Apomorphine has no effect on plasma homovanillic acid in schizophrenic patients.
Previous experiments suggest that pharmacological perturbations of the brain dopaminergic system may be reflected by concentrations of plasma homovanillic acid. This study examined the ability of low-dose apomorphine to reduce plasma homovanillic acid concentrations in schizophrenic patients chronically treated with neuroleptics. The data suggest that apomorphine does not reduce plasma homovanillic acid in those patients.


How could she? Psychosocial analysis of ten homicide cases committed by women.
Ten percent of all homicide perpetrators are female and homicidal acts committed by women are mostly a result of interpersonal conflicts. We carried out a retrospective psychosocial analysis of ten homicide cases committed by women with an urban mid-European background. We evaluated characteristic determinants regarding 1) deed circumstances and motives, 2) the perpetrators, and 3) the victims. Results were compared with the literature on female and male homicides. Autopsy records of the Institute of Legal Medicine of the University Hospital of Düsseldorf, Germany, during the time period from 2006 to 2011 were searched for homicides committed by female perpetrators. Prosecution files were reviewed for further information. The sample comprised N = 10 female homicide perpetrators and eleven victims. The mentioned determinants of the homicide were fairly consistent. All deeds occurred in the domestic context; they were mostly unplanned. All perpetrators were socially isolated and faced socially challenging situations. Most perpetrators were of low socioeconomic status. Furthermore, all victims were helpless and/or dependent on the perpetrator. The presence of a major psychiatric disorder was uncommon and, in contrast to male perpetrators, most women had no previous convictions. The potential value of these core findings in our sample regarding prevention is discussed.


Aqua-(1,4,7,10-tetra-aza-cyclo-dodeca-ne)zinc(II) bis-(perchlorate).
The cationic ZnII part of aqua-(1,4,7,10-tetra-aza-cyclo-dodeca-ne)zinc(II) bis-(perchlorate), [Zn(C8H20N4)(H2O)](ClO4)2, exhibits a slightly distorted square-pyramidal coordination environment with a water mol-ecule in the apical position. In the crystal, the macrocyclic ring alternates between two conformations with equal occupancies. Two of the three perchlorate anions are situated about a twofold rotation axis, and one of them shows disorder of the O atoms with occupancies of 0.62 (7) and 0.38 (7). In the crystal, the complexes are connected by inter-molecular hydrogen bonding via the perchlorate anions.


Lineage-Specific Early Differentiation of Human Embryonic Stem Cells Requires a G2 Cell Cycle Pause.
Human embryonic stem cells (hESCs) have an abbreviated G1 phase of the cell cycle that allows rapid proliferation and maintenance of pluripotency. Lengthening of G1 corresponds to loss of pluripotency during differentiation. However, precise mechanisms that link alterations in the cell cycle and early differentiation remain to be defined. We investigated initial stages of mesendodermal lineage commitment in hESCs, and observed a cell cycle pause. Transcriptome profiling identified several genes with known roles in regulation of the G2/M transition that were differentially expressed early during lineage commitment. WEE1 kinase, which blocks entry into mitosis by phosphorylating CDK1 at Y15, was the most highly expressed of these genes. Inhibition of CDK1 phosphorylation by a specific inhibitor of WEE1 restored cell cycle progression by preventing the G2 pause. Directed differentiation of hESCs revealed that cells paused during commitment to the endo- and mesodermal, but not ectodermal, lineages. Functionally, WEE1 inhibition during meso- and endodermal differentiation selectively decreased expression of definitive endodermal markers SOX17 and FOXA2. Our findings identify a novel G2 cell cycle pause that is required for endodermal differentiation and provide important new mechanistic insights into early events of lineage commitment. Stem Cells 2016;34:1765-1775.


Master techniques in digital arthrodesis.
This is a comprehensive review of various techniques of digital fusion. Evolution of the technique has afforded today's surgeons a valuable repertoire of surgical options. Ultimately, patient factors and surgeon preference determine the most appropriate method of fixation.


