Developmental plasticity of mitochondrial function in American alligators, Alligator mississippiensis.
The effect of hypoxia on cellular metabolism is well documented in adult vertebrates, but information is entirely lacking for embryonic organisms. The effect of hypoxia on embryonic physiology is particularly interesting, as metabolic responses during development may have life-long consequences, due to developmental plasticity. To this end, we investigated the effects of chronic developmental hypoxia on cardiac mitochondrial function in embryonic and juvenile American alligators (Alligator mississippiensis). Alligator eggs were incubated in 21% or 10% oxygen from 20 to 90% of embryonic development. Embryos were either harvested at 90% development or allowed to hatch and then reared in 21% oxygen for 3 yr. Ventricular mitochondria were isolated from embryonic/juvenile alligator hearts. Mitochondrial respiration and enzymatic activities of electron transport chain complexes were measured with a microrespirometer and spectrophotometer, respectively. Developmental hypoxia induced growth restriction and increased relative heart mass, and this phenotype persisted into juvenile life. Embryonic mitochondrial function was not affected by developmental hypoxia, but at the juvenile life stage, animals from hypoxic incubations had lower levels of Leak respiration and higher respiratory control ratios, which is indicative of enhanced mitochondrial efficiency. Our results suggest developmental hypoxia can have life-long consequences for alligator morphology and metabolic function. Further investigations are necessary to reveal the adaptive significance of the enhanced mitochondrial efficiency in the hypoxic phenotype.


Advanced MR imaging of the cruciate ligaments.
The anterior and posterior cruciate ligaments are crucial stabilizers of the knee. These ligaments are named by the location of their tibial attachments. Each ligament is composed of separate functional bundles that differ in size but are equally important in function. MR imaging is accurate and sensitive, making it the imaging technique of choice for evaluating these ligaments. Acute and chronic injuries involving the cruciate ligaments have typical appearances and associated findings. MR imaging interpretation must take into account atypical injuries and imaging pitfalls. Knowledge of normal ligament reconstruction techniques allows differentiation of the normal postoperative appearance from reconstruction failure and complications. Ligament reconstruction techniques, complications, and appearances are reviewed in this article.


Rehabilitation exoskeletal robotics. The promise of an emerging field.
Exoskeletons are wearable robots exhibiting a close cognitive and physical interaction with the human user. These are rigid robotic exoskeletal structures that typically operate alongside human limbs. Scientific and technological work on exoskeletons began in the early 1960s but have only recently been applied to rehabilitation and functional substitution in patients suffering from motor disorders. Key topics for further development of exoskeletons in rehabilitation scenarios include the need for robust human-robot multimodal cognitive interaction, safe and dependable physical interaction, true wearability and portability, and user aspects such as acceptance and usability. This discussion provides an overview of these aspects and draws conclusions regarding potential future research directions in robotic exoskeletons.


Beware of Bone Marrow: Incidental Detection and Primary Diagnosis of Solid Tumours in Bone Marrow Aspiration and Biopsies; A Study of 22 Cases.
Introduction: First detection of any solid tumour as metastatic deposits in bone marrow directs clinicians to start searching for the primary tumour. Detection of bone marrow metastasis determines the stage of the malignancy, prognosis, mode of treatment, chemotherapeutic response and follow-up in case of relapse. The aim of the current study was to analyse the clinico-haematological presentation and morphological pattern of infiltration of solid tumours detected first as metastatic deposits on bone marrow examination. Three-year retrospective analysis of MGG-stained bone marrow aspiration smears and touch imprints of the bone marrow biopsy and Hematoxylin and Eosin (H&E) stained histopathological sections of biopsies was performed at the Department of Pathology at a tertiary care institute (January 2014 to December 2016). The morphological pattern of metastatic deposits and haematological profiles of the patients were analysed. Exclusion criterion was the presence of hematolymphoid malignancies. In 22 cases, bone marrow was the first site of detection of metastasis. The age of the patients ranged from 3 years and 10 months to 82 years, with equal gender predilection. Overall, 16 cases had cytopenias, 9 cases each had leucocytosis and leukoerythroblastic presentation. The metastasis was from Ewing's sarcoma, prostate carcinoma, gastric adenocarcinoma invasive duct carcinoma breast, gallbladder carcinoma, lacrimal duct carcinoma and invasive papillary urothelial carcinoma. Bone marrow examination is a cheap and reliable investigation to detect metastasis in an unsuspecting case. Bilateral trephine biopsies are recommended to increase the efficacy of detecting bone marrow metastasis.


BCL6 repression of EP300 in human diffuse large B cell lymphoma cells provides a basis for rational combinatorial therapy.
B cell lymphoma 6 (BCL6), which encodes a transcriptional repressor, is a critical oncogene in diffuse large B cell lymphomas (DLBCLs). Although a retro-inverted BCL6 peptide inhibitor (RI-BPI) was recently shown to potently kill DLBCL cells, the underlying mechanisms remain unclear. Here, we show that RI-BPI induces a particular gene expression signature in human DLBCL cell lines that included genes associated with the actions of histone deacetylase (HDAC) and Hsp90 inhibitors. BCL6 directly repressed the expression of p300 lysine acetyltransferase (EP300) and its cofactor HLA-B-associated transcript 3 (BAT3). RI-BPI induced expression of p300 and BAT3, resulting in acetylation of p300 targets including p53 and Hsp90. Induction of p300 and BAT3 was required for the antilymphoma effects of RI-BPI, since specific blockade of either protein rescued human DLBCL cell lines from the BCL6 inhibitor. Consistent with this, combination of RI-BPI with either an HDAC inhibitor (HDI) or an Hsp90 inhibitor potently suppressed or even eradicated established human DLBCL xenografts in mice. Furthermore, HDAC and Hsp90 inhibitors independently enhanced RI-BPI killing of primary human DLBCL cells in vitro. We also show that p300-inactivating mutations occur naturally in human DLBCL patients and may confer resistance to BCL6 inhibitors. Thus, BCL6 repression of EP300 provides a basis for rational targeted combinatorial therapy for patients with DLBCL.


Mitochondrial and Clearance Impairment in p.D620N VPS35 Patient-Derived Neurons.
VPS35 is part of the retromer complex and is responsible for the trafficking and recycling of proteins implicated in autophagy and lysosomal degradation, but also takes part in the degradation of mitochondrial proteins via mitochondria-derived vesicles. The p.D620N mutation of VPS35 causes an autosomal-dominant form of Parkinson's disease (PD), clinically representing typical PD. Most of the studies on p.D620N VPS35 were performed on human tumor cell lines, rodent models overexpressing mutant VPS35, or in patient-derived fibroblasts. Here, based on identified target proteins, we investigated the implication of mutant VPS35 in autophagy, lysosomal degradation, and mitochondrial function in induced pluripotent stem cell-derived neurons from a patient harboring the p.D620N mutation. We reprogrammed fibroblasts from a PD patient carrying the p.D620N mutation in the VPS35 gene and from two healthy donors in induced pluripotent stem cells. These were subsequently differentiated into neuronal precursor cells to finally generate midbrain dopaminergic neurons. We observed a decreased autophagic flux and lysosomal mass associated with an accumulation of α-synuclein in patient-derived neurons compared to controls. Moreover, patient-derived neurons presented a mitochondrial dysfunction with decreased membrane potential, impaired mitochondrial respiration, and increased production of reactive oxygen species associated with a defect in mitochondrial quality control via mitophagy. We describe for the first time the impact of the p.D620N VPS35 mutation on autophago-lysosome pathway and mitochondrial function in stem cell-derived neurons from an affected p.D620N carrier and define neuronal phenotypes for future pharmacological interventions. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.


Can children aged 12 years or more refuse life-saving treatment without consent or assistance from anyone else?
The question of whether a child aged 12 years or more who is sufficiently mature and has the necessary mental capacity may refuse to consent to life-saving treatment without consent from a parent, guardian or caregiver or without the assistance of a parent or guardian is governed by the Constitution, the Children's Act, the National Health Act and the common law. The best interests of the child are paramount, and should the child unreasonably refuse to consent to life-saving treatment, the Minister of Social Development may give consent for such treatment in terms of the Children's Act. Otherwise, should a parent, guardian, caregiver or healthcare provider believe that such a refusal is not in the best interests of the child, he or she may approach the High Court for an order to provide such treatment.


Genetics of reproductive isolation in the Drosophila simulans clade: DNA marker-assisted mapping and characterization of a hybrid-male sterility gene, Odysseus (Ods).
In this study, we address the question of whether there exist major genes that cause complete male sterility in the interspecific hybrids of Drosophila and, if they do, how these genes may be characterized at the molecular level. Our approach is to introgress small segments of the X chromosome from Drosophila mauritiana (or Drosophila sechellia) into Drosophila simulans by repeated backcrosses for more than 20 generations. The introgressions are monitored by both visible mutations and a series of DNA markers. We compare the extent of introgressions that cause male sterility with those that do not. If a major sterility factor exists, there should be a sharp boundary between these two classes of introgressions and their breakpoints should demarcate such a gene. Furthermore, if male sterility is the only major fitness effect associated with the introgression, recombination analysis should yield a pattern predicted by the classical three-point cross. Both the genetic and molecular analyses suggest the presence of a major sterility factor from D. mauritiana, which we named Odysseus (Ods), in the cytological interval of 16D. We thus formalize three criteria for inferring the existence of a major gene within an introgression: (1) complete penetrance of sterility, (2) complementarity in recombination analysis, and (3) physical demarcation. Introgressions of Ods from D. sechellia do not cause sterility. Twenty-two introgressions in our collection have breakpoints in this interval of about 500 kb, making it possible to delineate Ods more precisely for molecular identification. The recombination analysis also reveals the complexity of the introgressed segments--even relatively short ones may contain a second male sterility factor and partial viability genes and may also interfere with crossovers. The spermatogenic defects associated with Ods and/or a second factor were characterized by phase-contrast microscopy.


Chondritic meteorite fragments associated with the Permian-Triassic boundary in Antarctica.
Multiple chondritic meteorite fragments have been found in two sedimentary rock samples from an end-Permian bed at Graphite Peak in Antarctica. The Ni/Fe, Co/Ni, and P/Fe ratios in metal grains; the Fe/Mg and Mn/Fe ratios in olivine and pyroxene; and the chemistry of Fe-, Ni-, P-, and S-bearing oxide in the meteorite fragments are typical of CM-type chondritic meteorites. In one sample, the meteoritic fragments are accompanied by more abundant discrete metal grains, which are also found in an end-Permian bed at Meishan, southern China. We discuss the implications of this finding for a suggested global impact event at the Permian-Triassic boundary.


