Optimizing the Design and Analysis of Clinical Trials for Antibacterials Against Multidrug-resistant Organisms: A White Paper From COMBACTE's STAT-Net.
Innovations are urgently required for clinical development of antibacterials against multidrug-resistant organisms. Therefore, a European, public-private working group (STAT-Net; part of Combatting Bacterial Resistance in Europe [COMBACTE]), has reviewed and tested several innovative trials designs and analytical methods for randomized clinical trials, which has resulted in 8 recommendations. The first 3 focus on pharmacokinetic and pharmacodynamic modeling, emphasizing the pertinence of population-based pharmacokinetic models, regulatory procedures for the reassessment of old antibiotics, and rigorous quality improvement. Recommendations 4 and 5 address the need for more sensitive primary end points through the use of rank-based or time-dependent composite end points. Recommendation 6 relates to the applicability of hierarchical nested-trial designs, and the last 2 recommendations propose the incorporation of historical or concomitant trial data through Bayesian methods and/or platform trials. Although not all of these recommendations are directly applicable, they provide a solid, evidence-based approach to develop new, and established, antibacterials and address this public health challenge.


The Persian Version of the Quick Mild Cognitive Impairment Screen (Qmci-Pr): Psychometric Properties among Middle-Aged and Older Iranian Adults.
Brief cognitive screening instruments are used to identify patients presenting with cognitive symptoms that warrant further assessment. This study aimed to evaluate the reliability and validity of the Persian version of the Quick Mild Cognitive Impairment (Qmci-Pr) among middle-aged and older Iranian adults. Consecutive patients aged ≥55 years and caregivers attending with them as normal controls (NCs) were recruited from geriatric outpatient clinics and a hospital in Tehran, Iran. All patients completed the Qmci-Pr before completing an independent detailed neuropsychological assessment and staging using the Clinical Dementia Rating (CDR) Scale. NCs underwent the same assessment. In all, 92 participants with a median age of 70 years (±13) were available. Of these, 20 participants were NCs, 24 had subjective memory complaints (SMC), 24 had mild cognitive impairment (MCI), and 24 had Alzheimer's disease (AD). The Qmci-Pr had good accuracy in differentiating SMC and NC from MCI (area under the curve (AUC): 0.80 (0.69-0.91)) and in identifying cognitive impairment (MCI and mild AD) (AUC: 0.87 (0.80-0.95)) with a sensitivity of 88% and specificity of 80%, at an optimal cut-off of <53/100. The Qmci-Pr is an accurate short cognitive screening impairment for separating NC and patients with SMC from MCI and identifying cognitive impairment. Further research with larger samples and comparison with other widely used instruments such as the Montreal Cognitive Assessment is needed. Given its established brevity, the Qmci-Pr is a useful screen for Iranian adults across the spectrum of cognitive decline.


[A case of elevated transaminases caused by congestive heart failure simulating chronic hepatitis].
We report the case of a young man first seen by is in 1989 at the age of 20 years. The diagnoses of hypertrophic cardiomyopathy, Wolf-parkinson-White syndrome, congestive heart failure and pulmonary hypertension were made. One month later the patient had jaundice and hepatomegaly and a diagnosis of acute viral hepatitis A was established by laboratory findings. The ALT and AST levels were persistently elevated, seven times the normal mean, during six years. Two liver biopsies in 1991 and 1993 showed liver injury secondary to congestive heart failure (CHF) as the only abnormality. This case illustrates the importance of liver injury secondary to CHF as a cause of a marked and persistent increase of ALT and AST that resembles that of other liver diseases.


Early experiences with a porcine hepatocyte-based bioartificial liver in acute hepatic failure patients.
Orthotopic liver transplantation (OLT) is the only effective therapeutic modality in severe acute hepatic failure (AHF). The scarcity of organs for transplantation leads to an urgent necessity for temporary liver support treatments in AHF patients. A hepatocyte-based bioartificial liver (BAL) is under investigation with the main purpose to serve as bridging treatment until a liver becomes available for OLT, or to promote spontaneous liver regeneration. We developed a novel radial-flow bioreactor (RFB) for three-dimensional, high-density hepatocyte culture and an integrated pumping apparatus in which, after plasmapheresis, the patient's plasma is recirculated through the hepatocyte-filled RFB. Two hundred thirty grams of freshly isolated porcine hepatocytes were loaded into the RFB for clinical liver support treatment. The BAL system was used 8 times in supporting 7 AHF patients in grade III-IV coma, all waiting for an urgent OLT Three patients with no history of previous liver diseases were affected by fulminant hepatic failure (FHF) due to hepatitis B virus, 3 by primary non-function (PNF) of the transplanted liver, and one by AHF due to previous abdominal trauma and liver surgery. Six out of 7 patients underwent OLT following BAL treatment(s), which lasted 6-24 hours. All patients tolerated the procedures well, as shown by an improvement in the level of encephalopathy, a decrease in serum ammonia, transaminases and an amelioration of the prothrombin time, with full neurological recovery after OLT Our initial clinical experience confirms the safety of this BAL configuration and suggests its clinical efficacy as a temporary liver support system in AHF patients.


[Efficiency of preventive use of bemethyl during long-term voyages].
A positive effect of bemityl in the 24-hour dose of 0.25-0.5 g on the cellular and humoral factors of nonspecific defence, blood neutrophils intracellular exchange, barrier properties of the skin, working ability of operators and on morbidity has been established. An important property of the drug is long duration of preservation of the pharmacological effect, which prevents the development of disadaptation states following the cessation of its use. The data obtained gives the basis to recommend the actoprotective drug bemityl to increase nonspecific resistance during long-term voyages.


ChIP-Array: combinatory analysis of ChIP-seq/chip and microarray gene expression data to discover direct/indirect targets of a transcription factor.
Chromatin immunoprecipitation (ChIP) coupled with high-throughput techniques (ChIP-X), such as next generation sequencing (ChIP-Seq) and microarray (ChIP-chip), has been successfully used to map active transcription factor binding sites (TFBS) of a transcription factor (TF). The targeted genes can be activated or suppressed by the TF, or are unresponsive to the TF. Microarray technology has been used to measure the actual expression changes of thousands of genes under the perturbation of a TF, but is unable to determine if the affected genes are direct or indirect targets of the TF. Furthermore, both ChIP-X and microarray methods produce a large number of false positives. Combining microarray expression profiling and ChIP-X data allows more effective TFBS analysis for studying the function of a TF. However, current web servers only provide tools to analyze either ChIP-X or expression data, but not both. Here, we present ChIP-Array, a web server that integrates ChIP-X and expression data from human, mouse, yeast, fruit fly and Arabidopsis. This server will assist biologists to detect direct and indirect target genes regulated by a TF of interest and to aid in the functional characterization of the TF. ChIP-Array is available at http://jjwanglab.hku.hk/ChIP-Array, with free access to academic users.


Attitudes and opinions of pregnant women who are not offered cystic fibrosis carrier screening.
Cystic fibrosis (CF) is the most common severe, autosomal recessive disease among Caucasians. A population-based CF carrier screening programme was implemented in Victoria, Australia, in 2006. Carrier screening for CF is currently only offered in the private health system. The aim of this study was to determine the attitudes and opinions of pregnant women in the public health system, towards screening for CF. Pregnant women were recruited in the antenatal clinics of two public hospitals, and invited to participate in the study. Results of this study were compared with previous studies where screening for CF carrier status was offered. Of the participants (n=158), the majority were aged 25-34 years old (66.1%) and were Caucasian (45.8%). Compared with those who were offered screening (reported in previous studies) participants in the current study were younger, had a lower level of education and a lower income. Knowledge was significantly lower in those who were not offered screening compared with those who were offered screening. The majority of participants believe CF carrier screening should be offered in the public health system (80.5%) and almost half would have liked to receive an offer of screening during their current pregnancy (49.7%). In order for the programme to be equitable, screening for CF carrier status needs to be offered in both the public and private health system and ideally should be at no cost to the user.


Transition from the polikilotherm to the homeotherm: possible role of sodium transport and thyroid hormone.
The evolutionary transition from poikilothermy to homeothermy required the recruitment of complex mechanisms that provided both higher rates of heat production and regulation of heat loss in the presence of wide variations in ambient temperature. Two pathways that have been considered to be contributors to the transition to homeothermy are thyroid-regulated thermogenesis and nonshivering thermogenesis in the adaptation to cold. These pathways may yield higher rates of heat production in homeotherms by two processes that need not be mutually exclusive: a) hydrolysis of ATP and consequent generation of the Pi acceptor--ADP, or b) decreased coupling of mitochondrial oxidative phosphorylation. A significant fraction of both thyroid and catecholamine thermogenesis has been ascribed to enhanced energy expenditure in active transmembrane Na+ transport (i.e., the Na+ pump). By extension these findings implicate the Na+ pump as a heat source in the evolution of the homeotherms. The thermogenic response to thyroid hormone is both rapid and profound in homeotherms (mammals), and more slowly evident and probably lesser in magnitude in poikilotherms (amphibia and reptiles). One crucial pathway in the evolution to homeothermy may be nonshivering thermogenesis in response to cold. In mice, most of the elevated rate of oxygen consumption of liver and skeletal muscle elicited by cold exposure is ouabain-sensitive. Thus, the Na+ pump appears to be an important heat source in the transition to homeothermy. The underlying biochemical mechanisms that mediate the contribution of the Na+ pump to heat production, including responsiveness to thyroid hormone and catecholamines, however, may not be unique to the homeotherms.


Nuclear import of insulin-like growth factor-binding protein-3 and -5 is mediated by the importin beta subunit.
Although insulin-like growth factor-binding protein (IGFBP)-3 and IGFBP-5 are known to modulate cell growth by reversibly sequestering extracellular insulin-like growth factors, several reports have suggested that IGFBP-3, and possibly also IGFBP-5, have important insulin-like growth factor-independent effects on cell growth. These effects may be related to the putative nuclear actions of IGFBP-3 and IGFBP-5, which we have recently shown are transported to the nuclei of T47D breast cancer cells. We now describe the mechanism for nuclear import of IGFBP-3 and IGFBP-5. In digitonin-permeabilized cells, where the nuclear envelope remained intact, nuclear translocation of wild-type IGFBP-3 appears to occur by a nuclear localization sequence (NLS)-dependent pathway mediated principally by the importin beta nuclear transport factor and requiring both ATP and GTP hydrolysis. Under identical conditions, an NLS mutant form of IGFBP-3, IGFBP-3[(228)KGRKR --> MDGEA], was unable to translocate to the nucleus. In cells where both the plasma membrane and nuclear envelope were permeabilized, wild-type IGFBP-3, but not the mutant form, accumulated in the nucleus, implying that the NLS was also involved in mediating binding to nuclear components. By fusing wild-type and mutant forms of NLS sequences (IGFBP-3 [215-232] and IGFBP-5 [201-218]) to the green fluorescent protein, we identified the critical residues of the NLS necessary and sufficient for nuclear accumulation. Using a Western ligand binding assay, wild-type IGFBP-3 and IGFBP-5, but not an NLS mutant form of IGFBP-3, were shown to be recognized by importin beta and the alpha/beta heterodimer but only poorly by importin alpha. Together these results suggest that the NLSs within the C-terminal domain of IGFBP-3 and IGFBP-5 are required for importin-beta-dependent nuclear uptake and probably also accumulation through mediating binding to nuclear components.