Leveraging artificial intelligence to advance the understanding of chemical neurotoxicity.
Neurotoxicology is a specialty that aims to understand and explain the impact of chemicals, xenobiotics and physical conditions on nervous system function throughout the life span. Herein, we point to the need for integration of novel translational bioinformatics and chemo-informatics approaches, such as machine learning (ML) and artificial intelligence (AI) to the discipline. Specifically, we advance the notion that AI and ML will be helpful in identifying neurotoxic signatures, provide reliable data in predicting neurotoxicity in the context of genetic variability, and improve the understanding of neurotoxic outcomes associated with exposures to mixtures, to name a few.


Safety of intracorporeal circular stapling esophagojejunostomy using trans-orally inserted anvil (OrVil) following laparoscopic total or proximal gastrectomy - comparison with extracorporeal anastomosis.
There have been several attempts to develop a unique and easier way to perform esophagojejunostomy during laparoscopy-assisted total gastrectomy or laparoscopy-assisted proximal gastrectomy. The OrVil system (Covidien, Mansfield, MA, USA) is one of those methods, but its technical and oncologic feasibility have not been proven and need to be observed. Among 87 patients who underwent laparoscopy-assisted total gastrectomy (LATG; 79 cases) and laparoscopy-assisted proximal gastrectomy with double tract anastomosis (LAPG_DT; 8 cases) from April 2004, 47 patients underwent the conventional extracorporeal method (Group I; 2004-2008) were compared with 40 patients treated with the intracorporeal OrVil system (Group II; 2009-2012). There was no significant difference in clinicopathologic characteristics between the two groups except tumor location; more cardia lesions were involved in group II (p = 0.012). The mean time for esophagojejunostomy (E-J), defined as the time from anvil insertion to closure of the jejunal entry site has no significant difference (Group I vs II: 22.2 ± 3.2 min vs 18.6 ± 3.5 min, p = 0.623). In terms of anastomotic complication, there was no significant difference in E-J leakage and stricture. E-J leakage occurred in 2 out of 47 (4.3%) cases in group I and 2 out of 40 (5%) in group II (p = 0.628); half of them were treated conservatively in each group and the others underwent reoperation. E-J stricture occurred in 2 (4.3%) cases in group I and 1 (2.5%) in group II (p = 0.561), which required postoperative gastrofiberscopic balloon dilatation. Esophagojejunostomy using the OrVil system was a feasible and safe technique compared with the conventional extracorporeal method through mini-laparotomy in terms of anastomotic complications. Moreover, it can help to reduce surgeon's stress regarding esophagojejunostomy because it needs no purse-string procedure and serves a secure operation view laparoscopically.


Cytokine-based biotherapy of gastrointestinal tumors.
Over the past 20 years the administration of cytokines has emerged as an important fourth modality for the treatment of human cancer. Advances in the field of therapy of gastrointestinal tumors have become a major focus of current research, given the lack of progress of conventional antineoplastic therapy in most of these tumors. Among the heterogeneous group of gastrointestinal malignancies, novel therapeutic strategies have been employed for each individual tumor type, and cytokines (interferon-alpha) have gained an established role in the treatment of advanced carcinoid tumors. Although our understanding of the mechanisms of biological response modification is still limited, further improvement in the management of gastrointestinal malignancies can be expected from multimodality therapy regimens employing cytokines in combination with other biological response modifiers, chemotherapeutic agents, active-specific immunotherapy, and immunotoxin- and radionuclide-conjugated monoclonal antibodies. A wide range of clinical and preclinical studies have been conducted in colorectal carcinoma; however, potential therapeutic benefit of cytokine-based biotherapy has not been fully defined. Therefore, largescale, i.e., multicenter, studies are required to quantify the potential therapeutic effects of cytokines in gastrointestinal tumors.