Surgical removal of visceral fat reverses hepatic insulin resistance.
We directly examined whether visceral fat (VF) modulates hepatic insulin action by randomizing moderately obese (body wt approximately 400 g) Sprague-Dawley rats to either surgical removal of epididymal and perinephric fat pads (VF-; n = 9) or a sham operation (VF+; n = 11). Three weeks later, total VF was fourfold increased (8.5 +/- 1.2 vs. 2.1 +/- 0.3 g, P < 0.001) in the VF+ compared with the VF- group, but whole-body fat mass (determined using 3H2O) was not significantly different. The rates of insulin infusion required to maintain plasma glucose levels and basal hepatic glucose production in the presence of hepatic-pancreatic clamp were markedly decreased in VF- compared with VF+ rats (0.57 +/- 0.02 vs. 1.22 +/- 0.19 mU x kg(-1) x min(-1), P < 0.001). Similarly, plasma insulin levels were more than twofold higher in the VF+ group (P < 0.001). The heightened hepatic insulin sensitivity is supported by the decrease in gene expression of both glucose-6-phosphatase and PEPCK and by physiological hyperinsulinemia in VF- but not VF+ rats. The improvement in hepatic insulin sensitivity in VF- rats was also supported by a approximately 70% decrease in the plasma levels of insulin-like growth factor binding protein-1, a marker of insulin's transcription regulation in the liver. The removal of VF pads also resulted in marked decreases in the gene expression of tumor necrosis factor-alpha (by 72%) and leptin (by 60%) in subcutaneous fat. We conclude that visceral fat is a potent modulator of insulin action on hepatic glucose production and gene expression.


[Surveillance and active search of suspected cases of hemorrhagic dengue in Ribeirão Preto, São Paulo].
A clinical-epidemiological case study was carried out to evaluate a surveillance and active search system for suspect cases of dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS) during a dengue epidemic in the Ribeirão Preto municipality, State of São Paulo, Brazil, between November 1990 and March 199. This was the first dengue epidemic ever recorded in this region. Although dengue is a growing public health problem in Brazil, and DHF/DSS has been reported to be evolving in the Americas, health officials have shown a passive attitude towards the disease, partly due to lack of experience. Reporting dengue occurrences, both of isolated cases and of epidemics, is essential to reduce mortality. The data analyzed were collected through the official epidemiological surveillance system during the 1990-1991 epidemic. Out of 2,521 confirmed cases of dengue, 34 cases of febrile acute illness with hemorrhagic manifestations were identified as possible cases of DHF/DSS, as well as two deaths associated to dengue. From these 36 cases, 12 cases were confirmed by laboratory exams as dengue with hemorrhagic manifestations. Examinations of clinical and laboratory data, and results of the autopsies suggested that the two deaths were cases of primary DHF/DSS. The difficulty of the health system in establishing the clinical suspicion of DHF/DSS was confirmed in the study. This resulted in delayed and inadequate clinical procedure. The present study also confirmed the need for a permanent active epidemiological surveillance system for the early identification of DHF/DSS suspect cases thus enabling quick and adequate control actions.


Diaryl-substituted norbornadienes with red-shifted absorption for molecular solar thermal energy storage.
Red-shifting the absorption of norbornadienes (NBDs), into the visible region, enables the photo-isomerization of NBDs to quadricyclanes (QCs) to be driven by sunlight. This is necessary in order to utilize the NBD-QC system for molecular solar thermal (MOST) energy storage. Reported here is a study on five diaryl-substituted norbornadienes. The introduced aryl-groups induce a significant red-shift of the UV/vis absorption spectrum of the norbornadienes, and device experiments using a solar-simulator set-up demonstrate the potential use of these compounds for MOST energy storage.


Sleepiness is a signal to go to bed: data and model simulations.
Assess the validity of a subjective measure of sleepiness as an indicator of sleep drive by quantifying associations between intraindividual variation in evening sleepiness and bedtime, sleep duration, and next morning and subsequent evening sleepiness, in young adults. Sleep timing and sleepiness were assessed in 19 students in late autumn and late spring on a total of 771 days. Karolinska Sleepiness Scales (KSS) were completed at half-hourly intervals at fixed clock times starting 4 h prior to participants' habitual bedtime, and in the morning. Associations between sleepiness and sleep timing were evaluated by mixed model and nonparametric approaches and simulated with a mathematical model for the homeostatic and circadian regulation of sleepiness. Intraindividual variation in evening sleepiness was very large, covering four or five points on the 9-point KSS scale, and was significantly associated with subsequent sleep timing. On average, a one point higher KSS value was followed by 20 min earlier bedtime, which led to 11 min longer sleep, which correlated with lower sleepiness next morning and the following evening. Associations between sleepiness and sleep timing were stronger in early compared to late sleepers. Model simulations indicated that the directions of associations between sleepiness and sleep timing are in accordance with their homeostatic and circadian regulation, even though much of the variance in evening sleepiness and details of its time course remain unexplained by the model. Subjective sleepiness is a valid indicator of the drive for sleep which, if acted upon, can reduce insufficient sleep.


Epidemiology and clinical characteristics of bullous congenital ichthyosiform erythroderma (keratinolytic ichthyosis) in Japan: results from a nationwide survey.
Detailed nationwide surveys of the epidemiologic and clinical characteristics of bullous congenital ichthyosiform erythroderma (BCIE) (novel synonym: keratinolytic ichthyosis) in a large population have not been performed previously to our knowledge. We sought to estimate the number of patients with BCIE who visited dermatology departments in Japan in 2002 and to clarify the clinical and epidemiologic features of the disease. A nationwide mail survey was sent to dermatology departments and consisted of an initial survey to estimate the number of individuals with BCIE and a second survey to obtain data on the clinical characteristics of these patients. The total number of patients with BCIE in Japan was estimated to be 55 (95% confidence interval, 35-75). Clinical data were able to be collected from 28 cases. Clinical manifestations included rash in 27 cases (96.4%), erythroderma in 19 cases (67.9%), and generalized blistering in 15 cases (57.7%). Approximately 75% of patients younger than 20 years showed generalized blistering. Hystrixlike scales were present in 8 female patients (57.1%), whereas large scales were present in 8 male patients (57.1%). Among the 19 patients for whom histopathological information was available, 17 (89.5%) showed granular degeneration. Patients with BCIE who have few subjective symptoms may not have visited a dermatology department, potentially resulting in an underestimation of the number of patients with BCIE. Important epidemiologic and clinical information on characteristics of BCIE in Japan was obtained, including an estimate of the total number of patients with BCIE in Japan.


Probing the Strength of Infants' Preference for Helpers over Hinderers: Two Replication Attempts of Hamlin and Wynn (2011).
Several studies indicate that infants prefer individuals who act prosocially over those who act antisocially toward unrelated third parties. In the present study, we focused on a paradigm published by Kiley Hamlin and Karen Wynn in 2011. In this study, infants were habituated to a live puppet show in which a protagonist tried to open a box to retrieve a toy placed inside. The protagonist was either helped by a second puppet (the "Helper"), or hindered by a third puppet (the "Hinderer"). At test, infants were presented with the Helper and the Hinderer, and encouraged to reach for one of them. In the original study, 75% of 9-month-olds selected the Helper, arguably demonstrating a preference for prosocial over antisocial individuals. We conducted two studies with the aim of replicating this result. Each attempt was performed by a different group of experimenters. Study 1 followed the methods of the published study as faithfully as possible. Study 2 introduced slight modifications to the stimuli and the procedure following the guidelines generously provided by Kiley Hamlin and her collaborators. Yet, in our replication attempts, 9-month-olds' preference for helpers over hinderers did not differ significantly from chance (62.5% and 50%, respectively, in Studies 1 and 2). Two types of factors could explain why our results differed from those of Hamlin and Wynn: minor methodological dissimilarities (in procedure, materials, or the population tested), or the effect size being smaller than originally assumed. We conclude that fine methodological details that are crucial to infants' success in this task need to be identified to ensure the replicability of the original result.


Resolution of polyneuropathy in a hypothyroid dog following thyroid supplementation.
An 8 yr old male golden retriever was evaluated because of chronic, progressive, multiple neurologic signs. Physical examination showed marked obesity and facial swelling with a "tragic facial expression." Neurologic evaluation revealed the dog had multiple cranial nerve deficits and lower motor neuron signs in the pelvic limbs. Serum biochemical analysis and thyroid function tests were consistent with hypothyroidism. A biopsy from the common peroneal nerve revealed a loss of myelinated fibers, inappropriately thin myelinated fibers, and resolving subperineurial edema. The diagnosis of polyneuropathy associated with hypothyroidism was made. Levothyroxine therapy was initiated. Response to levothyroxine treatment was slow, with most neurologic abnormalities persisting for >6 wk. However, the dog made a full neurologic recovery within 6 mo. Although the occurrence of polyneuropathy in dogs resulting from hypothyroidism has been controversial, the study authors demonstrated that hypothyroid polyneuropathy can occur in dogs as documented in humans. This is the first report describing long-term follow-up information together with detailed pathological features of hypothyroid polyneuropathy in a dog. In hypothyroid polyneuropathy, the response to thyroid replacement may be slow, but a recovery can be expected if treatment is initiated before peripheral nerve fiber loss becomes severe.


Historical origins and genetic diversity of wine grapes.
The genomic resources that are available to the grapevine research community have increased enormously during the past five years, in parallel with a renewed interest in grapevine (Vitis vinifera L.) germplasm resources and analysis of genetic diversity in grapes. Genetic variation, either natural or induced, is invaluable for crop improvement and understanding gene function, and the same is true for the grapevine. The history and vineyard cultural practices have largely determined the genetic diversity that exists today in grapevines. In this article, we provide a synopsis of what is known about the origin and genetics of grapes and how molecular genetics is helping us understand more about this plant: its evolution, historical development, genetic diversity and potential for genetic improvement.