[On the epidemiology of dermatophytoses in Granada (Andalousia, Spain).].
One hundred and fourteen dermatophytes were isolated during the period from January 1995 to May 1997 in our outpatient's center of Dermatology, at the Universitary Hospital of Granada. Trichophyton rubrum (35.96%) was the commonest species, followed by Trichophyton mentagrophytes (21.19%) and Microsporum canis (21.19%). On the clinical ground, tinea unguium (24.56%) was predominant, with tinea corporis (23.68%) and also tinea capitis (2192 %). Our results are compared with recent data from other Spanish regions, specially Andalousia.


Mechanistic insights into higher alcohol synthesis from syngas on Rh/Cu single-atom alloy catalysts.
Low cost Cu-based catalysts are attractive options in catalyzing higher alcohol synthesis (HAS) from syngas. Introducing isolated Rh single atoms into the surfaces of these Cu catalysts has the potential to dramatically improve the performance of these Cu-based catalysts. In this work, extensive density functional theory (DFT) calculations were performed with periodic slab models to systematically investigate the possibility of using Rh/Cu single-atom alloys (SAAs) as HAS catalysts. The mechanism of ethanol synthesis from syngas on the representative Rh/Cu(111) and Rh/Cu(100) surfaces was elucidated. All possible formation pathways of the C1 and C2 fragments leading to the ethanol main product, as well as the methane and methanol by-products were considered. Our calculations show that for ethanol formation, the C-C bond coupling is easier over the Rh/Cu SAA catalysts than pure Cu catalysts, suggesting that Rh/Cu SAA catalysts are more favorable for the formation of higher alcohols.


Association between obesity and medical care expenditure among Taiwanese adults.
The aim of this study is to evaluate the relationships between obesity and medical care expenditure among Taiwanese adults and to assess the influence of sex, age and socioeconomic status. Our study sample consisted of 12,250 adults aged 18 years or older from the 2001 National Health Interview Survey (NHIS), who had consented to the linking of their survey responses with their NHI claims records. Obesity was defined by Body Mass Index based on the WHO-Asia Pacific categories. Adjusted expenditure for obese class II and class I men were, respectively, 44.6% (95%CI: 27.1%-68.7%) and 39.5% (95%CI: 39.4%-41.2%) greater than normal weight men. For obese class II and class I women, the adjusted expenditure were, respectively, 93.3% (95%CI: 69.9%-114.6%) and 56.1% (95%CI: 50.4%-61.4%) greater than normal weight women. After adjusting for other factors, higher medical care expenditure was associated with a higher BMI for each age group. The relative magnitude of the association became more apparent as age increased. Annual medical care expenditure increased as the BMI increased among women, which was particularly apparent among low socioeconomic status women. On the other hand, the relationship between BMI and medical care expenditure in men varied by household income. In conclusion, there is a strong positive relationship between higher BMI and increased medical care expenditure and this varies according to sex, age and socioeconomic status. Our findings suggest that projections of future health care costs attributable to obesity will need to take into consideration the demographic make-up of the obese population.


A survey on the BWM Convention: analysing the stakeholders' perceptions with emphasis on the acquisition process and operational expenditure.
The International Convention for the Control and Management of Ships' Ballast Water and Sediments (IMO 2018 Edition) was adopted in 2004 and entered into force on 8 September 2017, aiming to introduce global regulations to control the transfer of potentially invasive species Resolution (IMO MEPC.207(62) 2011). These efforts are translated into a wide range of solutions for retrofitting and new building services, which is evidenced through the substantial amount of data disclosed and analysed by different parties showing that optimization processes will have an important role for the existent management systems. Analysing a ballast water management installation project for oil tankers, categorizing the stakeholders involved and assessing properly the outcomes from an engineering perspective are important matters. The experience considered at the BWM Convention and its amendments set an important call to the industry in terms of milestones. Avoiding any delay in terms of operation is not the only answer to this call but also setting up an optimized and sustainable operation after the implementation process. The project management, on the subfield of stakeholders' management (Bourne 2016), brings a myriad of individuals connected to ballast water management matters with different levels of knowledge, experience and commitment from an engineering perspective. This article aims to measure these factors and the stakeholders' experience based on qualitative research into the ballast water management convention, with emphasis on the installation process on board. The data herewith analysed was obtained from a series of interviews conducted from January 2019 to August 2019.


Hypoxia by Altitude and Welfare of Captive Beaded Lizards (Heloderma Horridum) in Mexico: Hematological Approaches.
Heloderma horridum is one of the few known venomous lizards in the world. Their populations are in decline due to habitat destruction and capture for the pet trade. In México, many zoos have decided to take care of this species, most of them at altitudes greater than the natural altitudinal distribution. However, we know little about the capacity of the reptiles to face high-altitude environments. The objective of this study was to compare hematological traits of H. horridum in captivity in high and low altitude environments. Our findings show that H. horridum does not respond to hypoxic environments, at least in blood traits, and that the organisms appear to be in homeostasis. Although we cannot know if individual H. horridum housed in high-altitude environments are completely comfortable, it appears hypoxia can be avoid without modifications of blood parameters. We suggest that future work should address changes in metabolic rates and in behavioral aspects to understand how to maintain the health and comfort of the reptiles native to low altitude when they are housed in high-altitude environments.


Low estradiol levels in women of reproductive age having low sleep variation.
Higher exposure to light at night, for example, owing to night shift work or decrease in sleep duration, may suppress melatonin production, which in turn may increase the reproductive hormone levels. High levels of steroid hormones, especially estrogens, may be associated with an increase of the breast cancer risk. This study investigated whether variation in the sleep duration during one entire menstrual cycle corresponds to estradiol saliva concentrations in healthy, urban women of reproductive age. During 2000-2001, 95 regularly menstruating women aged 24-36 in Poland collected daily saliva samples for one entire menstrual cycle. Saliva samples were analyzed for concentration of 17-beta estradiol (E2) using radio immunoassay. Information on the number of hours of sleep per night (sleep duration) was collected daily by questionnaires for one entire menstrual cycle. Using covariance analysis, after adjustments for sleep duration, we documented a positive relationship between the sleep variation (sleep coefficient of variation) and E2 levels in women of reproductive age. Mean levels of E2 differed significantly in women from the lowest sleep coefficient of variation quartile (13.93 pmol/l) in comparison with other quartiles (22.35 pmol/l), (P<0.001). The low sleep variation group, that is, the women who sleep regularly, had mean E2 levels 60% lower than other groups. These results suggest that sleep variation significantly correlates with E2 levels, whereas sleep duration does not show a statistically significant relationship. This study suggests that sleep variation may influence endogenous estrogens, which is of importance for risk of breast cancer.


Monoamine oxidase-B activity in alcohol withdrawal of smokers: is there any relationship with aggressiveness?
There is a considerable inconsistency in terms of the association between alcoholism and alterations in monoamine oxidase (MAO) activity. The main objectives of this study were to investigate the changes in platelet MAO-B activity throughout the alcohol withdrawal period and whether or not MAO-B activity differed between patients with high- and low-aggression tendency. We assayed platelet MAO-B levels spectrophotometrically in 22 male inpatients with alcohol dependence in their first and fourth weeks of withdrawal and in 20 healthy controls. Patients were divided into two high- and low-aggression subgroups according to scores obtained in a Brown-Goodwin Assessment for Life History of Aggression. Our data revealed that the significantly lower platelet MAO-B activity observed during the first week of alcohol withdrawal in patients, compared to controls, did not continue in the fourth week, and that there was no relationship between aggressiveness and MAO activity. These results suggest that low platelet MAO activity may be a state marker of alcohol withdrawal period or a result of high alcohol consumption rather than a trait marker of alcoholism.


Association between physical activity and functional and cognitive status in nonagenarians: results from the Mugello study.
This study aimed at assessing daily physical activity and its relationship with functional and cognitive status in nonagenarians. Cross-sectional study. 167 nonagenarians (124 women and 43 men, mean age 92 years ± 3) who participated in the Mugello study. Participants underwent daily step count through the SenseWear armband, which was considered as an indicator of physical activity. Other main variables were: handgrip strength, gait speed, depression, cognitive status and quality of life. The median value of steps per day was 883 and 658 in women and men, respectively, with a participant, in the women group, showing values up to 10,000. After adjusting for potential confounders, physical activity remained a significant positive correlate of handgrip strength (r = 0.4), gait speed (r = 0.8), and cognitive status (r = 0.6 and 0.8, respectively for raw scores and for scores adjusted for age and education). On the contrary, physical activity remained a significant negative correlate of depression (r = 0.5). Our results provide quantitative information on daily physical activity and show a significant relationship between daily physical activity and functional and cognitive status in nonagenarians.


TgIF2K-B Is an eIF2α Kinase in Toxoplasma gondii That Responds to Oxidative Stress and Optimizes Pathogenicity.
Toxoplasma gondii is an obligate intracellular parasite that persists in its vertebrate hosts in the form of dormant tissue cysts, which facilitate transmission through predation. The parasite must strike a balance that allows it to disseminate throughout its host without killing it, which requires the ability to properly counter host cell defenses. For example, oxidative stress encountered by Toxoplasma is suggested to impair parasite replication and dissemination. However, the strategies by which Toxoplasma mitigates oxidative stress are not yet clear. Among eukaryotes, environmental stresses induce the integrated stress response via phosphorylation of a translation initiation factor, eukaryotic initiation factor 2 (eIF2). Here, we show that the Toxoplasma eIF2 kinase TgIF2K-B is activated in response to oxidative stress and affords protection. Knockout of the TgIF2K-B gene, Δtgif2k-b, disrupted parasite responses to oxidative stresses and enhanced replication, diminishing the ability of the parasite to differentiate into tissue cysts. In addition, parasites lacking TgIF2K-B exhibited resistance to activated macrophages and showed greater virulence in an in vivo model of infection. Our results establish that TgIF2K-B is essential for Toxoplasma responses to oxidative stress, which are important for the parasite's ability to establish persistent infection in its host.IMPORTANCEToxoplasma gondii is a single-celled parasite that infects nucleated cells of warm-blooded vertebrates, including one-third of the human population. The parasites are not cleared by the immune response and persist in the host by converting into a latent tissue cyst form. Development of tissue cysts can be triggered by cellular stresses, which activate a family of TgIF2 kinases to phosphorylate the eukaryotic translation initiation factor TgIF2α. Here, we establish that the TgIF2 kinase TgIF2K-B is activated by oxidative stress and is critical for maintaining oxidative balance in the parasite. Depletion of TgIF2K-B alters gene expression, leading to accelerated growth and a diminished ability to convert into tissue cysts. This study establishes that TgIF2K-B is essential for the parasite's oxidative stress response and its ability to persist in the host as a latent infection.