Learning and happiness during Covid-19 school closure in urban Malaysia.
COVID-19 school closure has disrupted education systems globally raising concerns over learning time loss. At the same time, social isolation at home has seen a decline in happiness level among young learners. Understanding the link between cognitive effort and emotional wellbeing is important for post-pandemic learning recovery interventions particularly if there is a feedback loop from happiness to learning. In this context, we use primary survey data collected during the first school closure in urban Malaysia to study the complex association between learning loss and student happiness. Machine learning methods are used to accommodate the multi-dimensional and interaction effects between the covariates that influence this association. Empirically, we find that the most important covariates are student gender, social economic status (SES) proxied by the number of books ownership, time spent on play and religious activity. Based on the results, we develop a conceptual framework of learning continuity by formalizing the importance of investment in emotional wellbeing.


Drug bioactivation and protein adduct formation in the pathogenesis of drug-induced toxicity.
Adverse drug reactions (ADRs) remain a major complication of drug therapy and can be classified as 'on-target' or 'off-target' (idiosyncratic) reactions. On-target reactions can be predicted from the known primary or secondary pharmacology of the drug and often represent an exaggeration of the pharmacological effect of the drug. In contrast, off-target adverse reactions cannot be predicted from knowledge of the basic pharmacology of the drug. The exact mechanisms of idiosyncratic drug reactions are still unclear; however it is believed that they can be initiated by chemically reactive drug metabolites. It is well known that xenobiotics can undergo metabolic bioactivation reactions which have the potential to cause cellular stress and damage. Bioactivation of drugs is thought to have the potential of initiating covalent linkages between cellular protein and drugs which can be recognised by the adaptive immune system in the absence of detectable cellular stress. This process cannot yet be predicted in pre-clinical models or discovered in clinical trials. Because of this hazard perception, the formation of chemically reactive metabolites in early drug discovery remains a serious impediment to the development of new medicines and can lead to withdrawal of an otherwise effective therapeutic agent. The fear of such reactions occurring at the post-licensing stage - when such problems first become evident - is a major contribution to drug attrition. The first step towards such methodology has been the development of chemically reactive metabolite screens. The chemical basis of drug bioactivation can usually be rationalised and synthetic strategies put in place to prevent such bioactivation. However, there is no simple correlation between drug bioactivation in vitro and adverse drug reactions in the clinic. Such a chemical approach is clearly limited by the facts that (a) not all drugs that can undergo bioactivation by human drug-metabolising enzymes are associated with hypersensitivity in the clinic and (b) drug bioactivation may not always be a mandatory step in drug hypersensitivity. To predict such reactions in early drug development, it will require an integrated understanding of the chemical, immunological and genetic basis of adverse drug reactions in patients, which in turn will depend on the development of novel in vitro experimental systems.


Proteins bound to poly(A) sequences of polyribosomes from germinating wheat embryos.
A preparation of purified polyribosomes was isolated from wheat embryos germinating for 1 h with [3H]adenosine. Treatment of polyribosomes with pancreatic ribonuclease leads to the liberation of particles containing poly(A) sequences. Poly(A)-containing complexes show a heterogeneous distribution in the region 8--15 S. The ability of 8--15 S material to be absorbed to membrane filters under the conditions of low ionic strength and its sensitivity to pronase indicate that poly(A) sequences in polyribosomes are associated with protein. Analysis of this protein by electrophoresis in a polyacrylamide gel demonstrates the presence of two polypeptides with the molecular weights equal to 86,000 and 52,000.