How do socio-demographic and clinical factors interact with adherence attitude profiles in schizophrenia? A cluster-analytical approach.
Knowledge regarding socio-demographic and clinical risk factors of medication nonadherence does not always help in addressing adherence in individual patients. Classifying patients according to subjective adherence influencing factors may aid practitioners in choosing adequate strategies for improving medication adherence. A total of 171 outpatients with schizophrenia and schizoaffective disorder were classified according to factors influencing their medication adherence assessed using the Rating of Medication Influences Scale. Additionally, psychotic symptoms, depression, and insight, also known to influence pharmacological treatment motivation, were assessed. A cluster analysis yielded 3 groups that were distinguished both by the relative ranking of adherence influences and by specific associations with risk factors of nonadherence. For the "Interpersonal, Future-oriented Group" (n=59, 35% of the sample), interpersonal factors (positive therapeutic relationship, positive attitudes of significant others towards medication), immediate positive consequences of the medication intake (daily benefits, no perceived pressure to take medication), and avoiding future negative consequences of non-compliance, such as relapse and re-hospitalization, were essential for adherence. The "Autonomous, Future-oriented Group" (n=69, 40% of the sample) appraised interpersonal factors as being less important as compared to the other groups. This group exhibited significantly fewer depressive symptoms than the first group and had significantly more stable partnerships as compared to the other groups. The "Autonomous, Present-oriented Group" (n=43, 25% of the sample) was mainly motivated by immediate positive consequences and displayed higher levels of cognitive disorganization and negative symptoms than the second group, as well as the lowest level of insight of all groups. Treatment strategies addressing adherence enhancement in schizophrenia may profit by considering both the patient's subjective adherence attitude profile as well as the specific pattern of risk factors for nonadherence including depression, lack of insight, negative syndrome, cognitive disorganization and socio-demographic factors, which are differentially associated with each adherence attitude profile.


Predictors of mental illness stigma and attitudes among college students: using vignettes from a campus common reading program.
Research has demonstrated that stigmatizing mentally ill individuals is prevalent and often results in lack of adherence to or avoidance of treatment. The present study sought to examine attitudes of college students regarding mental illness as part of a campus-wide "common readings" program. The book selected was a non-fiction account of a young girl with mental illness and the program was developed to initiate dialogue about young people with mental problems. Faculty from multiple disciplines collaborated on the project. A sample of 309 students completed a web-based survey after reading a vignette about an adolescent girl with mental illness. The vignette description was based on a character in the book selected in the program. The instruments measured attribution of stigma, social distance, and familiarity with people who have mental illness. Results demonstrated that younger students and those who are less familiar with mental illness were more likely to stigmatize and maintain social distance from those who are mentally ill. Awareness of the study findings can assist health professionals and mental health workers to identify interventions that can decrease stigma. Psychiatric mental health nurses are well positioned to lead the education effort aimed at reducing stigmatizing attitudes among the public.


Elevated cardiac troponin I and functional recovery and disability in patients after aneurysmal subarachnoid hemorrhage.
Patients with aneurysmal subarachnoid hemorrhage experience myocardial injury at the time of rupture, but its effect on functional recovery and disability is unclear. To describe the prevalence of myocardial injury, as indicated by high serum levels of cardiac troponin I (≥0.3 ng/mL), within the first 5 days after aneurysmal subarachnoid hemorrhage and the effect of the injury on 3-month functional recovery and disability. In a prospective longitudinal study, 239 patients with Hunt/Hess grade 3 or greater and/or Fisher grade 2 or greater at admission had serum level of troponin I measured on days 0 to 5. Patients were interviewed at 3 months to evaluate functional recovery (Glasgow Outcome Scale) and functional disability (Modified Rankin Scale). Statistics included χ² analysis, t tests, and binary logistic regression. Troponin values were elevated in 33.5% of the patients, and few patients in either group had a history of coronary artery disease (7.4% with troponin levels ≥0.3 ng/mL vs 2.7% with levels <0.3 ng/mL, P = .12). Higher troponin levels were significantly related to age and Hunt/Hess and Fisher grades, but not race, and were significantly associated with poorer functional recovery (P < .001) and more functional disability (P < .001). Even after controls for age, race, and more severe Hunt/Hess grades, higher levels remained a significant predictor of poorer functional recovery (P = .04) and disability (P = .01). CONCLUSION Elevated levels of cardiac troponin I after aneurysmal subarachnoid hemorrhage are common in patients with no cardiac history, are associated with severity of the hemorrhage, and are independently predictive of poorer functional recovery and increased disability.


Metaphase chromosome structure. Involvement of topoisomerase II.
SCI is a prominent, 170,000 Mr, non-histone protein of HeLa metaphase chromosomes. This protein binds DNA and was previously identified as one of the major structural components of the residual scaffold structure obtained by differential protein extraction from isolated chromosomes. The metaphase scaffold maintains chromosomal DNA in an organized, looped conformation. We have prepared a polyclonal antibody against the SC1 protein. Immunolocalization studies by both fluorescence and electron microscopy allowed identification of the scaffold structure in gently expanded chromosomes. The micrographs show an immunopositive reaction going through the kinetochore along a central, axial region that extends the length of each chromatid. Some micrographs of histone-depleted chromosomes provide evidence of the substructural organization of the scaffold; the scaffold appears to consist of an assembly of foci, which in places form a zig-zag or coiled arrangement. We present several lines of evidence that establish the identity of SC1 as topoisomerase II. Considering the enzymic nature of this protein, it is remarkable that it represents 1% to 2% of the total mitotic chromosomal protein. About 60% to 80% of topoisomerase II partitions into the scaffold structure as prepared from isolated chromosomes, and we find approximately three copies per average 70,000-base loop. This supports the proposed structural role of the scaffold in the organization of the mitotic chromosome. The dual enzymic and apparent structural function of topoisomerase II (SC1) and its location at or near the base of chromatin loops allows speculation as to its involvement in the long-range control of chromatin structure.


Determinants of never having tested for HIV among MSM in the Netherlands.
Men who have sex with men (MSM) who are unaware of their HIV infection are more likely to infect others, and unable to receive treatment. Therefore, we aimed to identify the proportion and characteristics of Dutch MSM who never tested for HIV. In 2010, the European MSM Internet Survey (EMIS) recruited 174,209 men from 38 countries through an anonymous online questionnaire in 25 languages. We analysed data from participants living in the Netherlands (N=3787). The outcome we investigated was having never (lifetime) been tested for HIV. A total of 770 MSM (20.4%) had never been tested for HIV. In multivariate regression analyses, not being from Amsterdam (adjusted OR, aOR 1.54, CI 1.17 to 2.03), with low education (aOR 1.28, CI 1.04 to 1.57) and low knowledge on HIV-testing (aOR 2.23, CI 1.37 to 3.64) were significantly associated with never having tested. Lower sexual risk (including having fewer sexual partners (aOR 2.19, CI 1.57 to 3.04) and no anal intercourse (aOR 5.99, CI 3.04 to 11.77)), and less social engagement (including being less out (aOR 1.93, CI 1.55 to 2.40)) were also associated with having never been tested. Additionally, 36.1% of MSM who never tested for HIV reported high-risk sexual behaviour that may have put them at HIV risk. MSM make their own risk assessments that inform their choices about HIV-testing. Nevertheless, MSM who were never tested may have been at risk for HIV, and remain important to target for HIV interventions.


Prehospital Administration of Antibiotic Prophylaxis for Open Combat Wounds in Afghanistan: 2013-2014.
Military operations place injured Servicemembers at high risk for open wounds. Austere environments and initial wound contamination increase the risk for infection. Wound infections continue to cause significant morbidity among injured Servicemembers. Limited evidence suggests that early antibiotic therapy for open wounds reduces infection rates. We obtained data from the Prehospital Trauma Registry (PHTR) from January 2013 through September 2014. This database includes data from Tactical Combat Casualty Care (TCCC) cards, Department of Defense 1380 forms, and after-action reports to provide near-real-time feedback to units on prehospital medical care. We evaluated whether patients with open wounds received antibiotics in accordance with TCCC guidelines. Low adherence was defined at less than 80%. In this data set, overall, prefixed facility providers administered antibiotics to 54.0% of patients with an open combat wound. Of the antibiotics given, 11.1% were within TCCC guidelines. The relatively low administration and adherence rates persisted across subgroup analyses. Overall, relatively few patients with open combat wounds receive antibiotic administration as recommended by TCCC guidelines. In the group that received antibiotics, few received the specific antibiotics recommended by TCCC guidelines. The development of strategies to improve adherence to these TCCC recommendations is a research priority.


Is parenting a determinant of adolescent mental health? - A population based study in South India.
The transitional phase encompassing the physiological and psychological changes during our lifespan is termed as adolescence. Adolescents get mislead to substance use, violence related activities, dating relationships, unhealthy lifestyle. Minimal studies are conducted in India to identify the parenting factors that affect an adolescent's mind. The aim of our study was to explore the role of parenting and social surroundings on - adolescent's mental health and involvement in violence related activities. Cross sectional study design was adopted. Semi structured questionnaire was used. Data obtained was entered and analyzed using SPSS 15. Proportions were used to report the findings. Chi-square test was used to find associations between mental health issues, involvement in violence related activities and Interpersonal Relationship (IPR) Status. Multiple logistic regressions were done to identify independent predictors of mental health. A total of 1770 adolescents participated. Proportion of adolescents with good IPR with parents reported to be having a better mental health status and low involvement in violent related activities. Schools also displayed similar effects. Neighborhood, peers did not display any significant effect on adolescent's mental health. Most significant predictor for adolescent mental health was IPR with parents and at school. The study highlights the need of a cordial environment at places which does influence the adolescent's mental health. Interventions enhancing the relationship status of adolescents with parents, at school must be carried out to observe the change in adolescent behavior.


Relapse of depression after rapid depletion of tryptophan.
Major depression is a common disorder but the pathophysiology is poorly understood. Current hypotheses implicate deficient function of brain serotonin pathways because drugs that selectively increase brain serotonin activity are effective antidepressants. However, there is no direct evidence that lowered serotonin function causes major depression. We aimed to assess whether lowering of brain serotonin activity by depletion of its amino acid precursor, tryptophan, could provoke a short-term relapse of clinically significant symptoms in women vulnerable to major depressive disorder. We studied 15 women who had suffered recurrent episodes of major depression but had recovered and were no longer on drug treatment. Patients received two amino acid mixtures in a double-blind crossover design. One of the mixtures was nutritionally balanced and contained tryptophan and the other was identical except it contained no tryptophan. Participants were scored on the Hamilton rating scale for depression (HAMD) before and 7 h after drinking each mixture. They also completed hourly self-rated measures of mood during this period. Blood samples were also taken at baseline and 7 h for measurement of plasma tryptophan. The tryptophan-free mixture produced a 75% reduction in plasma tryptophan concentration. After drinking the tryptophan-free mixture, ten of the 15 women experienced temporary but clinically significant depressive symptoms. The mean difference in total HAMD scores (7 h minus baseline) were significantly higher after the tryptophan-free mixture than after the nutritionally balanced mixture (7.3 vs 0.15 [95% CI 4.5-9.9]; p < 0.001). No changes in mood were seen after taking the nutritionally balanced mixture. We conclude that rapid lowering of brain serotonin function can precipitate clinical depressive symptoms in well, untreated individuals who are vulnerable to major depressive disorder. The findings support a key role for deficient serotonin function in the aetiology of depression.