Human papillomavirus infection is not related with prostatitis-related symptoms: results from a case-control study.
To investigate the relationship between human papillomavirus (HPV) infection and prostatitis-related symptoms. All young heterosexual patients with prostatitis-related symptoms attending the same Center from January 2005 to December 2010 were eligible for this case-control study. Sexually active asymptomatic men were considered as the control group. All subjects underwent clinical examination, Meares-Stamey test and DNA-HPV test. Patients with prostatitis-related symptoms and asymptomatic men were compared in terms of HPV prevalence. Moreover, multivariable Cox proportional hazards regression analysis was performed to determine the association between HPV infection and prostatitis-related symptoms. Overall, 814 out of 2,938 patients (27.7%) and 292 out of 1,081 controls (27.0%) proved positive to HPV. The HPV genotype distribution was as follows: HR-HPV 478 (43.3%), PHR-HPV 77 (6.9%), LR-HPV 187 (16.9%) and PNG-HPV 364 (32.9%). The most common HPV genotypes were: 6, 11, 16, 26, 51, 53 and 81. No difference was found between the two groups in terms of HPV infection (OR 1.03; 95% CI 0.88-1.22; p = 0.66). We noted a statistically significant increase in HPV infection over the period 2005 to 2010 (p < 0.001) in both groups. Moreover, we found a statistically significant increase in HPV 16 frequency from 2005 to 2010 (p = 0.002). This study highlights that prostatitis-like symptoms are unrelated to HPV infection. Secondary, we highlight the high prevalence of asymptomatic HPV infection among young heterosexual men.


Dynamically monitoring tissue factor and tissue factor pathway inhibitor following secondary brain injury.
To study the altering rule of coagulation function at molecular level in patients with secondary brain injury (SBI). Tissue factor (TF) and tissue factor pathway inhibitor (TFPI) were studied in 32 patients 1, 2, 3 and 7 days after craniocerebral injury. Repeated cranial CT scans and platelet counts were made simultaneously. Same measurements were done in 30 normal adults except CT scan. No obvious difference was found in age, sex and platelet count between the injured and the normal groups. TFPI/TF decreased markedly in the first week after injury in patients with SBI, but only decreased on the 7th day in the patients without obvious SBI. For the patients who developed delayed intracranial hematoma (DIH) or hematoma enlargement, TF rose only 1 and 2 days after injury, but TFPI had a tendency to rise again after a fall on the 3rd day. For those patients who developed no DIH, TF rose all the time within the 1st week. Decrease of TFPI/TF for a long time, especially within 3 days after injury, may be one of the most important reasons for SBI. High expression of TF for a relative short time and increase of TFPI after a fall within 3 days may be one of the important reasons for DIH or hematoma enlargement.


Assessing the utility of a virtual environment for enhancing facial affect recognition in adolescents with autism.
Teenagers with autism spectrum disorder (ASD) and age-matched controls participated in a dynamic facial affect recognition task within a virtual reality (VR) environment. Participants identified the emotion of a facial expression displayed at varied levels of intensity by a computer generated avatar. The system assessed performance (i.e., accuracy, confidence ratings, response latency, and stimulus discrimination) as well as how participants used their gaze to process facial information using an eye tracker. Participants in both groups were similarly accurate at basic facial affect recognition at varied levels of intensity. Despite similar performance characteristics, ASD participants endorsed lower confidence in their responses and substantial variation in gaze patterns in absence of perceptual discrimination deficits. These results add support to the hypothesis that deficits in emotion and face recognition for individuals with ASD are related to fundamental differences in information processing. We discuss implications of this finding in a VR environment with regards to potential future applications and paradigms targeting not just enhanced performance, but enhanced social information processing within intelligent systems capable of adaptation to individual processing differences.


First-Degree Living-Related Donor Liver Transplantation in Autoimmune Liver Diseases.
Liver transplantation (LT) is the treatment of choice for end-stage autoimmune liver diseases. However, the underlying disease may recur in the graft in some 20% of cases. The aim of this study is to determine whether LT using living donor grafts from first-degree relatives results in higher rates of recurrence than grafts from more distant/unrelated donors. Two hundred sixty-three patients, who underwent a first LT in the Toronto liver transplant program between January 2000 and March 2015 for autoimmune liver diseases, and had at least 6 months of post-LT follow-up, were included in this study. Of these, 72 (27%) received a graft from a first-degree living-related donor, 56 (21%) from a distant/unrelated living donor, and 135 (51%) from a deceased donor for primary sclerosing cholangitis (PSC) (n = 138, 52%), primary biliary cholangitis (PBC) (n = 69, 26%), autoimmune hepatitis (AIH) (n = 44, 17%), and overlap syndromes (n = 12, 5%). Recurrence occurred in 52 (20%) patients. Recurrence rates for each autoimmune liver disease were not significantly different after first-degree living-related, living-unrelated, or deceased-donor LT. Similarly, time to recurrence, recurrence-related graft failure, graft survival, and patient survival were not significantly different between groups. In conclusion, first-degree living-related donor LT for PSC, PBC, or AIH is not associated with an increased risk of disease recurrence.


[A Case of Resected Metachronous Pancreatic Metastasis from Rectal Carcinoma].
A 69-year-old man underwent a Miles operation with D3 lymph node dissection for rectal cancer. The pathological diagnosis was adenocarcinoma(Rb, A, ly2, v3, N2M0P0H0, Stage Ⅲb). Adjuvant chemotherapy was added for 6 months after the rectal resection. Metastasis in the left lung was detected 1 year and 10 months after rectal resection for which large segmental resection was performed. Without the onset of any new lesions, the patient underwent subsequent follow-up examinations. Abdominal CT performed for increased tumor marker levels observed at 6 years and 8 months after rectal resection revealed a mass suggestive of pancreatic ductal adenocarcinoma for which distal pancreatectomy was performed. The pathological diagnosis was metastasis to the pancreas from the rectal cancer as the tumor cells were immunohistochemically negative for cytokeratin 7 and positive for cytokeratin 20. There has been no indication of recurrence for 13 months after the pancreatic surgery. Resectable pancreatic metastasis from colorectal cancer is rarely reported. However, pancreatic resection may result in long-term survival in some cases. Patients that tolerate pancreatectomy and have no metastasis in the other organs should be considered good candidates for pancreatic resection. We present this case with a review of the literature.


The Reliabilities of Several Measurement Methods of Cervical Sagittal Alignment in Cases with Cervical Spine Rotation Using X-ray Findings in Cervical Spine Disorders.
Several measurement methods designed to provide an understanding of cervical sagittal alignment have been reported, but few studies have compared the reliabilities of these measurement methods. The purpose of the present study was to investigate the intraexaminer and interexaminer reliabilities of several cervical sagittal alignment measurement methods and of the rotated cervical spine using plain lateral cervical spine X-rays of patients with cervical spine disorders. Five different measurement methods (Borden's method; Ishihara index method (Ishihara method); C2-7 Cobb method (C2-7 Cobb); posterior tangent method: absolute rotation angle C2-7 (ARA); and classification of cervical spine alignment (CCSA)) were applied by seven examiners to plain lateral cervical spine X-rays of 20 patients (10 randomly extracted cases from a rotated cervical spine group and 10 from a nonrotated group) with cervical spine disorders. Case 1 and Case 2 intraclass correlation coefficients (ICCs) were used to analyze intraexaminer and interexaminer reliabilities. The necessary number of measurements and the necessary number of examiners were also determined. The target coefficient of correlation was set at ≥0.81 (almost perfect ICC). In both groups, an ICC(1, 1) ≥ 0.81 was obtained with Borden's method, the Ishihara method, C2-7 Cobb, and ARA by all examiners. The necessary number of measurements was 1. With CCSA, a kappa coefficient of at least 0.9 was obtained. In both groups, with Borden's method, the Ishihara method, C2-7 Cobb, and ARA, the ICC(2, 1) was ≥0.9, indicating that the necessary number of examiners was 1. The standard error of measurement (SEM) was lowest with Borden's method, and the Ishihara method and C2-7 Cobb had almost the same values. Among cervical sagittal alignment measurement methods for cervical spine disorders, regardless of cervical spine rotation, Borden's method, Ishihara method, and C2-7 Cobb offer stronger reliability in terms of the ICC and SEM.


Temperature-sensitive mutants of Fujinami sarcoma virus: tumorigenicity and reversible phosphorylation of the transforming p140 protein.
Several clones of Fujinami sarcoma virus (FSV) isolated from a laboratory stock or from mutagenized virus were temperature sensitive (ts) in transformation of cells in culture. When shifted from the permissive (37 degrees C) to the nonpermissive (41.5 degrees C) temperature, the cellular phenotype reverted to normal within 2 h, but it required about 48 h at 37 degrees C to revert back to the transformed morphology. A temperature-resistant (tr) FSV clone was isolated from a tumor of an animal. All ts mutants were tumorigenic in animals but induced tumors only after latent periods of 12 to 25 days, compared to 5 to 6 days with tr virus. The ts lesions of the FSV mutants affected 90% of the phosphorylation of the nonstructural, gag-related 140,000-kilodalton phosphoprotein coded by FSV (p140), but did not affect virus replication or the synthesis of p140. Upon shifting from the permissive to the nonpermissive temperature, p140 was 90% dephosphorylated with an approximate (32)P half-life of 20 min. When shifted back to the permissive temperature, the preexisting p140 was rephosphorylated in the absence of protein synthesis within a 90-min test period. Likewise, most of the phosphate of fully phosphorylated p140 was exchanged at the permissive temperature within 30 to 90 min even when protein synthesis was inhibited. However, the protein structure of p140 had a half-life of 5 h at both temperatures. These results prove p140 to be a substrate of reversible phosphorylation. Superinfection and transformation of ts FSV-infected cells maintained at the nonpermissive temperature with acute leukemia virus MC29 failed to phosphorylate p140. It would follow that in vivo phosphorylation of ts p140 is controlled by an FSV-specific mechanism and is a prerequisite, not a consequence, of transformation. p140 of ts FSV recovered from cells maintained at 41.5 degrees C with anti-gag serum was over 10 times less phosphorylated by associated kinase than the same protein recovered from cells at 37 degrees C if assayed in vitro at 20 degrees C. This kinase activity associated with or dissociated from p140 with a half-life of less than 30 min during temperature shifts of ts FSV-infected cells. However, p140 recovered from ts FSV-infected cells maintained at 37 degrees C was phosphorylated by associated kinase in vitro not only at 20 degrees C but also, and essentially at the same level, at 41.5 degrees C. This suggests that the kinase associated with the immunocomplex of p140 of ts FSV is not temperature sensitive. p140 translated in vitro from ts and tr FSV RNA lacked kinase activity. We conclude that a fully phosphorylated p140 is necessary for the maintenance of transformation by FSV. This is consistent with the notion that other highly oncogenic viruses also code for nonstructural phosphoproteins with probable transforming function. A model which postulates that p140 is a substrate of reversible phosphorylation and that the lesion of the ts FSV clones described herein affects association of p140 with a cellular kinase rather than a hypothetical intrinsic kinase activity of the protein is most compatible with our data.


