort from the National Biological Sample and Data Repository for PAH (PAH Biobank, n = 2572). We then carried out rare deleterious variant identification followed by case-control gene-based association analyses. To control for population structure, only unrelated European cases (n = 1832) and controls (n = 12,771) were used in association tests. Empirical p values were determined by permutation analyses, and the threshold for significance defined by Bonferroni's correction for multiple testing. Tissue kallikrein 1 (KLK1) and gamma glutamyl carboxylase (GGCX) were identified as new candidate risk genes for idiopathic PAH (IPAH) with genome-wide significance. We note that variant carriers had later mean age of onset and relatively moderate disease phenotypes compared to bone morphogenetic receptor type 2 variant carriers. We also confirmed the genome-wide association of recently reported growth differentiation factor (GDF2) with IPAH and further implicate T-box 4 (TBX4) with child-onset PAH. We report robust association of novel genes KLK1 and GGCX with IPAH, accounting for ~ 0.4% and 0.9% of PAH Biobank cases, respectively. Both genes play important roles in vascular hemodynamics and inflammation but have not been implicated in PAH previously. These data suggest new genes, pathogenic mechanisms, and therapeutic targets for this lethal vasculopathy.


Surface channel patterned and endothelialized poly(glycerol sebacate) based elastomers.
Prevascularization of tissue equivalents is critical for fulfilling the need for sufficient vascular organization for nutrient and gas transport. Hence, endothelial cell culture on biomaterials is of great importance for researchers. Numerous alternate strategies have been suggested in this sense, with cell-based methods being the most commonly employed. In this study, poly (glycerol sebacate) (PGS) elastomers with varying crosslinking ratios were synthesized and their surfaces were patterned with channels by using laser ablation technique. In order to determine an ideal material for cell culture studies, the elastomers were subsequently mechanically, chemically, and biologically characterized. Following that, human umbilical vein endothelial cells (HUVECs) were seeded into the channels established on the PGS membranes and cultured under various culture conditions to establish the optimal culture parameters. Lastly, the endothelial cell responses to the synthesized PGS elastomers were evaluated. Remarkable cell proliferation and impressive cellular organizations were noticed on the constructs created as part of the investigation. On the concrete output of this research, arrangements in various geometries can be created by laser ablation method and the effects of various molecules, drugs or agents on endothelial cells can be evaluated. The platforms produced can be employed as an intermediate biomaterial layer containing endothelial cells for vascularization of tissue-engineered structures, particularly in layer-by-layer tissue engineering approaches.


Relationship between established cardiovascular risk factors and specific coronary angiographic findings in a large cohort of Greek catheterized patients.
We evaluated the relationship between coronary artery stenosis status and established cardiovascular risk factors in a large population of 1228 patients who consecutively underwent coronary angiography. Smoking proved to be the most important predictive factor for angiographically significant coronary artery disease (CAD), followed by dyslipidemia, diabetes, family history, and hypertension in a descending order of significance. Obesity rates did not differ significantly between the CAD positive and negative groups, nor changed significantly as the number of affected vessels increased. Smoking, dyslipidemia, and diabetes were positively associated with atherosclerotic involvement of all 3 major coronary arteries, whereas hypertension related only to significant stenosis of left anterior descending and left circumflex artery. The only established risk factors that could reliably predict left main stem disease were diabetes and age. Furthermore, large-scale studies will delineate the implications of the existing interrelationship between clinical and angiographic features.