Fruits and vegetables intake and risk of bladder cancer: a PRISMA-compliant systematic review and dose-response meta-analysis of prospective cohort studies.
Clinical practice recommends eating ≥2.5 cups of fruits and vegetables (FVs) each day for cancer prevention, in which the evidence from epidemiological studies for the association between FVs intake and bladder cancer (BC) prevention is inconsistent.We searched the PubMed, Embase, and Willy online Library for relevant studies published up to September 27, 2014. Prospective cohort studies investigated FVs intake, and the risk of BC with ≥3 categories of exposure was included. A dose-response meta-analysis was carried out to evaluate the association between FVs intake and risk of BC.Fourteen cohorts with 17 studies including 9447 cases were identified. No evidence of nonlinear association was examined between FVs intake and risk of BC. The summarized relevant risk (RR) of every 0.2 serving increment a day was 1.00 (95%CI: 0.99, 1.00; P = 0.17; I = 41.7%; n = 14) for total fruits; 0.99 (95%CI: 0.96, 1.01; P = 0.28; I = 37.0%; n = 13) for total vegetables; and 0.99 (95%CI: 0.97, 1.01; P = 0.24; I = 57.5%; n = 8) for both FVs. In further analysis, we observed inverse association between every 0.2 serving increment of green leafy vegetables intake a day and risk of BC (RR = 0.98, 95%CI: 0.96, 0.99; I = 0.0%; P < 0.01; Power = 0.76; n = 6), but neither for cruciferous vegetables (RR = 0.97, 95%CI: 0.93, 1.01; P = 0.19; I = 55.8%; n = 8) nor for citrus (RR = 1.00, 95%CI: 1.00, 1.00; P = 0.83; I = 0.0%; n = 7). Subgroup analysis showed consistent results.Little evidence supports a beneficial effect for total fruits, vegetables, both FVs, and citrus intake against bladder cancer. Green leafy vegetables may help prevent bladder cancer.


Mathematical model for calcium-assisted epidermal homeostasis.
Using a mathematical model of the epidermis, we propose a mechanism of epidermal homeostasis mediated by calcium dynamics. We show that calcium dynamics beneath the stratum corneum can reduce spatio-temporal fluctuations of the layered structure of the epidermis. We also demonstrate that our model can reproduce experimental results that the recovery from a barrier disruption is faster when the disrupted site is exposed to air. In particular, simulation results indicate that the recovery speed depends on the size of barrier disruption.


[Limitations of outpatient vitreoretinal surgery at the Toulouse University hospital between 2016 and 2020: Causes for traditional hospitalization].
Currently, the majority of patients undergoing vitreoretinal surgery (VRS) are managed on an outpatient basis; this has been made possible by major surgical and anesthetic advances over the past decades. Nevertheless, the conversion to "all outpatient" surgery still poses some problems that are interesting to identify, and traditional hospitalization remains the solution in many situations. All patients undergoing VRS at the Toulouse University Hospital between 2016 and 2020 were included retrospectively. For each patient, we analyzed the entire medical, anesthesia and demographic records. We performed a simple descriptive analysis of all parameters studied, followed by a bi-variate analysis between the "Outpatient/Hospitalization" parameter and all other parameters. Three thousand patients were included over the study period; 79.4% of patients were managed on an outpatient basis compared to 20.6% by traditional hospitalization. Failure of ambulatory care was the cause of 41.9% of the traditional hospitalizations, with the absence of an accompanying person on the evening of the surgery being the main reason (47.8%). Social isolation is found to be one of the main causes of failure of ambulatory care; improvements might be made at this level, in order to reduce the burden on the inpatient hospital system.


Implantation of rabbit embryo brain fragments into newborn mice: integration and survival of xenogeneic astrocytes.
Brain fragments containing embryonic rabbit glia were implanted into the brains of newborn mice. The hosts developed an astroglial reaction around the transplants and along the needle tracks. Transplant-derived astrocytes were identified in the operated brain by their expression of rabbit GFAP. During the first few days post-implantation (PI) glial cells were exchanged between the transplant and the host. Less than 3 to 5 days PI, the transplant was extensively invaded by host astrocytes. Xenogeneic astroglial cells were first detected 10 days PI in the immediate proximity of the transplant. At 2 to 11 weeks, they could be detected either close to or at distance from the point of implantation. Most often, transplant-derived astrocytes presented a morphology similar to that of neighboring host astrocytes. Xenogeneic glial cells were found to participate in various types of astroglial features: sub-pial, pericapillary, fibrous, and protoplasmic. This morphological integration suggests that they are physiologically integrated, at least to a certain degree, in the host tissue. In spite of their integration into the host, xenogeneic astrocytes disappear after 3 months without signs of an inflammatory reaction.