Non-proteolytic ubiquitin modification of PPARγ by Smurf1 protects the liver from steatosis.
Nonalcoholic fatty liver disease (NAFLD) is characterized by abnormal accumulation of triglycerides (TG) in the liver and other metabolic syndrome symptoms, but its molecular genetic causes are not completely understood. Here, we show that mice deficient for ubiquitin ligase (E3) Smad ubiquitin regulatory factor 1 (Smurf1) spontaneously develop hepatic steatosis as they age and exhibit the exacerbated phenotype under a high-fat diet (HFD). Our data indicate that loss of Smurf1 up-regulates the expression of peroxisome proliferator-activated receptor γ (PPARγ) and its target genes involved in lipid synthesis and fatty acid uptake. We further show that PPARγ is a direct substrate of Smurf1-mediated non-proteolytic lysine 63 (K63)-linked ubiquitin modification that suppresses its transcriptional activity, and treatment of Smurf1-deficient mice with a PPARγ antagonist, GW9662, completely reversed the lipid accumulation in the liver. Finally, we demonstrate an inverse correlation of low SMURF1 expression to high body mass index (BMI) values in human patients, thus revealing a new role of SMURF1 in NAFLD pathogenesis.


Induction of melanogenesis during the various melanoma growth phases and the role of tyrosinase, lysosome-associated membrane proteins, and p90 calnexin in the melanogenesis cascade.
Melanin biosynthesis (melanogenesis) is a metabolic pathway exclusively expressed by melanocytes and melanoma cells, and is often altered and/or markedly elevated in the latter cells. The changes in melanogenesis may be responsible for some of the clinical and histopathological features unique to melanoma. Melanogenesis may also contribute to the malignant transformation of melanoma precursors (i.e., atypical moles [or dysplastic nevi]) to melanoma as seen in patients with the familial atypical multiple-mole-melanoma (FAMMM) syndrome. However, it does not appear to affect the multi-step growth phases of melanoma cells from radial to vertical and lastly metastatic growth phases. Within the melanosomal compartment, eu- and pheomelanin pigments are synthesized. Both tyrosinase and lysosome-associated membrane protein (LAMP) gene products play important roles in this process. A coordinated interaction between these two gene family products is required for melanogenesis to occur properly. p90 calnexin is a new melanosome-associated molecule that is presumed to function as a melanogenesis chaperone by controlling the assembly and folding of glycoprotein intermediates of tyrosinase and LAMP gene families.


The Presence of White Matter Lesions Is Associated With the Fibrosis Severity of Nonalcoholic Fatty Liver Disease.
We tested whether nonalcoholic fatty liver disease (NAFLD) and/or its histological severity are associated with vascular white matter lesions (WML) in patients with biopsy-proven NAFLD and in non-NAFLD controls. Data were recorded in 79 consecutive biopsy-proven NAFLD, and in 82 controls with normal ALT and no history of chronic liver diseases, without ultrasonographic evidence of steatosis and liver stiffness value <6 KPa. All subjects underwent magnetic resonance assessment and WML were classified according to the Fazekas score as absent (0/III), or present (mild I/III; moderate II/III, and severe I/III). For the purpose of analyses, all controls were considered without NASH and without F2-F4 liver fibrosis. WML were found in 26.7% of the entire cohort (43/161), of moderate-severe grade in only 6 cases. The prevalence was similar in NAFLD versus no-NAFLD (29.1% vs 24.3%; P = 0.49), but higher in NASH vs no-NASH (37.7% vs 21.2%, P = 0.02) and F2-F4 vs F0-F1 fibrosis (47.3% vs 20.3%, P = 0.001). In both the entire cohort and in NAFLD, only female gender (OR 4.37, 95% CI: 1.79-10.6, P = 0.001; and OR 5.21, 95% CI: 1.39-19.6, P = 0.01), age > 45 years (OR 3.09, 95% CI: 1.06-9.06, P = 0.03; and OR 11.1, 95% CI: 1.14-108.7, P = 0.03), and F2-F4 fibrosis (OR 3.36, 95% CI: 1.29-8.73, P = 0.01; and OR 5.34, 95% CI: 1.40-20.3, P = 0.01) were independently associated with WML (mostly of mild grade) by multivariate analysis. Among NAFLD, the prevalence of WML progressively increased from patients without (1/18; 5.5%), or with 1 (1/17, 5.8%), to those with 2 (9/30; 30%) and further to those with 3 (12/14; 85.7%) risk factors. The presence of WML is not associated with NAFLD, but with metabolic diseases in general, and fibrosis severity of NAFLD. Clinical implications of this issue need to be assessed by longitudinal studies.


A robust host-response-based signature distinguishes bacterial and viral infections across diverse global populations.
Limited sensitivity and specificity of current diagnostics lead to the erroneous prescription of antibiotics. Host-response-based diagnostics could address these challenges. However, using 4,200 samples across 69 blood transcriptome datasets from 20 countries from patients with bacterial or viral infections representing a broad spectrum of biological, clinical, and technical heterogeneity, we show current host-response-based gene signatures have lower accuracy to distinguish intracellular bacterial infections from viral infections than extracellular bacterial infections. Using these 69 datasets, we identify an 8-gene signature to distinguish intracellular or extracellular bacterial infections from viral infections with an area under the receiver operating characteristic curve (AUROC) > 0.91 (85.9% specificity and 90.2% sensitivity). In prospective cohorts from Nepal and Laos, the 8-gene classifier distinguished bacterial infections from viral infections with an AUROC of 0.94 (87.9% specificity and 91% sensitivity). The 8-gene signature meets the target product profile proposed by the World Health Organization and others for distinguishing bacterial and viral infections.


Predicting chronic left ventricular dysfunction 90 days after ST-segment elevation myocardial infarction: An Assessment of Pexelizumab in Acute Myocardial Infarction (APEX-AMI) Substudy.
The purpose of this study was to determine predictors of 90-day left ventricular function following acute ST-segment elevation myocardial infarction (STEMI) using variables from clinical presentation, biomarker testing, and cardiovascular magnetic resonance imaging (CMR). Identifying patients with acute STEMI who experience adverse remodeling and develop left ventricular dysfunction 3 months post-MI is a priority for guiding subsequent therapy. The Assessment of Pexelizumab in Acute Myocardial Infarction trial tested pexelizumab treatment in STEMI patients presenting within 6 hours of symptom onset who were to undergo primary percutaneous coronary intervention. We studied 64 patients within this trial according to a prespecified substudy that included paired core laboratory delayed-enhancement CMR at days 3 and 90 as well as plasma N-terminal pro-B-type natriuretic peptide (NT-proBNP; in picograms per milliliter) measured at randomization and 24 hours. A multivariable model predicting day 90 left ventricular ejection fraction (LVEF) was developed from clinical, biomarker, and imaging findings. Patients had a median age of 60 years (52-68), 89% were male, and 60% had anterior STEMI. Time from symptom onset to percutaneous coronary intervention was 3 hours. The median baseline LVEF was 48% (38%-56%) and was 50% (40%-54%) at 90 days: 7 patients (11%) had an LVEF <35% at 90 days. Patients with a lower 90-day LVEF (as a continuous variable) had a higher 24-hour NT-proBNP (P = .02) and a larger baseline infarct size by CMR (median 15% LV [8%-20% LV]) (P < .01). Microvascular obstruction (no reflow) was greater as measured by CMR (median 2.8% [1.4%-6.1%]) in patients with a lower 90-day LVEF (P < .01). Median baseline and 24-hour NT-proBNP levels were 94 pg/mL (54-292 pg/mL) and 1,448 pg/mL (958-2,599 pg/mL), respectively. In a multivariable model with clinical, biomarker, and imaging variables, only 3 variables independently predicted 90-day LVEF: 24-hour NT-proBNP, baseline CMR infarct size, and microvascular obstruction. Three key pathophysiologic variables of the post-STEMI myocardium measuring baseline infarct size and the extent of microvascular obstruction on CMR and wall tension (24-hour NT-proBNP) independently predicted 90-day LVEF. Further studies linking these measures with earlier use of clinical therapies may be warranted.


Delayed endoscopy is associated with increased mortality in upper gastrointestinal hemorrhage.
To determine the association between delayed (>24 h) endoscopy and hospital mortality in patients with upper gastrointestinal hemorrhage (UGIH). We retrospectively analyzed all adult patients with UGIH who underwent endoscopy in a single emergency room for 2 years. The primary exposure was defined as >24 h from the ED visit to the first endoscopy. The primary outcome was defined as all cause hospital mortality. Secondary outcomes were intensive care unit admission rate, ED length of stay, and hospital length of stay. Among 1101 patients enrolled, 898 received endoscopy within 24 h (early group) and 203 received endoscopy after 24 h (delayed group). The hospital mortality of early and delayed group was 2.8% and 6.4%, respectively (unadjusted relative risk [RR] 2.30: 95% CI, 1.20-4.42, p = 0.012). This was significant after adjusting covariates including AIMS65 and Glasgow-Blatchford score (adjusted RR 2.23: 95% CI, 1.18-4.20, p = 0.013). Intensive care unit admission rate was not different between two groups. ED and hospital length of stay were significantly longer in delayed group. Endoscopy performed after 24 h was associated with increased hospital mortality in UGIH. Patients in the delayed group stayed longer in the ED and in the hospital.