Aliskiren combined with losartan in type 2 diabetes and nephropathy.
Diabetic nephropathy is the leading cause of end-stage renal disease in developed countries. We evaluated the renoprotective effects of dual blockade of the renin-angiotensin-aldosterone system by adding treatment with aliskiren, an oral direct renin inhibitor, to treatment with the maximal recommended dose of losartan (100 mg daily) and optimal antihypertensive therapy in patients who had hypertension and type 2 diabetes with nephropathy. We enrolled 599 patients in this multinational, randomized, double-blind study. After a 3-month, open-label, run-in period during which patients received 100 mg of losartan daily, patients were randomly assigned to receive 6 months of treatment with aliskiren (150 mg daily for 3 months, followed by an increase in dosage to 300 mg daily for another 3 months) or placebo, in addition to losartan. The primary outcome was a reduction in the ratio of albumin to creatinine, as measured in an early-morning urine sample, at 6 months. The baseline characteristics of the two groups were similar. Treatment with 300 mg of aliskiren daily, as compared with placebo, reduced the mean urinary albumin-to-creatinine ratio by 20% (95% confidence interval, 9 to 30; P<0.001), with a reduction of 50% or more in 24.7% of the patients who received aliskiren as compared with 12.5% of those who received placebo (P<0.001). A small difference in blood pressure was seen between the treatment groups by the end of the study period (systolic, 2 mm Hg lower [P=0.07] and diastolic, 1 mm Hg lower [P=0.08] in the aliskiren group). The total numbers of adverse and serious adverse events were similar in the groups. Aliskiren may have renoprotective effects that are independent of its blood-pressure-lowering effect in patients with hypertension, type 2 diabetes, and nephropathy who are receiving the recommended renoprotective treatment. (ClinicalTrials.gov number, NCT00097955 [ClinicalTrials.gov].).


Molecular remodeling of tip links underlies mechanosensory regeneration in auditory hair cells.
Sound detection by inner ear hair cells requires tip links that interconnect mechanosensory stereocilia and convey force to yet unidentified transduction channels. Current models postulate a static composition of the tip link, with protocadherin 15 (PCDH15) at the lower and cadherin 23 (CDH23) at the upper end of the link. In terminally differentiated mammalian auditory hair cells, tip links are subjected to sound-induced forces throughout an organism's life. Although hair cells can regenerate disrupted tip links and restore hearing, the molecular details of this process are unknown. We developed a novel implementation of backscatter electron scanning microscopy to visualize simultaneously immuno-gold particles and stereocilia links, both of only a few nanometers in diameter. We show that functional, mechanotransduction-mediating tip links have at least two molecular compositions, containing either PCDH15/CDH23 or PCDH15/PCDH15. During regeneration, shorter tip links containing nearly equal amounts of PCDH15 at both ends appear first. Whole-cell patch-clamp recordings demonstrate that these transient PCDH15/PCDH15 links mediate mechanotransduction currents of normal amplitude but abnormal Ca(2+)-dependent decay (adaptation). The mature PCDH15/CDH23 tip link composition is re-established later, concomitant with complete recovery of adaptation. Thus, our findings provide a molecular mechanism for regeneration and maintenance of mechanosensory function in postmitotic auditory hair cells and could help identify elusive components of the mechanotransduction machinery.


The nutrition transition: new trends in the global diet.
Analyses of economic and food availability data for 1962-1994 reveal a major shift in the structure of the global diet marked by an uncoupling of the classic relationship between incomes and fat intakes. Global availability of cheap vegetable oils and fats has resulted in greatly increased fat consumption among low-income nations. Consequently, the nutrition transition now occurs at lower levels of the gross national product than previously, and is accelerated further by high urbanization rates. Data from Asian nations, where diet structure is rapidly changing, suggest that diets higher in fats and sweeteners are also more diverse and more varied. Given that preferences for palatable diets are a universal human trait, fat consumption may be governed not by physiological mechanisms but by the amount of fat available in the food supply. Whereas economic development has led to improved food security and better health, adverse health effects of the nutrition transition include growing rates of childhood obesity. The implications of these trends are explored.


Survival of patients with alcoholic and cryptogenic cirrhosis without liver transplantation: a single center retrospective study.
There is no recent data addressing the long term survival of cirrhosis patients without transplantation, but with the availability of optimal pharmacological and endoscopic therapies. We compared the long term transplant free survival of alcoholic (AC) and cryptogenic (CC) cirrhosis patients in a setting where liver transplantation was, until very recently, not available. AC and CC patient details were extracted from our database, maintained since 1995. For those who had not attended clinics within the past 4 weeks, the patient or families were contacted to obtain survival status. If deceased, cause of death was ascertained from death certificates and patient records. Survival was compared using Kaplan-Meier curves. Complete details were available in 549/651 (84.3%) patients (AC 306, CC 243). Mean follow up duration (SD) (months) was 29.9 (32.6). 82/96 deaths (85.4%) among AC and 80/94 deaths (85.1%) among CC were liver related. Multivariate analysis showed age at diagnosis and Child's class predicted overall survival among all groups. The median survival in Child's class B and C were 53.5 and 25.3 months respectively. Survival was similar among AC and CC. Among AC survival was improved by abstinence [HR = 0.63 (95% CI: 0.40-1.00)] and was worse with diabetes [HR=1.59 (95% CI: 1.02- 2.48)] irrespective of alcohol status. The overall survival of AC was similar to CC. Death in both groups were predominantly liver related, and was predicated by age at diagnosis and Child class. Among AC, presence of diabetes and non-abstinence from alcohol were independent predictors for poor survival.


A regional cohort study of the treatment of critically ill children with bronchiolitis.
To describe the treatment practices in critically ill children with RSV bronchiolitis across four regional PICUs in the northeastern United States, and to determine the factors associated with increased ICU length of stay in this population. We conducted a retrospective cohort study of children who were admitted with RSV bronchiolitis between July 2009 and July 2011 to the PICUs of Connecticut Children's Medical Center, Yale-New Haven Children's Hospital, Maria Fareri Children's Hospital, and Baystate Children's Hospital. Data were collected regarding clinical characteristics and intensive care course among these hospitals. During the study period, 323 children were admitted to one of the four ICUs with RSV bronchiolitis. Despite similar mortality risk scores among ICUs, there was considerable variation in the use of therapies, particularly intubation and mechanical ventilation, in which there was greater than a 3.5-fold increased risk of intubation between sites with the highest and lowest frequency of intubation (odds ratio: 3.8; 95% confidence interval: 2.2-6.4). Albuterol was the most commonly used respiratory treatment, followed by chest physiotherapy, high-flow nasal cannula, and hypertonic saline. Longer stays in the ICU were associated with more frequent use of therapies, specifically invasive mechanical ventilation, inhaled corticosteroids, intrapulmonary percussive ventilation, and chest physiotherapy. Even within a close geographic region, there is significant variation in the treatment provided to critically ill children with RSV bronchiolitis. None of these treatments were associated with shorter durations of hospitalization in this population and some, such as mechanical ventilation, were associated with longer ICU lengths of stay.


Cyclin-Dependent Kinase 5 Regulates Dendritic Spine Formation and Maintenance of Cortical Neuron in the Mouse Brain.
Cyclin-dependent kinase 5 (Cdk5) activity is dependent on its association with 1 of 2 neuron-specific activators, p35 or p39. Cdk5 and its activators play an important role in brain development as well as higher functions like synaptic plasticity, learning, and memory. Reduction in p35 was reported in postmortem schizophrenia brain, in which reduced dendritic spine density was observed. Previous in vitro experiments have shown that Cdk5 is involved in dendritic spine formation, although in vivo evidence is limited. We examined dendritic spine formation in inducible-p35 conditional knockout (p35 cKO); p39 KO mice. When we deleted the p35 gene either during early postnatal days or at adult stage, we observed reduced spine densities of layer V neurons in the cerebral cortex and CA1 pyramidal neurons in the hippocampus. We further generated CA1-specific p35 conditional knockout (CA1-p35 cKO) mice and also CA1-p35 cKO; p39 KO mice in which have specific deletion of p35 in the CA1 region of hippocampus. We found a greater reduction in spine densities in CA1 pyramidal neurons in CA1-p35 cKO; p39 KO mice than in CA1-p35 cKO mice. These results indicate that dendritic spine formation and neuronal maintenance are dependent on Cdk5 activity.


Thylakoid Membrane Architecture in Synechocystis Depends on CurT, a Homolog of the Granal CURVATURE THYLAKOID1 Proteins.
Photosynthesis occurs in thylakoids, a highly specialized membrane system. In the cyanobacterium Synechocystis sp PCC 6803 (hereafter Synechocystis 6803), the thylakoids are arranged parallel to the plasma membrane and occasionally converge toward it to form biogenesis centers. The initial steps in PSII assembly are thought to take place in these regions, which contain a membrane subcompartment harboring the early assembly factor PratA and are referred to as PratA-defined membranes (PDMs). Loss of CurT, the Synechocystis 6803 homolog of Arabidopsis thaliana grana-shaping proteins of the CURVATURE THYLAKOID1 family, results in disrupted thylakoid organization and the absence of biogenesis centers. As a consequence, PSII is less efficiently assembled and accumulates to only 50% of wild-type levels. CurT induces membrane curvature in vitro and is distributed all over the thylakoids, with local concentrations at biogenesis centers. There it forms a sophisticated tubular network at the cell periphery, as revealed by live-cell imaging. CurT is part of several high molecular mass complexes, and Blue Native/SDS-PAGE and isoelectric focusing demonstrated that different isoforms associate with PDMs and thylakoids. Moreover, CurT deficiency enhances sensitivity to osmotic stress, adding a level of complexity to CurT function. We propose that CurT is crucial for the differentiation of membrane architecture, including the formation of PSII-related biogenesis centers, in Synechocystis 6803.