Rice peptide nanoparticle as a bifunctional food-grade Pickering stabilizer prepared by ultrasonication: Structural characteristics, antioxidant activity, and emulsifying properties.
In this study, a novel food-grade Pickering stabilizer was fabricated from insoluble rice peptide aggregates that are considered undesirable and formed during the hydrolysis of rice protein using ultrasonication. The results confirmed that ultrasonication was effective in fabricating rice peptide nanoparticles (RPNs) with a spherical appearance, and the particle size was reduced with ultrasonic time, reaching a minimum size of 357.8 nm in 30 min. Moreover, ultrasonic treatment could improve the antioxidant activity of RPNs by promoting the DPPH scavenging (3.5-fold increase) and Fe2+ chelating activity (3.8-fold increase). Notably, the bioactive RPNs could form stable Pickering emulsions that possess both physical and oxidative stability during storage, which might be due to the antioxidative physical barrier formed by RPNs. These findings suggest a new approach for the effective utilization of insoluble aggregates produced during protein hydrolysis as well as provide a novel bifunctional Pickering stabilizer with intrinsic antioxidant properties.


[Knowledge facilitates health: the "Fit in Health" program for strengthening the health literacy of students].
In Germany, more than half of the population has low health literacy. These people have difficulties in finding and classifying health-related information and adapting it to their own situation. Among them are many young people, highlighting the importance of interventions early in life to promote health literacy.This is where the "Fit in Health" program of the Health Information Services of the Helmholtz Munich Research Center and the German Cancer Research Center starts. The objective is to contribute to the promotion of different dimensions of health literacy among children and adolescents. To this end, innovative training formats for teachers and teaching materials for students at secondary levels I and II are being designed and evaluated. The major diseases cancer and diabetes mellitus are used as models to provide basic knowledge on their pathogenesis, prevention, treatment, and research. In addition, information about the structures of the healthcare system and materials to strengthen health literacy are provided. An accompanying evaluation collects indicator data on coverage and acceptance of the measures.Since 2018, the program has published 46 teaching materials and three course readers with background knowledge for teachers. Furthermore, 50 training courses have been held, with approximately 1600 teachers and multipliers taking part in face-to-face and online events by the end of 2021. More than 90% of the participants gave the respective events very good or good evaluations. Around 80% of the participants said they would like to include the topics taught in their lessons. Further expansion of the offers is planned. Testing of a set of materials with respect to the gain of health literacy in a sample of students is currently being prepared.


Pericallosal aneurysm simulating corpus callosum tumour.
The MRI characteristics of an isolated subacute aneurysmal corpus callosum hematoma, without evidence of blood in cerebrospinal fluid (CSF) spaces or ventricles, have not been previously reported. This report highlights the difficulty of accurate diagnosis and treatment in a patient with an unusual ruptured pericallosal aneurysm simulating a corpus callosum tumour. Additionally we analyse the particular radiological configuration and appearance of blood products in this region.


Protection of gastric mucosa by sucralfate from aspirin-induced erosions.
The protective effect of sucralfate against aspirin caused damage to the gastric mucosa was studied in healthy male volunteers (age range 18 to 44 years) with no history of gastrointestinal disease. Each was randomly assigned to placebo or sucralfate. As determined by endoscopic studies, 8 of 12 subjects on sucralfate experienced complete protection; 3 were partially protected. The question was raised whether sucralfate might have inhibited the absorption of aspirin from the gastrointestinal tract, but measurement of salicylate levels showed no statistically significant difference between salicylate levels achieved after sucralfate and after placebo.


Distribution of some anystid mites (Acari: Anystidae) in Australia and Indonesia and their role as possible predators of the cattle tick, Boophilus microplus (Acari: Ixodidae).
The geographic and habitat distributions of Anystis baccarum, A. jabanica, A. salicinus, and A. sp. B Walzia australica Womersley and Chaussieria warregense in Australia and parts of Indonesia are presented. Laboratory trials showed that A. baccarum will feed upon the larvae of the cattle tick Boophilus microplus, whilst A. jabanica also showed some predatory potential. Walzia australica and C. warregense had no effect on survival of tick larvae.