Causes, spectrum and effects of surgical child abuse and neglect in a Nigerian city.
Children are dependent on parents and care givers for the quality of health care services received and in developing countries, where they are not protected against child abuse; many die as a result of denial of appropriate treatment. The objective of this study was to determine the causes, spectrum and effects of abuse and neglect on surgical children. Analysis of cases of surgical child abuse and neglect between January, 1998 and December, 2007 at the University of Benin Teaching Hospital, Benin City, Nigeria, was done. A total of 281 children aged two days and 12 years comprising 113 males and 168 females with male to female ratio 1:1.4, mainly with congenital malformation, suffered surgical child abuse and neglect ranging from delayed presentation, to child abandonment which was perpetuated by ignorance, poverty, superstitious beliefs, customs as well as non availability of free medical services for children. Counselling and home visits in addition to surgeries were done and 198 (70.5%) children were successfully treated with those abandoned happily reunited with their families, while 56 (19.9%) mortality was recorded due to complications of the primary surgical pathology, and this was statistically significant compared with other children with similar lesions but without abuse or neglect during the period (p=0.0102). Whereas 27 (9.6%) among those discharged against medical advice were lost to follow-up, of the 198 children that survived, 22 suffered psychological trauma and were co-managed with psychologists while seven were transferred to orphanage homes. Surgical child abuse/neglect is rampant, hence, it is hoped that these findings will influence policy makers in this sub-region to formulate policies that will protect children against this form of child abuse.


Nanoscale Chemical Diversity of Coke Deposits on Nanoprinted Metal Catalysts Visualized by Tip-Enhanced Raman Spectroscopy.
Coke formation is the prime cause of catalyst deactivation, where undesired carbon wastes block the catalyst surface and hinder further reaction in a broad gamut of industrial chemical processes. Yet, the origins of coke formation and their distribution across the catalyst remain elusive, obstructing the design of coke-resistant catalysts. Here, the first-time application of tip-enhanced Raman spectroscopy (TERS) is demonstrated as a nanoscale chemical probe to localize and identify coke deposits on a post-mortem metal nanocatalyst. Monitoring coke at the nanoscale circumvents bulk averaging and reveals the local nature of coke with unmatched detail. The nature of coke is chemically diverse and ranges from nanocrystalline graphite to disordered and polymeric coke, even on a single nanoscale location of a top-down nanoprinted SiO2 -supported Pt catalyst. Surprisingly, not all Pt is an equal producer of coke, where clear isolated coke "hotspots" are present non-homogeneously on Pt which generate large amounts of disordered coke. After their formation, coke shifts to the support and undergoes long-range transport on the surrounding SiO2 surface, where it becomes more graphitic. The presented results provide novel guidelines to selectively free-up the coked metal surface at more mild rejuvenation conditions, thus securing the long-term catalyst stability.


Tetrandrine Inhibits Epithelial-Mesenchymal Transition in IL-6-Induced HCT116 Human Colorectal Cancer Cells.
Patients with colorectal cancer (CRC) often develop distant metastases, which significantly reduces the 5-year survival rate. Epithelial-mesenchymal transition (EMT) is a crucial process for the invasion and metastasis of cancer cells. Tetrandrine has been reported to inhibit the viability and EMT of CRC cells; however, to the best of our knowledge, the molecular mechanism remains undetermined. The MTT assay was used to determine HCT116 cell viability. Wound healing and Transwell assays were used to determine that cell migration and invasion, respectively. Western blotting analysis was performed to detect the expression of migration-related genes. Four different lengths of the E-cadherin gene promoter were constructed and cloned into pGL3 reporter plasmids to evaluate E-cadherin gene promoter activity. The results of the MTT assay revealed that tetrandrine inhibited HCT116 cell viability, with an IC50 value of 7.2 μM following 24 h of treatment. Tetrandrine inhibited IL-6-induced cell migration and invasion, respectively. Tetrandrine regulates the expression of migration-related genes in IL-6-stimulated HCT116 cells. Tetrandrine significantly downregulated the expression and enzyme activity of MMP-2 in IL-6-stimulated HCT116 cells. In addition, tetrandrine restored E-cadherin gene promoter activity. The findings of the present study suggested that tetrandrine may inhibit EMT in IL-6-stimulated HCT116 cells; therefore, it may represent a potential drug for CRC.


Prevalence of diabetes in glaucoma.
Oral glucose 75 g was given to 352 patients with chronic glaucoma, acute glaucoma, or ocular hypertension and 73 patients without glaucoma. The proportion of patients with shallow anterior chambers who showed an abnormal response was significantly greater than that in patients with deep anterior chambers and in the control group (p less than 0.005). The probability of developing an abnormal response to oral glucose tests increased as the depth of the anterior chamber decreased; these two variables showed a significant negative linear correlation (r = -0.79, p less than 0.001). The high prevalence of autonomic dysfunction in patients with shallow anterior chambers and glaucoma may explain this association. Because of this, acute glaucoma should be regarded as a symptom of diabetes.


Elemental and organic carbon exposure in highway tollbooths: a study of Taiwanese toll station workers.
The carbon composition of fine particles (PM(2.5)) from traffic exhausts may play a role in adverse health effects. The objective of this study was to assess the concentrations of elemental and organic carbon in PM(2.5) in traffic exhausts from different types of vehicles in the booths of Taiwanese toll station workers and estimate the relations between traffic density and carbon concentrations. Tollbooth indoor monitoring samples were collected for 10 days to assess the 8 h integrated PM(2.5) concentration. Particle samples were analyzed for the content of total carbon, and elemental, and organic carbon. The mean carbon concentrations in the bus and truck lanes were [total: 167.7 microg/m(3) (SD 79.8 microg/m(3)); elemental: 131.7 (66.2); organic: 36.0 (25.8)], substantially higher compared with the car lanes with cash payment [39.2 (29.5); 20.2 (19.5); 19.2 (14.6)] and the car lanes with ticket payment [34.1 (26.1); 15.8 (17.6); 18.5 (12.2)]. The increase in elemental carbon concentration per vehicle in the bus and truck lane was 14 and 9 times greater than that of car lanes of ticket payment and car lanes of cash payment. The mass fraction of carbonaceous species in PM(2.5) accounted for 54% in bus and truck lanes, whereas the corresponding figure was 30-31% for car lanes. Elemental carbon is an important component of diesel exhaust. Workers in toll stations are exposed to high levels of both elemental and organic carbon.


Phagocytic reticuloendothelial function after hemorrhage and resuscitation: modulation by different fluids.
Although the efficacy of colloid resuscitation fluids in restoring cardiovascular status in hemorrhagic shock is accepted, the effect they have on the activity of the reticuloendothelial system (RES) is less clear. As interaction with the RES may be important in determining susceptibility to infections after resuscitation the effects of three such fluids, hydroxyethyl starch, Haemaccel, and fresh autologous blood on RES function after a 40% hemorrhage have been investigated in BALB/C mice. The mice, anesthetized with isoflurane, were bled over a 10 min period, left hypovolemic for 30 min, and then resuscitated with their shed blood or the same volume of asanguineous fluid. Normothermia was maintained throughout the experiments. Whole body phagocytic activity was assessed at 1, 6, 24, 48, and 72 h after the end of hemorrhage by measuring the clearance rate (K) of intravenously injected 51Cr-labeled sheep red blood cells. No significant change in K was found at any time in animals resuscitated with shed blood. However, significant increases in K were found 48 h after resuscitation with Haemaccel. Hepatic uptake of sheep red blood cells was significantly increased at 48 and 72 h in Haemaccel-resuscitated animals compared with hydroxyethyl starch or shed blood resuscitation, whereas spleen uptake decreased at 72 h. Lung uptake was not affected at any time with any fluid. The same volume of Haemaccel had no significant effect either on K or on organ uptake when given to normovolemic animals. The changes in organ uptake after hemorrhage and resuscitation with Haemaccel were partially prevented if animals were resuscitated with Haemaccel plus autologous red cells.


Fluorescent nanocarriers targeting VCAM-1 for early detection of senescent endothelial cells.
Endothelial senescence has been identified as an early event in the development of endothelial dysfunction, a hallmark of cardiovascular disease. This study developed theranostic nanocarriers (NC) decorated with VCAM-1 antibodies (NC-VCAM-1) in order to target cell surface VCAM-1, which is overexpressed in senescent endothelial cells (ECs) for diagnostic and therapeutic purposes. Incubation of Ang II-induced premature senescent ECs or replicative senescent ECs with NC-VCAM-1 loaded with lipophilic fluorescent dyes showed higher fluorescence signals than healthy EC, which was dependent on the NC size and VCAM-1 antibodies concentration, and not observed following masking of VCAM-1. NC loaded with omega 3 polyunsaturated fatty acid (NC-EPA:DHA6:1) were more effective than native EPA:DHA 6:1 to prevent Ang II-induced VCAM-1 and p53 upregulation, and SA-β-galactosidase activity in coronary artery segments. These theranostic NC might be of interest to evaluate the extent and localization of endothelial senescence and to prevent pro-senescent endothelial responses.


Proposal of the Autopsy Guideline for Infectious Diseases: Preparation for the Post-COVID-19 Era (abridged translation).
With the rapidly spreading coronavirus disease 2019 (COVID-19) pandemic over the past few months, the world is facing an unprecedented crisis. Innumerable lives have been lost to this novel infectious disease, the nature of which supersedes conventional medical understanding. The COVID-19 pandemic is not just a global health crisis, several aspects of life in the post-COVID-19 era are also being contemplated. Experts in unison are warning that the upcoming changes in all areas of life could potentially be far more drastic than ever experienced in the entire human civilization. The medical community is no exception, and therefore, personnel involved in forensic medicine also need to be adequately prepared for the future. Forensic medicine is a branch of medicine dedicated to one of the most important stages of the human lifecycle and has always been at the forefront in times of unprecedented social change. The autopsy, one of the most important tools of forensic medicine, is also useful to infectious diseases because it identifies the causal relationship between death and infection, reveals medical and epidemiological knowledge, and provides objective evidence for legal disputes. We present new autopsy guidelines in forensic medicine, formulated based on the various infectious diseases that we presently live with and may encounter in the future. In formulation of these guidelines several considerations have been taken into account, namely, the role forensic pathologists should play in the post-COVID-19 era and the necessary preparations as well as the support needed from society to fulfill that role. The present COVID-19 outbreak should be a starting point for formulating improvements in current practices in forensic science, including autopsy biosafety practices and the medicolegal death investigation system.