Apoptosis-inducing factor and caspase-dependent apoptotic pathways triggered by different grape seed extracts on human colon cancer cell line Caco-2.
Consumption of grape seed extract (GSE) is widely marketed as a dietary supplement and is considered safe for human health. Nevertheless, the analytical composition of GSE from different grape cultivars, growing in special agronomic constraints, differs greatly in flavan-3-ols content. The major concern with GSE studies is a lack of availability of uniformly standardised preparations, which raises an important question whether different GSE samples have comparable activity and trigger the same mechanisms of action on a given biological system. Therefore, it is tempting to speculate that GSE, obtained from different cultivars, could exert differentiated anticancer effects. The focus of the present study is to determine the selective biological efficacy of GSE obtained from three different sources on the human colon cancer cell line Caco-2. Irrespective of its source, high doses of GSE induced a significant inhibition on Caco-2 cell growth. Moreover, apoptosis was enhanced through both caspase-dependent and caspase-independent mechanisms, leading to an early apoptosis-inducing factor release and, further, to a dramatic increase in caspase 7 and 3 activity. However, a significant difference in apoptotic rates induced by the three grape sources clearly emerged when treating cancer cells with low and intermediate GSE concentrations (25 and 50 microg/ml).


A novel registration method for retinal images based on local features.
Sometimes it is very hard to automatically detect the bifurcations of vascular network in retinal images so that the general feature based registration methods will fail to register two images. In order to solve this problem, we developed a novel local feature based retinal image registration method. We first detect the corner points instead of bifurcations since corner points are sufficient and uniformly distributed in the overlaps. Second, a novel highly distinctive local feature is extracted around each corner point. These local features are invariant to rotation and contrast, and partially invariant to scaling. Third, a bilateral matching technique is applied to identify the corresponding features between two images. Finally a second order polynomial transformation is used to register two images. Experimental results show that our method is very robust and compute efficient to register retinal images even of very low quality.


Transcriptome profiling of mouse samples using nanopore sequencing of cDNA and RNA molecules.
Our vision of DNA transcription and splicing has changed dramatically with the introduction of short-read sequencing. These high-throughput sequencing technologies promised to unravel the complexity of any transcriptome. Generally gene expression levels are well-captured using these technologies, but there are still remaining caveats due to the limited read length and the fact that RNA molecules had to be reverse transcribed before sequencing. Oxford Nanopore Technologies has recently launched a portable sequencer which offers the possibility of sequencing long reads and most importantly RNA molecules. Here we generated a full mouse transcriptome from brain and liver using the Oxford Nanopore device. As a comparison, we sequenced RNA (RNA-Seq) and cDNA (cDNA-Seq) molecules using both long and short reads technologies and tested the TeloPrime preparation kit, dedicated to the enrichment of full-length transcripts. Using spike-in data, we confirmed that expression levels are efficiently captured by cDNA-Seq using short reads. More importantly, Oxford Nanopore RNA-Seq tends to be more efficient, while cDNA-Seq appears to be more biased. We further show that the cDNA library preparation of the Nanopore protocol induces read truncation for transcripts containing internal runs of T's. This bias is marked for runs of at least 15 T's, but is already detectable for runs of at least 9 T's and therefore concerns more than 20% of expressed transcripts in mouse brain and liver. Finally, we outline that bioinformatics challenges remain ahead for quantifying at the transcript level, especially when reads are not full-length. Accurate quantification of repeat-associated genes such as processed pseudogenes also remains difficult, and we show that current mapping protocols which map reads to the genome largely over-estimate their expression, at the expense of their parent gene.


Antipsychotic medications and stroke in schizophrenia: A case-crossover study.
The association between antipsychotic use and the risk of stroke in schizophrenic patients is controversial. We sought to study the association in a nationwide cohort with schizophrenia. Using a retrospective cohort of patients with schizophrenia (N = 31,976) derived from the Taiwan National Health Insurance Research Database, 802 new-onset cases of stroke were identified within 10 years of follow-up (from 2000 through 2010). We designed a case-crossover study using 14-day windows to explore the risk factors of stroke and the association between antipsychotic drugs and the risk of stroke. We analyzed the risks of individual antipsychotics on various subgroups of stroke including ischemic, hemorrhagic, and other strokes, and the risks based on the antipsychotic receptor-binding profile of each drug. Use of any second-generation antipsychotic was associated with an increased risk of stroke (adjusted risk ratio = 1.45, P = .009) within 14 days while the use of any first-generation antipsychotic was not. Intriguingly, the use of any second-generation antipsychotic was associated with ischemic stroke but not hemorrhagic stroke. The antipsychotic receptor-binding profile analysis showed that the antihistamine 1 receptor was significantly associated with ischemic stroke (adjusted risk ratio = 1.72, P = .037), and the sensitivity analysis based on the 7-day window of exposure validated the association (adjusted risk ratio = 1.87, P = .015). Use of second-generation antipsychotic drugs appeared to be associated with an increased risk of ischemic stroke in the patients studied, possibly mediated by high affinity for histamine-1 receptor blockade. Further research regarding the underlying biological mechanism and drug safety is suggested.


Rapid Telehealth Implementation during the COVID-19 Global Pandemic: A Rapid Review.
The implementation and continued expansion of telehealth services assists a variety of health care organizations in the delivery of care during the current COVID-19 global pandemic. However, limited research has been conducted on recent, rapid telehealth implementation and expansion initiatives regarding facilitators and barriers surrounding the provision of quality patient care. Our rapid review evaluated the literature specific to rapid telehealth implementation during the current COVID-19 pandemic from three research databases between January 2020 and May 2020 and reported using preferred reporting items for systematic reviews and meta-analyses (PRISMA). The results indicate the rapid implementation and enhanced use of telehealth during the COVID-19 pandemic in the United States surrounding the facilitators and barriers to the provision of patient care, which are categorized into three identified themes: (1) descriptive process-oriented implementations, (2) the interpretation and infusion of the CARES Act of 2020 telehealth exemptions related to the relaxation of patient privacy and security (HIPAA) protocols, and (3) the standard of care protocols and experiences addressing organizational liability and the standard of care. While the study limitation of sample size exists (n = 21), an identification of rapid telehealth implementation advancements and challenges during the current pandemic may assist health care organizations in the delivery of ongoing quality care during the COVID-19 pandemic.


Biology of soft tissue wound healing and regeneration--consensus report of Group 1 of the 10th European Workshop on Periodontology.
The scope of this consensus was to review the biological processes of soft tissue wound healing in the oral cavity and to histologically evaluate soft tissue healing in clinical and pre-clinical models. To review the current knowledge regarding the biological processes of soft tissue wound healing at teeth, implants and on the edentulous ridge. Furthermore, to review soft tissue wound healing at these sites, when using barrier membranes, growth and differentiation factors and soft tissue substitutes. Searches of the literature with respect to recessions at teeth and soft tissue deficiencies at implants, augmentation of the area of keratinized tissue and soft tissue volume were conducted. The available evidence was collected, categorized and summarized. Oral mucosal and skin wound healing follow a similar pattern of the four phases of haemostasis, inflammation, proliferation and maturation/matrix remodelling. The soft connective tissue determines the characteristics of the overlaying oral epithelium. Within 7-14 days, epithelial healing of surgical wounds at teeth is completed. Soft tissue healing following surgery at implants requires 6-8 weeks for maturation. The resulting tissue resembles scar tissue. Well-designed pre-clinical studies providing histological data have been reported describing soft tissue wound healing, when using barrier membranes, growth and differentiation factors and soft tissue substitutes. Few controlled clinical studies with low numbers of patients are available for some of the treatments reviewed at teeth. Whereas, histological new attachment has been demonstrated in pre-clinical studies resulting from some of the treatments reviewed, human histological data commonly report a lack of new attachment but rather long junctional epithelial attachment and connective tissue adhesion. Regarding soft tissue healing at implants human data are very scarce. Oral soft tissue healing at teeth, implants and the edentulous ridge follows the same phases as skin wound healing. Histological studies in humans have not reported new attachment formation at teeth for the indications studied. Human histological data of soft tissue wound healing at implants are limited. The use of barriers membranes, growth and differentiation factors and soft tissue substitutes for the treatment of localized gingival/mucosal recessions, insufficient amount of keratinized tissue and insufficient soft tissue volume is at a developing stage.


[Characteristics of catatonia in schizophrenia and mood disorders].
Catatonia is a psychomotor symptom cluster that co-occurs with schizophrenia and with mood disorders. The characterisation and the differentiation of psychomotor symptom clusters can contribute to a more accurate diagnosis and a better understanding of underlying neurobiological processes. To compare epidemiology, clinical presentation and treatment of catatonia in schizophrenia and in mood disorders. We reviewed the literature using PubMed. Catatonia is highly prevalent in both schizophrenia and mood disorders, but is slightly more prevalent in the latter. In spite of a considerable overlap, there are differentiating trends in the catatonic symptom profile of schizophrenia and mood disorders. In both of these disorders catatonia is a marker for increasing severity of the course of the illness. Compared to catatonia in mood disorders, catatonia in schizophrenia has a poorer response to benzodiazepines and ECT. Catatonia in schizophrenia and mood disorders is characterized by a distinctive profile. Comparative research on clinical presentation and neurobiological processes is warranted in order to arrive at a more accurate characterisation of these psychomotor symptom clusters.


Microbial status of apical root canal system of human mandibular first molars with primary apical periodontitis after "one-visit" endodontic treatment.
To assess the in vivo intracanal microbial status of apical root canal system of mesial roots of human mandibular first molars with primary apical periodontitis immediately after one-visit endodontic treatment. The residual intracanal infection was confirmed by correlative light and transmission electron microscopy. Sixteen diseased mesial roots of mandibular first molars were treated endodontically, each in one visit. Mesio-buccal canals were instrumented using stainless steel hand files and mesio-lingual canals with a nickel-titanium rotary system. The canals were irrigated with 5.25% sodium hypochlorite (NaOCl) during the instrumentation procedures, rinsed with 10 mL of 17% ethylenediamine tetraacetic acid (EDTA), and obturated with gutta-percha and zinc oxide eugenol cement. Thereafter, the apical portion of the root of each tooth was removed by flap-surgery. The specimens were fixed, decalcified, subdivided in horizontal plane, embedded in plastic, processed, and evaluated by correlative light and transmission electron microscopy. Fourteen of the 16 endodontically treated teeth revealed residual intracanal infection after instrumentation, antimicrobial irrigation, and obturation. The microbes were located in inaccessible recesses and diverticula of instrumented main canals, the intercanal isthmus, and accessory canals, mostly as biofilms. The results show (1) the anatomical complexity of the root canal system of mandibular first molar roots and (2) the organization of the flora as biofilms in inaccessible areas of the canal system that cannot be removed by contemporary instruments and irrigation alone in one-visit treatment. These findings demonstrate the importance of stringent application of all nonantibiotic chemo-mechanical measures to treat teeth with infected and necrotic root canals so as to disrupt the biofilms and reduce the intraradicular microbial load to the lowest possible level so as to expect a highly favorable long-term prognosis of the root canal treatment.