Tracking Development of Connectivity in the Human Brain: Axons and Dendrites.
The neuron doctrine laid the foundation for our current thinking about the structural and functional organization of the human brain. With the basic units of the nervous system-neurons-being physically separate, their connectivity relies on the conduction of action potentials in axons and their transmission across the synaptic cleft to the dendrites of other neurons. This study reviews available ex vivo data about the cellular composition of the human cerebral cortex, focusing on axons and dendrites, to conceptualize biological sources of signals detected in vivo with magnetic resonance imaging. To bridge the gap between ex vivo and in vivo observations, I then explain the basic principles of virtual histology, an approach that integrates spatially cell- or process-specific transcriptomic data with magnetic resonance signals to facilitate their neurobiological interpretation. Finally, I provide an overview of the initial insights gained in this manner in studies of brain development and maturation, in both health and disease.


Plasma fibronectin in normolipidaemic and hyperlipidaemic uraemic patients treated with haemodialysis.
Plasma fibronectin (PF) concentrations, were investigated in normolipidaemic and hyperlipidaemic (type IV) patients with chronic renal failure treated with hemodialysis (n = 29) and in controls (n = 34). Mean PF was significantly reduced in both subsets of dialysed patients. Among the hemodialysed patients the presence of hyperlipidaemia did not modify PF levels, which resulted, on the contrary, significantly higher in hyperlipidaemic controls as compared with the normolipidaemic group. In controls, according to a multivariate analysis model, PF was directly related with age and inversely with HDL-cholesterol. In the hemodialysed patients total cholesterol was the unique significant PF related variate, being this group, therefore, characterized by the lack of any inverse relation between PF and HDL-cholesterol. Finally, no PF modifications were observed in hemodialyzed patients affected by arterial hypertension or clinically evident atherosclerotic lesions.


Evaluation of a simulation-based learning activity for communicating about at-risk opioid behaviors in a community pharmacy setting.
The purpose of our study was to evaluate a learning activity that included an objective structured learning examination (OSLE) focused on identifying and communicating at-risk opioid behaviors in a community pharmacy setting through student perceptions and OSLE performance. The activity included a didactic lecture and an OSLE with two opioid use patient cases. Third-year pharmacy students' communication skills were evaluated using faculty-created rubrics. A voluntary, anonymous pre-/post-survey evaluated students' skills confidence and OSLE satisfaction. Responses were analyzed using independent t-tests. An inductive conventional content analysis identified the impact on students' perceptions and future behaviors from post-simulation reflections. One hundred forty-three and 111 students completed the pre- and post-surveys, respectively. Students self-reported confidence in their ability to identify red flags and assess at-risk opioid behaviors, counsel on opioid risk behaviors, refuse opioid prescription fills, and respond to patients' nonverbal responses, all significantly improved pre-to-post. Students reported the OSLE was beneficial to their learning. The mean overall OSLE score was 34.2 out of 45 points (SD ± 6.21). Identified student reflection themes included: importance of patient-centered care, pharmacists' role in patients with at-risk opioid behaviors, recognition of judgement against patients taking opioids, and importance of communication and empathy as strategies to mitigate conflict. Implementing a new learning activity focused on communication regarding at-risk opioid behaviors allowed students to engage in difficult conversations with standardized patients in a safe simulation environment. Students demonstrated competent skills, increased their self-reported confidence, and were highly satisfied with the learning activity.