Male hypogonadism due to nontumorous hyperestrogenism.
Male hypogonadism due to the nontumorous production of estrogen was studied in a patient with gynecomastia and bilateral small testicles. Both the gynecomastia and the decrease in testicular size developed in the 5-year period before presentation. Peripheral serum concentrations of testosterone were in the low to low-normal range, while those of 17 beta-estradiol (E2) were significantly elevated, as were the urinary concentrations of total estrogen. Steroid hormone concentrations were measured in the left and right spermatic veins and the left and right adrenal veins in the basal state, and after stimulation with GnRH and ACTH. Spermatic vein concentrations of E2 were 3 to 20 times higher than concentrations previously reported in normal males. Spermatic vein concentrations of testosterone were normal. The spermatic vein concentrations of androstenedione were approximately three times higher than the mean concentration of androstenedione previously reported in the spermatic vein of normal males. The concentrations of E2 and androstenedione in the adrenal veins were also significantly elevated when compared to the concentrations previously reported in normal subjects. The authors postulate that the hyperestrogenism in this patient was due to increased aromatization of the precursor substrates, testosterone in the testes, and androstenedione in the adrenals to E2 and E1 in the testes and adrenals, respectively. Alternatively, an increased abundance or activity of the 17 beta-hydroxysteroid dehydrogenase isoenzyme which converts estrone (E1) to E2 or a relative deficiency of the 17 beta-hydroxysteroid dehydrogenase isoenzyme, which converts androstenedione to testosterone, could theoretically account for the reported abnormalities.


BMI, WC, WHtR, VFI and BFI: which indictor is the most efficient screening index on type 2 diabetes in Chinese community population.
Obesity is a major risk factor for type 2 diabetes, many indexes can be used to describes obesity and predict diabetes. This research attempts to identify the best indicator of obesity to screening diabetes in Chinese population. A cross-sectional data of 8121 subjects aged 35-60 years were included in this research belongs to the Diabetes Appropriate Technology Intervention Study. Anthropometric indicators including body weight, height, waist circumferences (WC), body fat index (BFI) and visceral fat index (VFI) and blood biochemical indicators after an overnight fast [fasting blood glucose, total cholesterol, high-density lipoprotein (HDL) cholesterol, and triacylglycerol] were measured. BMI (body mass index) and Weight to Height Ratio was calculated. Subjects with obesity had a higher risk of physician diagnosed diabetes (OR=2.50, 95% CI 1.83-3.43), new diagnosed diabetes (OR=4.23, 95% CI 2.91-6.15) and pre-diabetes (OR=1.75, 95% CI 1.31-2.34) compared to those with normal Body mass index (BMI). There was a significant trend of increased risk of all diabetes status with increased waist circumference (WC). The waist-to-height ratio (WHtR) yielded the most significant association with new diagnosed diabetes and physician diagnosed diabetes than other indices. Central obesity is significantly correlated with diabetes. VFI was most correlated with pre-diabetes while WHtR is an efficient screening index than BMI and WC in Chinese community diabetes screening.


Tension Type Headache.
Tension type headache (TTH) is the most common headache and it has been discussed for years without reaching consensus on its pathophysiology, or proper rationale management. This primary headache remains a challenge into its management for clinicians. This review aims to provide an updated and critical discussion on what is currently known and supported by scientific evidence about TTH and which gaps there still may be in our understanding of this condition. Clinical features of TTH resemble common manifestations of muscle referred pain. Episodic TTH may evolve into the chronic form by different aspects and several triggers may be involved at the same time. Both peripheral and central sensitization mechanisms seem to be clearly involved in this process. Individuals with episodic TTH exhibit higher levels of peripheral excitability whereas chronic TTH clearly show central sensitization manifestations. The role of associated muscle hyperalgesia seems to be important factors in TTH. Therapeutic management of individuals with TTH should be multimodal including appropriate use of pharmacological and non-pharmacological interventions to reduce the nociceptive peripheral drive to the central nervous system. If properly applied, treatment may not only reduce the number of TTH attacks but may also prevent or delay the transition from episodic to chronic TTH. Scientific evidence of pharmacological and nonpharmacological treatment is discussed in this review.


High-coverage ITS primers for the DNA-based identification of ascomycetes and basidiomycetes in environmental samples.
The kingdom Fungi is estimated to include 1.5 million or more species, playing key roles as decomposers, mutualists, and parasites in every biome on the earth. To comprehensively understand the diversity and ecology of this huge kingdom, DNA barcoding targeting the internal transcribed spacer (ITS) region of the nuclear ribosomal repeat has been regarded as a prerequisite procedure. By extensively surveying ITS sequences in public databases, we designed new ITS primers with improved coverage across diverse taxonomic groups of fungi compared to existing primers. An in silico analysis based on public sequence databases indicated that the newly designed primers matched 99% of ascomycete and basidiomycete ITS taxa (species, subspecies or varieties), causing little taxonomic bias toward either fungal group. Two of the newly designed primers could inhibit the amplification of plant sequences and would enable the selective investigation of fungal communities in mycorrhizal associations, soil, and other types of environmental samples. Optimal PCR conditions for the primers were explored in an in vitro investigation. The new primers developed in this study will provide a basis for ecological studies on the diversity and community structures of fungi in the era of massive DNA sequencing.


Seventh cranial neuropathy.
Facial neuropathy, or seventh cranial neuropathy, is the most common cranial neuropathy. The anatomy of the facial nerve is rather complex for a cranial nerve, with a long intracranial course, in which the nerve takes three bends (or genu). Electrodiagnosis can be helpful in prognosis, but not before several days. Imaging is rarely indicated in Bell's palsy, but is often abnormal nonetheless, and can be very useful in other causes of facial neuropathy. The clinical presentation is of unilateral facial weakness of upper and lower face, hyperacusis, dysgeusia, and disordered lacrimation and salivation. Many different disease processes can result in facial neuropathy, but 70% of cases are idiopathic, or as it is best known, Bell's palsy. Ramsay Hunt syndrome, defined as facial neuropathy with herpes zoster oticus, is another common cause. Steroids given acutely are beneficial in improving outcome in Bell's palsy, and antiviral therapy seems helpful in more severe cases. Antiviral therapy is definitely helpful in Ramsay Hunt disease when given within 3 days of onset. Antibiotics are helpful in Lyme facial neuropathy, which has a very good prognosis.


Becoming a high reliability organization.
Aircraft carriers, electrical power grids, and wildland firefighting, though seemingly different, are exemplars of high reliability organizations (HROs)--organizations that have the potential for catastrophic failure yet engage in nearly error-free performance. HROs commit to safety at the highest level and adopt a special approach to its pursuit. High reliability organizing has been studied and discussed for some time in other industries and is receiving increasing attention in health care, particularly in high-risk settings like the intensive care unit (ICU). The essence of high reliability organizing is a set of principles that enable organizations to focus attention on emergent problems and to deploy the right set of resources to address those problems. HROs behave in ways that sometimes seem counterintuitive--they do not try to hide failures but rather celebrate them as windows into the health of the system, they seek out problems, they avoid focusing on just one aspect of work and are able to see how all the parts of work fit together, they expect unexpected events and develop the capability to manage them, and they defer decision making to local frontline experts who are empowered to solve problems. Given the complexity of patient care in the ICU, the potential for medical error, and the particular sensitivity of critically ill patients to harm, high reliability organizing principles hold promise for improving ICU patient care.


Glycemic control and associated factors among type 2 diabetes mellitus patients: a cross-sectional study of Azar cohort population.
Despite the growing prevalence of diabetes and its complications, there is a dearth of data regarding factors associated with glycemic control. Therefore, in this cross-sectional study, we aimed to identify factors influencing glycemic control in patients with type 2 diabetes mellitus (T2DM) in the Iranian population. This cross-sectional study was conducted among the Azar cohort population and the glycemic control status of patients with T2DM was investigated. Possible risk factors including age, sex, marital status, educational level, smoking status, sleep duration, family history of diabetes and hypertension, socioeconomic status, physical activity level, and co-existence of other chronic diseases and their relationship with glycemic control status were also assessed. Multivariate logistic regression analysis was used to identify determinants of glycemic control. Among 1,710 T2DM patients (60.2% female), the overall prevalence of poor glycemic control was 56.8%. In the unadjusted logistic regression analysis model, a low wealth score index significantly increased the risk of poor glycemic control (OR: 1.49;1.10-2.02). Variables significantly associated with poor glycemic control even after adjusting for confounding factors were first-degree family history of diabetes (OR: 1.34; 1.08-1.65), and sleep duration (OR: 1.29 ;1.02-1.62 for 6.6-8 h/d; OR:1.42;1.10-1.88 for > 8 h/d). Interestingly, we found that the co-existence of ≥ 3 chronic diseases with diabetes decreased the risk of poor glycemic control. In the current study, most of the patients with T2DM had uncontrolled glycemic control. Due to the individual and social costs of diabetes complications, it is necessary to suggest tailored and effective interventions for controlling blood glucose levels in people with diabetes.


Centennial conference on laryngeal cancer papers. Primary laryngoplasty.
A new procedure is described for the surgical reconstruction of the larynx following total laryngectomy. Postoperatively, the voice was as good as that resulting from Asai's laryngoplasty. Aspiration of fluid into the trachea was minimal. The procedure may be briefly summarized as follows: 1. The lateral portion of both thyroid cartilages are left in situ. 2. The posterior laryngeal wall is formed with the superior horns of the same cartilages. 3. The inner surface of the reconstructed larynx is lined by mucosal flaps from the hypopharynx. 4. The reconstructed larynx is firmly sutured to the base of the tongue. This procedure was employed in 19 cases with an extensive laryngeal carcinoma. In five of them healing was retarded by the formation of postoperative pharyngeal fistulas. All patients regained their voices and their ability to swallow.


The hypertension of autonomic failure and its treatment.
We studied the incidence and severity of supine hypertension in 117 patients with severe primary autonomic failure presenting to a referral center over a 9-year period. Patients were uniformly characterized by disabling orthostatic hypotension, lack of compensatory heart rate increase, abnormal autonomic function tests, and unresponsive plasma norepinephrine. Fifty-four patients had isolated autonomic impairment (pure autonomic failure). Sixty-three patients had central nervous system involvement in addition to autonomic impairment (multiple-system atrophy). Patients were studied off medications, in a metabolic ward, and on a controlled diet containing 150 mEq of sodium. Fifty-six percent of patients had supine diastolic blood pressure > or =90 mm Hg. The prevalence of hypertension was slightly greater in females (63%) than in males (52%). Potential mechanisms responsible for this hypertension were investigated. No correlation was found between blood volume and blood pressure. Similarly, plasma norepinephrine (92+/-15 pg/mL) and plasma renin activity (0.3+/-0.05 ng/mL per hour) were very low in the subset of patients with pure autonomic failure and supine hypertension (mean systolic/diastolic pressure, 177 +/- 6/108 +/- 2 mm Hg, range 167/97 to 219/121). Supine hypertension represents a challenge in the treatment of orthostatic hypotension. We found these patients to be particularly responsive to the hypotensive effects of transdermal nitroglycerin. Doses ranging from 0.025 to 0.1 mg/h decreased systolic blood pressure by 36+/-7 mm Hg and may effectively treat supine hypertension overnight, but the dose should be individualized and used with caution.