Exploring the optical properties of Vernier phase yttrium oxyfluoride thin films grown by pulsed liquid injection MOCVD.
In this work, we report on the first successful deposition of Vernier phase yttrium oxyfluoride (V-YOF) thin films on Si (100) wafers using pulsed liquid injection metal organic chemical vapor deposition (PLI-MOCVD). The formation of V-YOF has been confirmed by X-ray diffraction measurements and electron probe microanalysis. The infrared phonon modes of V-YOF thin films and their corresponding optical constants as inferred from spectroscopic ellipsometry are reported here for the first time. The V-YOF thin films are featured by a broad absorption band centering around 370-373 cm-1; their refractive index is located between those of YF3 and Y2O3, and which shows an intimate relationship with the oxygen content in the film. The luminescence properties of Er3+ doped V-YOF thin films are finally examined and compared with that of YF3. Our results highlight that the as-deposited V-YOF thin films by PLI-MOCVD serve as promising candidates as efficient host material for spectral conversion for photovoltaic applications.


Anti-MSP-10 IgG indicates recent exposure to Plasmodium vivax infection in the Peruvian Amazon.
BACKGROUNDSerological tools for the accurate detection of recent malaria exposure are needed to guide and monitor malaria control efforts. IgG responses against Plasmodium vivax and P. falciparum merozoite surface protein-10 (MSP10) were measured as a potential way to identify recent malaria exposure in the Peruvian Amazon.METHODSA field-based study included 470 participants in a longitudinal cohort who completed a comprehensive evaluation: light microscopy and PCR on enrollment, at least 1 monthly follow-up by light microscopy, a second PCR, and serum and dried blood spots for serological analysis at the end of the follow-up. IgG titers against novel mammalian cell-produced recombinant PvMSP10 and PfMSP10 were determined by ELISA.RESULTSDuring the follow-up period, 205 participants were infected, including 171 with P. vivax, 26 with P. falciparum, 6 with infections by both species but at different times, and 2 with mixed infections. Exposure to P. vivax was more accurately identified when serological responses to PvMSP10 were obtained from serum (sensitivity, 58.1%; specificity, 81.8%; AUC: 0.76) than from dried blood spots (sensitivity, 35.2; specificity, 83.5%; AUC: 0.64) (PAUC < 0.001). Sensitivity was highest (serum, 82.9%; dried blood spot, 45.7%) with confirmed P. vivax infections occurring 7-30 days before sample collection; sensitivity decreased significantly in relation to time since last documented infection. PvMSP10 serological data did not show evidence of interspecies cross-reactivity. Anti-PfMSP10 responses poorly discriminated between P. falciparum-exposed and nonexposed individuals (AUC = 0.59; P > 0.05).CONCLUSIONAnti-PvMSP10 IgG indicates recent exposure to P. vivax at the population level in the Amazon region. Serum, not dried blood spots, should be used for such serological tests.FUNDINGCooperative agreement U19AI089681 from the United States Public Health Service, NIH/National Institute of Allergy and Infectious Diseases, as the Amazonian International Center of Excellence in Malaria Research.


Toxic Colors: The Use of Deep Learning for Predicting Toxicity of Compounds Merely from Their Graphic Images.
The majority of computational methods for predicting toxicity of chemicals are typically based on "nonmechanistic" cheminformatics solutions, relying on an arsenal of QSAR descriptors, often vaguely associated with chemical structures, and typically employing "black-box" mathematical algorithms. Nonetheless, such machine learning models, while having lower generalization capacity and interpretability, typically achieve a very high accuracy in predicting various toxicity endpoints, as unambiguously reflected by the results of the recent Tox21 competition. In the current study, we capitalize on the power of modern AI to predict Tox21 benchmark data using merely simple 2D drawings of chemicals, without employing any chemical descriptors. In particular, we have processed rather trivial 2D sketches of molecules with a supervised 2D convolutional neural network (2DConvNet) and demonstrated that the modern image recognition technology results in prediction accuracies comparable to the state-of-the-art cheminformatics tools. Furthermore, the performance of the image-based 2DConvNet model was comparatively evaluated on an external set of compounds from the Prestwick chemical library and resulted in experimental identification of significant and previously unreported antiandrogen potentials for several well-established generic drugs.


Golgi apparatus, GERL, and secretory granule formation within neurons of the hypothalamo-neurohypophysial system of control and hyperosmotically stressed mice.
The vasopressin-producing neurons of the hypothalamo-neurohypophysial system are a particularly good model with which to consider the relationship between the Golgi apparatus nd GERL and their roles in secretory granule production because these neurons increase their synthesis and secretion of vasopressin in response to hyperosmotic stress. Enzyme cytochemical techniques for acid phosphatase (AcPase) and thiamine pyrophosphatase (TPPase) activities were used to distinguish GERL from the Golgi apparatus in cell bodies of the supraoptic nucleus from normal mice, mice hyperosmotically stressed by drinking 2% salt water, and mice allowed to recover for 5-10 d from hyperosmotic stress. In nonincubated preparations of control supraoptic perikarya, immature secretory granules at the trans face of the Golgi apparatus were frequently attached to a narrow, smooth membrane cisterna identified as GERL. Secretory granules were occasionally seen attached to Golgi saccules. TPPase activity was present in one or two of the trans Golgi saccules; AcPase activity appeared in GERL and attached immature secretory granules, rarely in the trans Golgi saccules, and in secondary lysosomes. As a result of hyperosmotic stress, the Golgi apparatus hypertrophied, and secretory granules formed from all Golgi saccules and GERL. Little or no AcPase activity could be demonstrated in GERL, whereas all Golgi saccules and GERL-like cisternae were TPPase positive. During recovery, AcPase activity in GERL returned to normal; however, the elevated TPPase activity and secretory granule formation seen in GERL-like cisternae and all Golgi saccules during hyperosmotic stress persisted. These results suggest that under normal conditions GERL is the predominant site for the secretory granule formation, but during hyperosmotic stress, the Golgi saccules assume increased importance in this function. The observed cytochemical modulations in Golgi saccules and GERL suggest that GERL is structurally and functionally related to the Golgi saccules.


Immune response to ultraviolet-induced tumors. II. Effector cells in tumor immunity.
Skin tumors induced in mice by chronic ultraviolet irradiation are highly antigenic and can induce a state of transplantation immunity in syngeneic hosts. In the present study, we compared the in vitro cytolytic activity of splenic lymphocytes from mice immunized with either a regressor or a progressor UV-tumor. The results of this comparison supported previous work implicating a role for tumor-specific cytolytic T lymphocytes in the rejection of regressor UV-tumors. The results also revealed that immunization with the progressor UV-tumor 2237 failed to elicit detectable levels of progressor tumor-specific CTL in animals capable of rejecting the immunizing tumor. Interestingly, following in vitro resensitization of both regressor and progressor immune spleen cells, we found a previously undetected lymphocyte population with anti-UV-tumor activity. Besides lysing UV-tumors in vitro, these lymphocytes also lysed a wide variety of additional tumor targets. This effector activity along with the analysis of cell surface markers indicated that these lymphocytes belong to that category of effector cells mediating natural-cell-mediated cytotoxicity (NCMC). As we had not detected cells with this activity in splenic lymphocyte preparations prior to in vitro resensitization, we examined lymphocytes from the local tumor environment during the course of progressor 2237 tumor rejection for either NCMC activity or tumor-specific CTL activity. This in situ analysis revealed lymphocytes exhibiting significant levels of cytolytic activity against several UV-tumors, thus implicating NK cells as effector cells in the rejection of progressor UV-tumors by immune animals. The mechanisms whereby NK cells with NCMC activity could be induced in immune animals are discussed in the context of class-II-restricted immune responses by helper/inducer T lymphocytes.


Laparoscopic left pancreatectomy: complication risk score correlates with morbidity and risk for pancreatic fistula.
Surgeons are performing laparoscopic left pancreatectomy (LLP) with increasing frequency; however, determinants of perioperative outcome after LLP are not well defined. We evaluated factors contributing to morbidity after LLP. Records from patients undergoing LLP from 2000 to 2008 from nine academic medical centers were evaluated to assess risk factors for perioperative complications. Extent of pancreatic resection was determined by the length of the gross pancreatic specimen. Complications and pancreatic fistula rates were assessed, and a model was developed to identify those at risk of postoperative adverse events. Among the 219 LLP cases, indications were cystic neoplasms in 122 (56%), solid neoplasms in 83 (38%), and chronic pancreatitis in 14 (6%). Thirty-day morbidity and mortality were 39% and 0, respectively. Major complications occurred in 11%. Pancreatic fistulae were detected in 23%, with clinically important fistulae (International Study Group on Pancreatic Fistula Definition grade B/C) seen in 10%. On multivariate analysis, only greater estimated blood loss (EBL), higher body mass index (BMI), and longer length of resected pancreas were associated with major complications. A complication risk score consisting of 1 point each for BMI >27, pancreatic specimen length >8 cm, or EBL > or =150 mL predicted an increased risk of complications and pancreatic fistulae. The risk of major complications after LLP is 11%, with clinically important pancreatic fistulae occurring in 10%. A complication risk score incorporating BMI, extent of pancreatic resection, and EBL correlates with all end points evaluated. The complication risk score should be used when quality outcome measures are evaluated.