Modified photoactivated methylene blue-incorporated quartz particles for dentin disinfection: A scanning electron microscope and spectroscopic analysis.
The aim of this study was to synthesize methylene blue-incorporated quartz particles (MB@QP) and to investigate its anti-bactericidal properties. Methylene blue was incorporated inside QP and characterized for morphology and chemical structure using scanning electron microscope (SEM) and Fourier transformed infrared spectroscopy (FTIR). Specimens were randomly divided into experimental and control groups (n = 9/groups). The dentin specimen infected with Enterococcus faecalis was treated using different treatment modalities: Control groups: treatment with 5.25% of sodium hypochlorite (NaOCl) for 60 s; MB: treatment with 1 ml MB solution and incubated for 60 s; MB-PDT (photodynamic therapy): treatment with 1 ml MB solution followed by irradiation using diode laser for 60 s; MB-QP-PDT: specimens treated with MB@QP and irradiated by the diode laser for 60s, and Er,Cr:YSGG laser alone. MB@PDT therapy showed the highest efficacy in reducing the survival rate of E. faecalis (0.49%) in comparison to control NaOCl (0.78%) and Er,Cr:YSGG laser treatment (2.17%). Encapsulating MB into QP followed by the PDT significantly improved the bactericidal capacity and significantly reduced the bacterial survival rate to 0.11% (p < .05) compared to other groups. The combination of MB incorporated into QP and PDT could be an alternative treatment modality to conventional disinfection method for eliminating bacteria from the tooth dentin. RESEARCH HIGHLIGHTS: Quartz particles are potent in delivering the photosensitizer. Photoactivated MB@QP has a higher efficacy in eliminating bacteria from tooth dentin.


Association of Perceived Stress Levels With Long-term Mortality in Patients With Peripheral Artery Disease.
Identifying modifiable risk factors, such as stress, that could inform the design of peripheral artery disease (PAD) management strategies is critical for reducing the risk of mortality. Few studies have examined the association of self-perceived stress with outcomes in patients with PAD. To examine the association of high levels of self-perceived stress with mortality in patients with PAD. This cohort study analyzed data from the registry of the Patient-Centered Outcomes Related to Treatment Practices in Peripheral Arterial Disease: Investigating Trajectories (PORTRAIT) study, a multicenter study that enrolled patients with new or worsening symptoms of PAD who presented to 16 subspecialty clinics across the US, the Netherlands, and Australia from June 2, 2011, to December 3, 2015. However, the present study included only patients in the US sites because assessments of mortality for patients in the Netherlands and Australia were not available. Data analysis was conducted from July 2019 to March 2020. Self-perceived stress was quantified using the 4-item Perceived Stress Scale (PSS-4), with a score range of 0 to 16. A score of 6 or higher indicated high stress in this cohort. Missing scores were imputed using multiple imputation by chained equations with predictive mean matching. Stress was assessed at baseline and at 3-, 6-, and 12-month follow-up. Patients who reported high levels of stress at 2 or more follow-up assessments were categorized as having chronic stress. All-cause mortality was the primary study outcome. Such data for the subsequent 4 years after the 12-month follow-up were obtained from the National Death Index. The final cohort included 765 patients, with a mean (SD) age of 68.4 (9.7) years. Of these patients, 57.8% were men and 71.6% were white individuals. High stress levels were reported in 65% of patients at baseline and in 20% at the 12-month follow-up. In an adjusted Cox proportional hazards regression model accounting for demographics, comorbidities, disease severity, treatment type, and socioeconomic status, exposure to chronic stress during the 12 months of follow-up was independently associated with increased risk of all-cause mortality in the subsequent 4 years (hazard ratio, 2.12; 95% CI, 1.14-3.94; P = .02). In thie cohort study of patients with PAD, higher stress levels in the year after diagnosis appeared to be associated with greater long-term mortality risk, even after adjustment for confounding factors. These findings suggest that, given that stress is a modifiable risk factor for which evidence-based management strategies exist, a holistic approach that includes assessment of chronic stress has the potential to improve survival in patients with PAD.