The effect of prenatal protein-calorie malnutrition on kidney development in the rat.
Our studies show that prenatal protein deprivation has a long-term (if not permanent) effect on kidney morphology in the young and effects on renal function that persist at least to the end of weaning. Since animals are still alive and growing, we might ask whether this has any real physiological significance. At this point, it is important to mention that 50% of the young born of protein-deprived dams in these studies did not survive more than 3 d. Those animals that were the subject of the study of postnatal kidneys were presumably less affected. We do not know the extent to which compromised renal function contributed to neonatal death in the others. These results can be extrapolated to other species only with great caution, since the rat kidney is relatively immature at birth. It is probable that increased postnatal feeding has a more beneficial effect on these rapidly developing tissues than it would have in species in which the kidneys are more mature at birth. Yet, kidney function did not reach the control level in spite of improved postnatal nutrition. Compromised renal function in the more mature kidneys of other species may be less amenable to postnatal recovery and--at the very least--leave the kidneys less able to respond to postnatal stress factors.


Profiles of bacterial communities and environmental factors associated with proliferation of malaria vector mosquitoes within the Kenyan Coast.
Since Anopheles mosquitoes which transmit and maintain the malaria parasite breed in the outdoor environment, there is an urgent need to manage these mosquito breeding sites. In order to elaborate more on the ecological landscape of mosquito breeding sites, the bacterial community structure and their interactions with physicochemical factors in mosquito larval habitats was characterised in Kwale County (Kenya), where malaria is endemic. The physical characteristics and water physicochemical parameters of the habitats were determined and recorded. Water samples were also collected from the identified sites for total metagenomic DNA extraction in order to characterise the bacterial communities within the breeding sites. Sites where mosquito larvae were found were described as positive and those without mosquito larvae as negative. Electrical conductivity, total dissolved solids, salinity and ammonia were lower in the rainy season than in the dry season, which also coincided with a high proportion of positive sites. Pseudomonadota was the most common phyla recovered in all samples followed by Bacteroidota and then Actinomycetota. The presence or absence of mosquito larvae in a potential proliferation site was not related to the bacterial community structure in the sampled sites, but was positively correlated with bacterial richness and evenness. Generally, the presence of Anopheles mosquito larvae was found to be positively correlated with rainy season, bacterial richness and evenness, and negatively correlated with electrical conductivity, total dissolved solids, salinity and ammonia. The findings of this study have implications for predicting the potential of environmental water samples to become mosquito proliferation sites.


CYP2C9 polymorphism in patients with epilepsy: genotypic frequency analyzes and phenytoin adverse reactions correlation.
CYP2C9 is a major enzyme in human drug metabolism and the polymorphism observed in the corresponding gene may affect therapeutic outcome during treatment. The distribution of variant CYP2C9 alleles and prevalence of phenytoin adverse reactions were hereby investigated in a population of patients diagnosed with epilepsy. Allele-specific PCR analysis was carried out in order to determine frequencies of the two most common variant alleles, CYP2C9*2 and CYP2C9*3 in genomic DNA isolated from 100 epileptic patients. We also analyzed the frequency of phenytoin adverse reactions among those different genotypes groups. The data was presented as mean±standard deviation. The mean age at enrollment was 39.6±10.3 years (range, 17-72 years) and duration of epilepsy was 26.5±11.9 years (range 3-48 years). The mean age at epilepsy onset was 13.1±12.4 years (range, 1 month-62 years). Frequencies of CYP2C9*1 (84%), CYP2C9*2 (9%) and CYP2C9*3 (7%) were similar to other published reports. Phenytoin adverse reactions were usually mild and occurred in 15% patients, without correlation with the CYP2C9 polymorphism (p=0.34). Our findings indicate an overall similar distribution of the CYP2C9 alleles in a population of patients diagnosed with epilepsy in the South of Brazil, compared to other samples. This sample of phenytoin users showed no drug related adverse reactions and CYP2C9 allele type correlation. The role of CYP2C9 polymorphism influence on phenytoin adverse reaction remains to be determined since some literature evidence and our data found negative results.