A novel semisynthetic route to insulin analogues modified at the N-terminus of the A-chain.
We report a novel route for the semi-synthetic production of insulin analogues modified at the amino-terminus of the A-chain. The route proceeds from insulin via [Nalpha-Boc-GlyA1]-insulin to [Nalpha-(Z-methionyl)-PheB1, Nepsilon-(Z-methionyl)-LysB29]des-GlyA1-insulin. We have replaced residue A1 with glycine, to give a fully crystalline resynthesized insulin, and with D-lysine.


A 14-day ecological momentary assessment study on whether resilience and early family risk moderate daily stress and affect on cortisol diurnal slope.
This study examined whether resilience capacity moderates the association of daily perceived stress and affect with cortisol diurnal slope among relocated emerging adults. Relocated undergraduates (N = 98; aged 18-25 years) were recruited from three groups: Resilient, Vulnerable, and Control. The Resilient group required Risky Family Questionnaire (RFQ) scores ≥ 29 and Brief Resilience Scale (BRS) scores ≥ 3.6. The Vulnerable group required RFQ scores ≥ 29 and BRS scores ≤ 3. The comparison Control group required RFQ scores ≤ 21 and T-scores < 60 on PROMIS anxiety and depression symptoms. Mixed-effects models were used to test the unique associations of perceived stress, negative affect, and positive affect x group interactions (predictors) on diurnal cortisol slope (outcome) across 14 consecutive days. The Resilient group did not moderate the associations between daily stress or affect on cortisol diurnal slope. Instead, both the Resilient and Vulnerable groups with early family risk, showed a steeper diurnal slope unique to higher stress and a flatter slope unique to higher negative affect. Results suggest that riskier early family life was significantly associated with altered cortisol diurnal slope outcomes to stress (i.e., demand) and negative affect (i.e., distress). These associations were not attenuated by current resilience capacity.


Cost-Effectiveness Analysis of Sacubitril/Valsartan for Reducing the Use of Implantable Cardioverter-Defibrillator (ICD) and the Risk of Death in ICD-Eligible Heart Failure Patients With Reduced Ejection Fraction.
This critical review of Kaddoura et al.'s article on sacubitril/valsartan in heart failure patients underscores the importance of considering potential adverse effects, including renal failure, hyperkalemia, angioedema, and increased reports of sudden cardiac death. It highlights the need for rigorous monitoring and precise treatment regimens, especially in diabetic heart failure patients. Additionally, the review questions the generalizability of the study's results to diverse healthcare settings and emphasizes the importance of grounded patient follow-up data for accurate long-term assessment. These considerations are vital for informed decision-making regarding sacubitril/valsartan use in heart failure management.


[Microflora of reproductive system in women with tubal-peritoneal sterility].
To study the composition of microflora of lower and upper parts of reproductive system in women with tubal-peritoneal sterility. One hundred and forty-five women with tubal-peritoneal sterilitywere examined. Laparoscopy with biopsy of ovaries and endometrium with evaluation of specimens by histology and PCR was performed in all patients. Cervical material, endometrial and ovarian biopsy specimens, and peritoneal fluid were tested by PCR on the presence of genetic material of sexually-transmitted microorganisms. Cervical material was tested for human papillomaviruses (types 16 and 18). Bacteria were isolated from cervical canal specimens in 40% of women. Chlamydia, Ureaplasma, herpes virus type 1 and 2, cytomegalovirus were detected in specimens of cervical canal, endometrium, ovaries and peritoneal fluid in 80%, 38,6%, 34,3%, and 38,46% of women, respectively. In cases of tubal-peritoneal sterility female reproductive system is infected with different pathogenic microorganisms. Growth of microorganisms was detected in 40% of cervical mucosa samples. Intracellular pathogens persist in upper and lower parts of female reproductive system. It was noted that Herpes simplex infection predominated in ovaries.


Genome-wide transcriptional analysis suggests hydrogenase- and nitrogenase-mediated hydrogen production in Clostridium butyricum CWBI 1009.
Molecular hydrogen, given its pollution-free combustion, has great potential to replace fossil fuels in future transportation and energy production. However, current industrial hydrogen production processes, such as steam reforming of methane, contribute significantly to the greenhouse effect. Therefore alternative methods, in particular the use of fermentative microorganisms, have attracted scientific interest in recent years. However the low overall yield obtained is a major challenge in biological H2 production. Thus, a thorough and detailed understanding of the relationships between genome content, gene expression patterns, pathway utilisation and metabolite synthesis is required to optimise the yield of biohydrogen production pathways. In this study transcriptomic and proteomic analyses of the hydrogen-producing bacterium Clostridium butyricum CWBI 1009 were carried out to provide a biomolecular overview of the changes that occur when the metabolism shifts to H2 production. The growth, H2-production, and glucose-fermentation profiles were monitored in 20 L batch bioreactors under unregulated-pH and fixed-pH conditions (pH 7.3 and 5.2). Conspicuous differences were observed in the bioreactor performances and cellular metabolisms for all the tested metabolites, and they were pH dependent. During unregulated-pH glucose fermentation increased H2 production was associated with concurrent strong up-regulation of the nitrogenase coding genes. However, no such concurrent up-regulation of the [FeFe] hydrogenase genes was observed. During the fixed pH 5.2 fermentation, by contrast, the expression levels for the [FeFe] hydrogenase coding genes were higher than during the unregulated-pH fermentation, while the nitrogenase transcripts were less abundant. The overall results suggest, for the first time, that environmental factors may determine whether H2 production in C. butyricum CWBI 1009 is mediated by the hydrogenases and/or the nitrogenase. This work, contributing to the field of dark fermentative hydrogen production, provides a multidisciplinary approach for the investigation of the processes involved in the molecular H2 metabolism of clostridia. In addition, it lays the groundwork for further optimisation of biohydrogen production pathways based on genetic engineering techniques.


Immunohistochemical studies on the distribution of nerve fibers in chronic liver diseases.
Innervation of the liver with or without chronic liver disease was immunohistochemically studied. In normal liver tissues, gamma-enolase [neuron-specific enolase (NSE)]- and S-100 protein (S-100)-positive nerve fibers were found around hepatic arteries, portal veins, and bile ductules in the portal area, along the sinusoid, and around central veins inside the hepatic lobule. Neuropeptide Y (NPY)-immunoreactive (IR) nerve fibers were detected in close contact with hepatic arteries and portal veins in the portal area and along the sinusoid in the parenchyma. Vasoactive intestinal polypeptide (VIP)-IR nerve fibers were found in the portal area but were scarce in the parenchyma. VIP-IR nerve fibers were much fewer than NPY-IR fibers. In patients with chronic active hepatitis, NSE- and S-100-positive nerve fibers, as well as NPY-IR nerve fibers, proliferated in the enlarged portal area. In cirrhotic liver, NSE- and S-100-positive nerve fibers and NPY-IR fibers increased remarkably in the fibrous septa, whereas they decreased or vanished inside the pseudolobules. These findings suggest that, in chronic liver disease, intrahepatic nerve fibers change their distribution, accompanying the structural changes in the hepatic lobules.


Lithospermic acid B is more responsive to silver ions (Ag+) than rosmarinic acid in Salvia miltiorrhiza hairy root cultures.
LAB (lithospermic acid B) is a dimer of RA (rosmarinic acid) and has been suggested to be derived from RA, but the detailed biosynthesis process has not yet been identified. The accumulation of RA has been intensively investigated in the plant species of Boraginaceae and Lamiaceae. In the present study, we report that silver ions (Ag+; 15 microM), an abiotic elicitor, did not stimulate RA accumulation but dramatically enhanced LAB from approx. 5.4% to 18.8% of dry weight in Salvia miltiorrhiza hairy root cultures, and the rise in LAB was found to be coincident with the decline of RA content at each time point after treatment. Meanwhile, a profiling analysis of genes and metabolites (intermediates) involved in the RA synthesis pathway was performed; the result indicated that several gene transcripts and metabolite accumulations show temporal changes in abundance consistent with LAB production. Thus a potential (putative) biosynthetic route from RA to LAB was presumed, which was suggested to be significantly activated by Ag+ in S. miltiorrhiza hairy root cultures. Further intermediate monitoring and compound feeding experiments were performed to rank the strength of this hypothesis. Our study, for the first time, provides evidence that RA is a precursor leading to LAB synthesis.


[Tunica vaginalis of testis and spermatic fascia: a good alternative for the repair of urethral fistula resulting from hypospadias operation].
To evaluate the methods of repairing urethral fistula resulting from hypospadias operation. We analyzed the clinical data of 46 cases of surgical repair of urethral fistula resulting from hypospadias operation. The patients ranged in age from 3 to 26 (mean 11.7) years. There were 52 fistulas in all, with the diameters of less than 5 mm, of which 25 were in the midshaft of the penis, 12 in the penoscrotum, and 9 in the scrotum. Of the 46 cases, 20 were repaired by continuous knock suture and 26 by tunica vaginalis of testis and spermatic fascia. The one-stage success rate of continuous knock suture repair was 55% (11/20) and that of the combined use of continuous knock suture with tunica vaginalis of testis and spermatic fascia repair was 84.6% (22/26). Based on continuous knock suture, the additional use of tunica vaginalis of testis and spermatic fascia yields a high success rate in repairing urethral fistula resulting from hypospadias operation.


Decreased ovalbumin-gene response to oestrogen in the prenatally diethylstilboestrol-exposed chick oviduct.
Prenatal exposure of the female chick-embryo Müllerian duct to diethylstilboestrol (DES) decreases its future capacity for epithelial tubular-gland-cell differentiation and oviduct ovalbumin-gene expression. Chick Müllerian ducts after prenatal exposure to different concentrations of DES were tested after birth to determine the response of the oviduct toward the oestrogen induction. The quantity of DNA was biochemically determined, the differentiation of tubular-gland cells in the oviduct was studied by light microscopy, and the expression of the ovalbumin gene was detected by hybridization of the total RNA with radioactive ovalbumin cDNA. Comparisons among these three parameters revealed that the expression of the ovalbumin gene was affected most by DES exposure. Exposure to high doses of DES suppressed ovalbumin-gene expression by 75-78%, and inhibited tubular-gland-cell differentiation and thus decreased the DNA content by 29 and 32% respectively. Exposure to low doses of DES caused suppression of ovalbumin-gene expression by 47-53%, but it did not affect the other two parameters. Prenatal DES exposure has strong inhibitory effects on the Müllerian duct at the age (5-8-day-old embryos) when the organ is undifferentiated. Less inhibition is observed when the organ becomes differentiated (15-day-old embryos and older).