Hospitalization trends after prostate and bladder surgery: implications of potential payment reforms.
Hospital stays have decreased for patients undergoing surgery for urological cancer. However, there are concerns that patients are being discharged from the hospital prematurely. We examined associations between hospital stay and short-term outcomes for a low risk procedure (prostatectomy) and high risk procedure (cystectomy). We used SEER (Surveillance, Epidemiology and End Results)-Medicare data from 1992 through 2005 to identify 46,781 prostatectomy and 9,035 cystectomy cases. We assessed our main outcome (adjusted likelihood of hospital readmission within 30 days) using a logistic regression model. Secondary outcomes included mortality rates and discharge disposition. In comparing patients from 1992 to 1993, to 2004 to 2005, hospital stay decreased approximately 3 days for both surgeries (relative decrease of more than 50% for prostatectomy and 21% for cystectomy). Hospital readmission rates were 4.5% and 25.2% for prostatectomy and cystectomy, respectively, and remained stable with time. Skilled nursing/intermediate care use was stable for patients who underwent prostatectomy (approximately 1%), but increased from 8.2% (95% CI 5.4-11.4) to 18.9% (95% CI 16.8-21.3) for those treated with cystectomy. Use of home care increased from 8.1% (95% CI 7.3-9.0) to 11.1% (95% CI 10.1-12.1) and from 34.2% (95% CI 29.7-38.7) to 47.5% (95% CI 44.5-50.1) for prostatectomy and cystectomy cases, respectively. Reductions in hospital stay were more dramatic for patients who underwent prostatectomy and were associated with stable short-term outcomes. Conversely, smaller reductions in hospitalization for patients undergoing cystectomy were met with substantial increases in the use of post-acute care. Going forward, close surveillance of how imminent policy reforms affect patterns and quality of care will be necessary.


Gold glyconanoparticles for mimics and measurement of metal ion-mediated carbohydrate-carbohydrate interactions.
To mimic and measure calcium ion-mediated carbohydrate-carbohydrate interactions, four lactose derivatives have been synthesized for assembly on gold nanoparticles. The series of lactose derivatives varied by the length of the thiolated ethylene glycol anchor chain [O(CH2CH2O)(m)CH2CH2SH; where m = 0, 1, 2, and 3] used to self-assemble the carbohydrates to the preformed gold nanoparticles of ca. 16 nm diameter. Upon addition of calcium ions to the lactose-stabilized nanoparticles, rapid carbohydrate-carbohydrate interactions were visualized and subsequently measured using UV-visible spectrometry and transmission electron microscopy (TEM). The nanoparticle aggregates formed via metal-mediated carbohydrate-carbohydrate interactions could be readily redispersed through the addition of EDTA. Multiple reaggregation and redispersion cycles were achieved, confirming that the aggregation process was due to metal ion-mediated carbohydrate interactions rather than calcium chelation by residual citrate ions on the particle surface. The essential involvement of the lactose moiety in Ca2+ complexation was shown by control measurements on related D-glucose-derivatized nanoparticles, where a significantly reduced aggregation response was obtained only at high ion concentrations. Other group 2 metal ions with radii larger than that of calcium, viz., barium and strontium, were also shown to mediate the aggregation of the lactose-stabilized nanoparticles. The induced aggregation of the lactose nanoparticles was determined to be quantitatively dependent upon the calcium ion concentration. Furthermore, the analytical sensitivity of the calcium-induced aggregation and the linear dynamic range were dependent on the length of the ethylene glycol anchor chain. The shortest ethylene glycol chain (m = 0) gave the most sensitive response with the optimum limit of detection (0.8 mM Ca2+), whereas the longest ethylene glycol chain (m = 3) provides a measurement of calcium ion concentration over the largest linear dynamic range (10-35 mM Ca2+). This work has shown that the self-assembled deposition of lactose derivatives on gold nanoparticles provides multivalent carbohydrate surfaces that can be used as mimics for the measurement of biologically relevant carbohydrate-carbohydrate interactions. Additionally, this study has highlighted the importance of the structure and length of the ligand that anchors the carbohydrate sugar to the gold particle surface to facilitate such carbohydrate interactions and for "tuning" the analytical characteristics of bioassays developed using metal nanoparticle technology.


Sodium channel myotonia may be associated with high-risk brief resolved unexplained events.
Brief resolved unexplained events (BRUEs) have numerous and varied causes posing a challenge to investigation and management. A subset of infants with the neuromuscular disorder sodium channel myotonia, due to mutations in the SCN4A gene, experience apnoeic events due to laryngospasm (myotonia) of the upper airway muscles that may present as a BRUE. We sought to ascertain the frequency, severity and outcome of infants carrying the G1306E SCN4A mutation commonly associated with this presentation. We report 12 new cases of individuals with the G1306E mutation from three unrelated families and perform a literature review of all published cases. Infants with the G1306E mutation almost universally experience laryngospasm and apnoeic events. The severity varies significantly, spans both low and high-risk BRUE categories or can be more severe than criteria for a BRUE would allow. At least a third of cases require intensive care unit (ICU) care. Seizure disorder is a common erroneous diagnosis. Apnoeas are effectively reduced or abolished by appropriate treatment with anti-myotonic agents. Probands with the G1306E mutation who are family planning need to be counselled for the likelihood of post-natal complications. There is readily available and extremely effective treatment for the episodic laryngospasm and apnoea caused by this mutation. Proactively seeking clinical evidence of myotonia or muscle hypertrophy with consideration of CK and EMG in high risk BRUEs or more complex apnoeic events may reduce avoidable and prolonged ICU admissions, patient morbidity and potentially mortality.


HIV/HCV therapy with ledipasvir/sofosbuvir after randomized switch to emtricitabine-tenofovir alafenamide-based single-tablet regimens.
Guidelines advocate the treatment of HCV in all HIV/HCV co-infected individuals. The aim of this randomized, open-label study (ClinicalTrials.gov identifier: NCT02707601; https://clinicaltrials.gov/ct2/show/NCT02707601) was to evaluate the safety/efficacy of ledipasvir/sofosbuvir (LDV/SOF) co-administered with elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide (E/C/F/TAF) or rilpivirine/F/TAF (R/F/TAF) in HIV-1/HCV co-infected participants. Participants with HIV-1 RNA <50 copies/mL and chronic HCV-genotype (GT) 1 (HCV treatment-naïve ± compensated cirrhosis or HCV treatment-experienced non-cirrhotic) were randomized 1:1 to switch to E/C/F/TAF or R/F/TAF. If HIV suppression was maintained at Week 8, participants received 12 weeks of LDV/SOF. The primary endpoint was sustained HCV virologic response 12 weeks after LDV/SOF completion (SVR12). Of 150 participants, 148 received ≥1 dose of HIV study drug and 144 received LDV/SOF (72 in each F/TAF group; 83% GT1a, 94% HCV treatment-naïve, 12% cirrhotic). Overall, SVR12 was 97% (95% confidence interval: 93-99%). Black race did not affect SVR12. Of four participants not achieving SVR12, one had HCV relapse, one had HCV virologic non-response due to non-adherence, and two missed the post-HCV Week 12 visit. Of 148 participants, 96% receiving E/C/F/TAF and 95% receiving R/F/TAF maintained HIV suppression at Week 24; no HIV resistance was detected. No participant discontinued LDV/SOF or E/C/F/TAF due to adverse events; one participant discontinued R/F/TAF due to worsening of pre-existing hypercholesterolemia. Renal toxicity was not observed in either F/TAF regimen during LDV/SOF co-administration. In conclusion, high rates of HCV SVR12 and maintenance of HIV suppression were achieved with LDV/SOF and F/TAF-based regimens. This study supports LDV/SOF co-administered with an F/TAF-based regimen in HIV-1/HCV-GT1 co-infected patients.


Treatment of posttraumatic stress disorder with amitriptyline and placebo.
Amitriptyline hydrochloride was compared with placebo in 46 veterans with chronic posttraumatic stress disorder. Treatment continued up to 8 weeks, and efficacy was measured by five observer and two self-rated scales. Percent recovery rates were higher for amitriptyline than placebo on two measures. In patients who completed 4 weeks (n = 40), better outcome with amitriptyline was noted on the Hamilton depression scale only. In the group completing 8 weeks of treatment (n = 33), the drug was superior to placebo on Hamilton depression, Hamilton anxiety, Clinical Global Impression severity, and Impact of Event scales. There was no evidence for drug effects on the structured interview for posttraumatic stress disorder. Drug-placebo differences were greater in the presence of comorbidity in general, although recovery rates were uniformly low in the presence of major depression, panic disorder, and alcoholism. At the end of treatment, 64% of the amitriptyline and 72% of the placebo samples still met diagnostic criteria for posttraumatic stress disorder.


Distribution of Pestivirus exposure in wild ruminants in Spain.
A large-scale study was carried out to determine the prevalence of antibodies against Pestivirus species in wild ruminants and describe their spatial variation in mainland Spain. Serum samples of 1,874 wild ruminants from different regions of this country were collected between the years 2000 and 2017. A total of 6.6% (123/1,874) animals showed antibodies against Pestivirus by both blocking ELISA (bELISA) and virus neutralization tests (VNT). The prevalence of antibodies against pestiviruses was different both among species and regions. Seroprevalence by species was 30.0% (75/250) in Southern chamois (Rupicapra pyrenaica), 7.0% (25/357) in fallow deer (Dama dama), 2.5% (10/401) in red deer (Cervus elaphus), 2.4% (8/330) in Iberian wild goat (Capra pyrenaica), 1.1% (4/369) in roe deer (Capreolus capreolus) and 0.8% (1/130) in mouflon (Ovis aries musimon), not detecting seropositivity (0/37) in Barbary sheep (Ammotragus lervia). The results confirm that exposure to pestiviruses was detected throughout mainland Spain, with significantly higher seroprevalence in Northern regions associated with the presence of Southern chamois. This indicates an endemic circulation of pestiviruses in Southern chamois and a limited circulation of these viruses in the remaining wild ruminant species during the last two decades, thus suggesting that non-chamois species are not true Pestivirus reservoirs in Spain. Nonetheless, the high spatial spread of these viruses points out that new epidemic outbreaks in naïve wild ruminant populations or transmission to livestock may occur, evidencing the usefulness of monitoring pestiviruses in wild ruminants, especially at the wildlife-livestock interface.