Disparity in physician perception of patients' adherence to medications by obesity status.
Physician perception of medication adherence may alter prescribing patterns. Perception of patients has been linked to readily observable factors, such as race and age. Obesity shares a similar stigma to these factors in society. We hypothesized that physicians would perceive patients with a higher BMI as nonadherent to medication. Data were collected from the baseline visit of a randomized clinical trial of patient-physician communication (240 patients and 40 physicians). Physician perception of patient medication adherence was measured on a Likert scale and dichotomized as fully adherent or not fully adherent. BMI was the predictor of interest. We performed Poisson regression analyses with robust variance estimates, adjusting for clustering of patients within physicians, to examine the association between BMI and physician perception of medication adherence. The mean (s.d.) BMI was 32.6 (7.7) kg/m(2). Forty-five percent of patients were perceived as nonadherent to medications by their physicians. Higher BMI was significantly and negatively associated with being perceived as adherent to medication (prevalence ratio (PrR) 0.76, 95% confidence interval (CI): 0.64-0.90; P = 0.002; per 10 kg/m(2) increase in BMI). BMI remained significantly and negatively associated with physician perception of medication adherence after adjustment for patient and physician characteristics (PrR 0.80, 95% CI: 0.66-0.96; P = 0.020). In this study, patients with higher BMI were less likely to be perceived as adherent to medications by their providers. Physician perception of medication adherence has been shown to affect prescribing patterns in other studies. More work is needed to understand how this perception may affect the care of patients with obesity.


Tumor necrosis factor receptor-2 signaling pathways promote survival of cancer stem-like CD133+ cells in clear cell renal carcinoma.
Clear cell renal cell carcinoma (ccRCC) contains cancer stem-like cells (CSCs) that express CD133 (ccRCC-CD133+). CSCs are rarely in cell cycle and, as nonproliferating cells, resist most chemotherapeutic agents. Previously, we reported that tumor necrosis factor receptor-2 (TNFR2) signaling promotes the cell cycle entry of ccRCC-CD133+CSCs, rendering them susceptible to cell-cycle-dependent chemotherapeutics. Here, we describe a TNFR2-activated signaling pathway in ccRCC-CD133+CSCs that is required for cell survival. Wild-type (wt)TNF or R2TNF but not R1TNF (TNF muteins that selectively bind to TNFR2 and TNFR1) induces phosphorylation of signal transducer and activator of transcription 3 (STAT3) on serine727 but not tyrosine705, resulting in pSTAT3Ser727 translocation to and colocalization with TNFR2 in mitochondria. R2TNF signaling activates a kinase cascade involving the phosphorylation of VEGFR2, PI-3K, Akt, and mTORC. Inhibition of any of the kinases or siRNA knockdown of TNFR2 or STAT3 promotes cell death associated with mitochondrial morphological changes, cytochrome c release, generation of reactive oxygen species, and TUNEL+cells expressing phosphorylated mixed lineage kinase-like (MLKL). Pretreatment with necrostatin-1 is more protective than z-VAD.fmk, suggesting that most death is necroptotic and TNFR2 signaling promotes cell survival by preventing mitochondrial-mediated necroptosis. These data suggest that a TNFR2 selective agonist may offer a potential therapeutic strategy for ccRCC.


A ligand-mediated hydrogen bond network required for the activation of the mineralocorticoid receptor.
Ligand binding is the first step in hormone regulation of mineralocorticoid receptor (MR) activity. Here, we report multiple crystal structures of MR (NR3C2) bound to both agonist and antagonists. These structures combined with mutagenesis studies reveal that maximal receptor activation involves an intricate ligand-mediated hydrogen bond network with Asn770 which serves dual roles: stabilization of the loop preceding the C-terminal activation function-2 helix and direct contact with the hormone ligand. In addition, most activating ligands hydrogen bond to Thr945 on helix 10. Structural characterization of the naturally occurring S810L mutant explains how stabilization of a helix 3/helix 5 interaction can circumvent the requirement for this hydrogen bond network. Taken together, these results explain the potency of MR activation by aldosterone, the weak activation induced by progesterone and the antihypertensive agent spironolactone, and the binding selectivity of cortisol over cortisone.