Pathological fracture of the femoral neck following septic coxitis and chronic osteomyelitis: a potential complication of Lemierre's syndrome.
We portray the case of a 16-year-old girl who was initially admitted to the paediatric emergency department with non-specific symptoms of a severe cold and was first treated symptomatically on an ambulatory basis. Within 6 days she developed the full clinical picture of Lemierre's syndrome with the extraordinary manifestation of involvement of her right hip. Despite an interdisciplinary coordinated treatment as well as surgical therapy, a full-blown sepsis evolved within a short time period and resulted in almost 2 months of intensive care. While the primary focus could be successfully controlled, a progressive avascular necrosis of the right proximal femur developed on the basis of a chronic osteomyelitis. This finally led to a pathological fracture of the femoral neck. After excluding the possibility of an enduring bacterial infection, the fracture was treated with a total hip replacement.


Native rodent species are unlikely sources of infection for Leishmania (Viannia) braziliensis along the Transoceanic Highway in Madre de Dios, Peru.
An estimated 2.3 million disability-adjusted life years are lost globally from leishmaniasis. In Peru's Amazon region, the department of Madre de Dios (MDD) rises above the rest of the country in terms of the annual incidence rates of human leishmaniasis. Leishmania (Viannia) braziliensis is the species most frequently responsible for the form of disease that results in tissue destruction of the nose and mouth. However, essentially nothing is known regarding the reservoirs of this vector-borne, zoonotic parasite in MDD. Wild rodents have been suspected, or proven, to be reservoirs of several Leishmania spp. in various ecosystems and countries. Additionally, people who live or work in forested terrain, especially those who are not regionally local and whose immune systems are thus naïve to the parasite, are at most risk for contracting L. (V.) braziliensis. Hence, the objective of this study was to collect tissues from wild rodents captured at several study sites along the Amazonian segment of the newly constructed Transoceanic Highway and to use molecular laboratory techniques to analyze samples for the presence of Leishmania parasites. Liver tissues were tested via polymerase chain reaction from a total of 217 rodents; bone marrow and skin biopsies (ear and tail) were also tested from a subset of these same animals. The most numerous rodent species captured and tested were Oligoryzomys microtis (40.7%), Hylaeamys perenensis (15.7%), and Proechimys spp. (12%). All samples were negative for Leishmania, implying that although incidental infections may occur, these abundant rodent species are unlikely to serve as primary reservoirs of L. (V.) braziliensis along the Transoceanic Highway in MDD. Therefore, although these rodent species may persist and even thrive in moderately altered landscapes, we did not find any evidence to suggest they pose a risk for L. (V.) braziliensis transmission to human inhabitants in this highly prevalent region.


A Systematic Review and Meta-Synthesis of Barriers and Facilitators of Help-Seeking Behaviors in South Asian Women Living in High-Income Countries who Have Experienced Domestic Violence: Perception of Domestic Violence Survivors and Service Providers.
There has been little research on domestic violence (DV) within ethnic minority communities in high-income countries. This study reports on the findings of a meta-ethnography that examined the barriers and facilitators of help-seeking behaviors in South Asian women living in high-income countries who have experienced DV to inform practice, understand the limits of the evidence, and identify research gaps. Qualitative studies were identified which were available in English by electronic databases. After an initial search, 2,465 articles were reviewed by title and abstract and 135 articles were reviewed for full text. Thirty-five papers were included for this review and were synthesized using meta-ethnography. Key findings included barriers and facilitators of help-seeking behaviors: (1) Socio-cultural norms to prohibit help-seeking behaviors, (2) Fear of negative consequences, (3) Negative aspects of immigration status, (4) Insufficient support from statutory, and voluntary agencies, (5) Safety strategies and facilitators for surviving. Although this review investigated the perceptions of two different populations (survivors and service providers) both groups had similar views about the barriers and facilitators of help-seeking behaviors. It is crucial for the government and non-government organizations to understand the barriers for women who are DV survivors to seek help from their organizations and also from South Asian ethnicities. The awareness and understanding of these barriers and facilitators may help support the development of interventions to encourage effective help-seeking amongst South Asian women affected by DV. Suggestions for research, practice, and policies are discussed.


Structural Insights into the Dimeric Form of Bacillus subtilis RNase Y Using NMR and AlphaFold.
RNase Y is a crucial component of genetic translation, acting as the key enzyme initiating mRNA decay in many Gram-positive bacteria. The N-terminal domain of Bacillus subtilis RNase Y (Nter-BsRNaseY) is thought to interact with various protein partners within a degradosome complex. Bioinformatics and biophysical analysis have previously shown that Nter-BsRNaseY, which is in equilibrium between a monomeric and a dimeric form, displays an elongated fold with a high content of α-helices. Using multidimensional heteronuclear NMR and AlphaFold models, here, we show that the Nter-BsRNaseY dimer is constituted of a long N-terminal parallel coiled-coil structure, linked by a turn to a C-terminal region composed of helices that display either a straight or bent conformation. The structural organization of the N-terminal domain is maintained within the AlphaFold model of the full-length RNase Y, with the turn allowing flexibility between the N- and C-terminal domains. The catalytic domain is globular, with two helices linking the KH and HD modules, followed by the C-terminal region. This latter region, with no function assigned up to now, is most likely involved in the dimerization of B. subtilis RNase Y together with the N-terminal coiled-coil structure.


Functional diversification within the family of B-GATA transcription factors through the leucine-leucine-methionine domain.
The transcription of the Arabidopsis (Arabidopsis thaliana) GATA transcription factors GATA, NITRATE-INDUCIBLE, CARBON METABOLISM-INVOLVED (GNC) and GNC-LIKE (GNL)/CYTOKININ-RESPONSIVE GATA FACTOR1 is controlled by several growth regulatory signals including light and the phytohormones auxin, cytokinin, and gibberellin. To date, GNC and GNL have been attributed functions in the control of germination, greening, flowering time, floral development, senescence, and floral organ abscission. GNC and GNL belong to the 11-member family of B-class GATA transcription factors that are characterized to date solely by their high sequence conservation within the GATA DNA-binding domain. The degree of functional conservation among the various B-class GATA family members is not understood. Here, we identify and examine B-class GATAs from Arabidopsis, tomato (Solanum lycopersicon), Brachypodium (Brachypodium distachyon), and barley (Hordeum vulgare). We find that B-class GATAs from these four species can be subdivided based on their short or long N termini and the presence of the 13-amino acid C-terminal leucine-leucine-methionine (LLM) domain with the conserved motif LLM. Through overexpression analyses and by complementation of a gnc gnl double mutant, we provide evidence that the length of the N terminus may not allow distinguishing between the different B-class GATAs at the functional level. In turn, we find that the presence and absence of the LLM domain in the overexpressors has differential effects on hypocotyl elongation, leaf shape, and petiole length, as well as on gene expression. Thus, our analyses identify the LLM domain as an evolutionarily conserved domain that determines B-class GATA factor identity and provides a further subclassification criterion for this transcription factor family.


Simultaneous detection of six diarrhea-causing bacterial pathogens with an in-house PCR-luminex assay.
Diarrhea can be caused by a range of pathogens, including several bacteria. Conventional diagnostic methods, such as culture, biochemical tests, and enzyme-linked immunosorbent assay (ELISA), are laborious. We developed a 7-plex PCR-Luminex assay to simultaneously screen for several of the major diarrhea-causing bacteria directly in fecal specimens, including pathogenic Aeromonas, Campylobacter jejuni, Campylobacter coli, Salmonella, Shigella, enteroinvasive Escherichia coli (EIEC), Vibrio, and Yersinia. We included an extrinsic control to verify extraction and amplification. The assay was first validated with reference strains or isolates and exhibited a limit of detection of 10(3) to 10(5) CFU/g of stool for each pathogen as well as quantitative detection up to 10(9) CFU/g. A total of 205 clinical fecal specimens from individuals with diarrhea, previously cultured for enteric pathogens and tested for Campylobacter by ELISA, were evaluated. Using these predicate methods as standards, sensitivities and specificities of the PCR-Luminex assay were 89% and 94% for Aeromonas, 89% and 93% for Campylobacter, 96% and 95% for Salmonella, 94% and 94% for Shigella, 92% and 97% for Vibrio, and 100% and 100% for Yersinia, respectively. All discrepant results were further examined by singleplex real-time PCR assays targeting different gene regions, which revealed 89% (55/62 results) concordance with the PCR-Luminex assay. The fluorescent signals obtained with this approach exhibited a statistically significant correlation with the cycle threshold (C(T)) values from the cognate real-time PCR assays (P < 0.05). This multiplex PCR-Luminex assay enables sensitive, specific, and quantitative detection of the major bacterial causes of gastroenteritis.


Interdisciplinary dentofacial therapy (IDT): a comprehensive team approach.
Modern dentistry, with its various disciplines, has an exciting and unmatched potential to enhance the overall quality of life for our patients. In this environment one of the greatest challenges for clinicians is to properly utilize this vast potential. It can be very difficult to consistently establish health and physiological occlusal relationships in patients with significant dental, periodontal, dentoalveolar, temporomandibular, and/or skeletal problems. This task is further complicated by ever-increasing patient and provider demands for results with optimal dentofacial aesthetics and long-term stability. Interdisciplinary Dentofacial Therapy (IDT) is a proven diagnostic and clinical pathway for consistently maximizing patient outcomes in these complicated areas. Within a climate of increasing scientific and technological advances in dentistry, today's dental professional must study continuously to stay abreast in one area, let alone in all of them. The responsibility to the patient, however, is to utilize fully the extensive options that the profession can provide. As stated above, a proven treatment philosophy for accomplishing this is called Interdisciplinary Dentofacial Therapy, or IDT. When properly performed, IDT can produce unparalleled professional satisfaction and camaraderie by reaching higher levels of patient care through optimal coordination of knowledge and skills in the various disciplines. In addition, IDT can consistently produce optimal treatment results while simultaneously producing profound practice management, time management and marketing benefits for practitioners. This paper briefly describes these benefits while defining the philosophies and hallmarks of IDT. It will also give insight into the implementation of IDT and why it will be even more necessary and valuable in the future than it is today.