Timely community palliative and end-of-life care: a realist synthesis.
Community-based and home-based palliative and end-of-life care (PEoLC) services, often underpinned by primary care provision, are becoming increasingly popular. One of the key challenges associated with them is their timely initiation. The latter requires an accurate enough prediction of how close to death a patient is. Using 'realist synthesis' tools, this review sought to develop explanations of how primary care and community PEoLC programmes generate their outcomes, with the explanations presented as context-mechanism-outcome configurations. Medline, Embase, CINAHL, PsycINFO, Web of Science, ASSIA, Sociological Abstracts and SCIE Social Care Online were originally searched. A multistage process of focusing the review was employed, with timely identification of the EoL stage and timely initiation of associated services representing the final review focus. Synthesised sources included 21 full-text documents and 324 coded abstracts, with 253 'core contents' abstracts generating >800 codes. Numerous PEoLC policies and programmes are embedded in a framework of Preparation and Planning for Death and Dying, with identification of the dying stage setting in motion key systems and services. This is challenged by: (1) accumulated evidence demonstrating low accuracy of prognostic judgements; (2) many individuals' orientation towards Living and Hope; (3) expanding grey zones between palliative and curative care; (4) the complexity of referral decisions; (5) the loss of pertinent information in hierarchical relationships and (6) the ambiguous value of having 'more time'. Prioritising temporal criteria in initiating PEoLC services is not sufficiently supported by current evidence and can have significant unintended consequences. CRD42018097218.


Predictors of Complications and Comparison of Outcomes Using SurgiMend Fetal Bovine and AlloDerm Human Cadaveric Acellular Dermal Matrices in Implant-Based Breast Reconstruction.
Implant-based breast reconstruction with an acellular dermal matrix is one of the most common procedures performed by plastic surgeons. Although numerous matrices are available, there is little literature comparing them. This study compares the rates of complications between two commonly used products: AlloDerm (human cadaveric) and SurgiMend (fetal bovine) acellular dermal matrices. A retrospective review of a single center's 6-year experience was performed for consecutive, immediate breast reconstructions with acellular dermal matrix from 2009 to 2014. The authors compared demographics and surgical characteristics between patients receiving AlloDerm versus SurgiMend. Multivariate logistic regression was used to determine any association between type of matrix and surgical complications and to identify other clinical predictors for complications. A total of 640 patients underwent 952 reconstructions using AlloDerm [578 breasts (61 percent)] or SurgiMend [374 breasts (39 percent)]. The average follow-up was 587 days. Multivariate analysis revealed that type of matrix was not an independent risk factor for the development of complications. However, smoking, age, radiotherapy, and initial tissue expander fill volume were associated with increased risk of postoperative complications. Both AlloDerm and SurgiMend acellular dermal matrices demonstrate similar rates of major complications when used in immediate implant-based breast reconstruction. In contrast, preoperative radiation therapy, smoking, increasing age, and initial tissue expander fill volume are independent risk factors for postoperative complications. Reconstructive surgeons should take these findings into consideration when performing implant-based breast reconstruction with a dermal matrix.


Peripheral artery disease is associated with frailty in chronic hemodialysis patients.
Objectives The clinical condition of frailty is a common problem in the elderly population. However, the relationship between peripheral artery disease and frailty in hemodialysis patients remains unknown. The aim of this study was to identify the relationships between peripheral artery disease and frailty in Japanese chronic hemodialysis patients. Methods A total of 362 chronic hemodialysis patients who regularly visited six institutions were enrolled. To evaluate frailty, the modified Fried's frailty phenotype adjusted for Japanese were used. Peripheral artery disease was defined as ankle-brachial index <0.9. Results Of 362 patients, 62 patients (17.1%) were categorized as peripheral artery disease group and 300 patients (82.9%) as Non-peripheral artery disease group. The prevalence of frailty in the peripheral artery disease group was significantly higher than in the Non-peripheral artery disease group (34% vs. 18%, P = 0.0103). Non-shunt side grip strength was significantly stronger in the Non-peripheral artery disease group (23.6 kg vs. 17.0 kg, P < 0.0001). Thigh circumferences were also significantly larger in the Non-peripheral artery disease group (41.7 cm vs. 39.7 cm, P = 0.0054). A multivariate logistic regression analysis demonstrated that the factors independently associated with peripheral artery disease were as follows: frailty (odds ratio = 2.06, 95% confidence interval 1.09-3.89) and myocardial infarction (odds ratio = 3.74, 95% confidence interval 2.05-6.83). Conclusions It is concluded that peripheral artery disease is closely associated with frailty in hemodialysis patients.


Repair of canine medial orbital bone defects with miR-31-modified bone marrow mesenchymal stem cells.
To investigate the role of miR-31 genetically modified bone marrow mesenchymal stem cells (BMSCs) composited with porous β-tricalcium phosphate (β-TCP) scaffolds in repairing canine medial orbital wall defects. A circular bone defect (10 mm in diameter) was created on the canine medial orbital wall. After canine BMSCs were isolated and transfected with lentiviral vectors encoding miR-31, anti-miR-31 (anti-miR), and negative control (miR-Neg) in vitro, they were seeded onto porous β-TCP scaffolds and implanted to repair the orbital defects. Spiral computed tomography (CT) scans were conducted at 4 and 16 weeks after surgery. Micro-CT and histological analysis were performed at 16 weeks after surgery. The results were analyzed to evaluate the extent of bone repair. Examination with CT revealed good recovery in the anti-miR group at 16 weeks after surgery. In addition, the micro-CT analysis showed that the bone mineral density and new bone volume increased in the anti-miR group and decreased in the miR-31 group compared with that in the miR-Neg group. Histologic analysis confirmed that the formation of new bone and extent of β-TCP degradation were enhanced in the anti-miR and attenuated in the miR-31 group. In situ hybridization and immunohistochemical analysis further confirmed the micro-CT findings. The use of BMSCs with suppression of miR-31 expression combined with β-TCP scaffolds can efficiently repair medial orbital wall defects in dogs.


The Patterning Cascade Model and Carabelli's trait expression in metameres of the mixed human dentition: exploring a morphogenetic model.
The Patterning Cascade Model (PCM) provides an evolutionary developmental framework for exploring diversity in tooth crown form. According to the model, proximity of secondary enamel knots and tooth germ size track underlying developmental processes that dictate ultimate crown morphology (i.e., cusp number, accessory cusp presence/size). Previous research has shown the model to successfully predict variation in Carabelli's trait expression between antimeric and metameric pairs of human permanent molars. In this study, we quantify Carabelli's trait expression for metameres of the mixed dentition (dm2 and M1) and assess the PCM's potential for explaining differences in expression between the two elements. Crown dimensions, intercusp distances, and Carabelli's trait expression were collected from 49 subadults possessing observable dm2/M1 pairs. Wilcoxon signed-rank tests and paired t-tests were performed to assess whether metameres differ significantly in morphometric variables. We explored the relationships between relative intercusp distances (RICDs) and Carabelli's trait expression using proportional odds logistic regression. Intra-individual dm2/M1 pairs differed significantly in Carabelli's trait expression (p = 0.01), with dm2 exhibiting higher grades of expression more commonly despite its smaller crown size. Paired molars differed in only one statistically significant RICD: metacone-hypocone (p < 0.01). Most RICDs shared the predicted negative relationship with Carabelli's trait expression, but this relationship was only statistically significant for three RICDs in the dm2 (mean, protocone-paracone, metacone-hypocone). We found mixed support for the PCM's ability to explain differences in Carabelli's trait expression between metameres of the mixed molar row. Results suggest that protocone-paracone enamel knot spacing has the greatest influence on Carabelli's trait expression. Lack of statistical significance for many of the relationships explored may reflect limitations related to sample composition and sample size.


Enhancing disease surveillance with novel data streams: challenges and opportunities.
Novel data streams (NDS), such as web search data or social media updates, hold promise for enhancing the capabilities of public health surveillance. In this paper, we outline a conceptual framework for integrating NDS into current public health surveillance. Our approach focuses on two key questions: What are the opportunities for using NDS and what are the minimal tests of validity and utility that must be applied when using NDS? Identifying these opportunities will necessitate the involvement of public health authorities and an appreciation of the diversity of objectives and scales across agencies at different levels (local, state, national, international). We present the case that clearly articulating surveillance objectives and systematically evaluating NDS and comparing the performance of NDS to existing surveillance data and alternative NDS data is critical and has not sufficiently been addressed in many applications of NDS currently in the literature.


Overall Effects and Moderators of Rehabilitation in Patients With Wrist Fracture: A Systematic Review.
Wrist fractures constitute the most frequently occurring upper limb fracture. Many individuals report persistent pain and functional limitations up to 18 months following wrist fracture. Identifying which individuals are likely to gain the greatest benefit from rehabilitative treatment is an important research priority. This systematic review aimed to summarize effectiveness of rehabilitation after wrist fracture for pain and functional outcomes and identify potential effect moderators of rehabilitation. A comprehensive search of 7 databases (including MEDLINE, EMBASE, and the Physiotherapy Evidence Database) was performed for randomized controlled trials involving adults >50 years of age who sustained wrist fracture and had received 1 or more conservative treatments (eg, exercise/manual therapy, lifestyle, diet, or other advice). Study selection, data extraction, and risk-of-bias assessment were conducted independently by 2 reviewers. Results of included trials were summarized in a narrative synthesis. A total of 3225 titles were screened, and 21 studies satisfying all eligibility criteria were reviewed. Over one-half of the included studies (n = 12) comprised physical therapist and/or occupational therapist interventions. Rehabilitative exercise/manual therapy was generally found to improve function and reduce pain up to 1 year after wrist fracture. However, effects were small, and home exercises were found to be comparable with physical therapist-led exercise therapy. Evidence for the effects of other nonexercised therapy (including electrotherapy, whirlpool) was equivocal and limited to the short term (<3 months). Only 2 studies explored potential moderators, and they did not show evidence of moderation by age, sex, or patient attitude of the effects of rehabilitation. Effectiveness of current rehabilitation protocols after wrist fracture is limited, and evidence for effect moderators is lacking. Currently available trials are not large enough to produce data on subgroup effects with sufficient precision. To aid clinical practice and optimize effects of rehabilitation after wrist fracture, potential moderators need to be investigated in large trials or meta-analyses using individual participant data. Many patients report persistent pain and functional limitations up to 18 months following wrist fracture. Effectiveness of current rehabilitation protocols after wrist fracture is limited and may be due to insufficient targeting of specific rehabilitation to individuals who are likely to benefit most. However, evidence for effect moderators is lacking within the currently available literature. To aid clinical practice and optimize effects of rehabilitation, investigating potential moderators of rehabilitation in individuals with wrist fracture via large trials or meta-analysis of individual participant data is research and policy imperative.