Interaction Between Determinants Governing Urine Volume in Patients With ADPKD on Tolvaptan and its Impact on Quality of Life.
Autosomal dominant polycystic kidney disease (ADPKD) is the most prevalent genetic cause of kidney failure. Tolvaptan, a vasopressin 2 receptor antagonist, is the first drug with proven disease-modifying activity. Long-term treatment adherence is crucial, but a considerable fraction of patients discontinue treatment, because of aquaretic side effects. Twenty-four-hour urine was collected in 75 patients with ADPKD during up-titration of tolvaptan and, in combination with clinical characteristics, examined to identify factors influencing urine volume. Patient-reported outcomes were analyzed using the Short Form-12 (SF-12) and patient-reported outcomes questionnaires reporting micturition frequency and burden of urine volume. Initiation of therapy led to a large increase in urine volume followed by only minor further increase during up-dosing. Younger patients and patients with better kidney function experienced a larger relative rise. Twenty-four-hour urine osmolality dropped by about 50% after therapy initiation independently of dose, with a considerable proportion of patients achieving adequate suppression. Sodium and potassium intake turned out to be the only significant modifiable factors for urine volume after multivariate linear regression models, whereas age and weight could be identified as non-modifiable factors. No change in quality of life (QoL) was detected in relation to treatment or urine volume using SF-12 questionnaires, a finding that was further supported by the results of the patient-reported outcomes assessment. This study provides an in-detail analysis of factors associated with the degree of polyuria on tolvaptan and puts them into the context of QoL. These findings will contribute to optimized patient counseling regarding this treatment option in ADPKD.


Delivery fidelity of the REACT (REtirement in ACTion) physical activity and behaviour maintenance intervention for community dwelling older people with mobility limitations.
Fidelity assessment of behaviour change interventions is vital to understanding trial outcomes. This study assesses the delivery fidelity of behaviour change techniques used in the Retirement in ACTion (REACT) randomised controlled trial. REACT is a community-based physical activity (PA) and behaviour maintenance intervention to prevent decline of physical functioning in older adults (≥ 65 years) at high risk of mobility-related disability in the UK. The delivery fidelity of intervention behaviour change techniques and delivery processes were assessed using multi-observer coding of purposively sampled in-vivo audio recordings (n = 25) of health behaviour maintenance sessions over 12-months. Delivery fidelity was scored using a modified Dreyfus scale (scores 0-5) to assess competence and completeness of delivery for each technique and delivery process. "Competent delivery" was defined as a score of 3 points or more for each item. Examples of competent intervention delivery were identified to inform recommendations for future programme delivery and training. The mean intervention fidelity score was 2.5 (SD 0.45) with delivery fidelity varying between techniques/processes and intervention groups. Person-centred delivery, Facilitating Enjoyment and Promoting Autonomy were delivered competently (scoring 3.0 or more). There was scope for improvement (score 2.0-2.9) in Monitoring Progress (Acknowledging and Reviewing), Self-Monitoring, Monitoring Progress (Eliciting Benefits of Physical Activity), Goal Setting and Action Planning, Modelling, Supporting Self-Efficacy for Physical Activity and Supporting Relatedness. Managing Setbacks and Problem Solving was delivered with low fidelity. Numerous examples of both good and sub-optimal practice were identified. This study highlights successes and improvements needed to enhance delivery fidelity in future implementation of the behavioural maintenance programme of the REACT intervention. Future training of REACT session leaders and assessment of delivery fidelity needs to focus on the delivery of Goal setting and Action Planning, Modelling, Supporting Relatedness, Supporting Self-Efficacy for Physical Activity, and Managing Setbacks/ Problem Solving.


Hydrolytic degradation and drug release properties of ganciclovir-loaded biodegradable microspheres.
The in vitro hydrolytic degradation of ganciclovir (GCV)-loaded biodegradable microspheres of poly(D,L-lactide) and poly(D,L-lactide-co-glycolide) polymers were studied. Microspheres of size 120+/-40 microm were prepared using an oil-in-water emulsification/solvent evaporation technique. The effects of polymer molecular weight, lactide (LA) to glycolide (GA) ratio and GCV payload on the degradation and drug release profiles were investigated in vitro in phosphate-buffered solution (pH 7.0) at 37 degrees C. GCV accelerated the hydrolysis process of the low (5-7 wt.%) GCV-loaded microspheres due to a basic catalytic effect, giving a larger degradation rate, k', compared with blank and high (18-20 wt.%) GCV-loaded microspheres. In the high GCV-loaded microspheres, hydrolysis of the polymer backbone occurred with little and/or no autocatalytic effect, resulting in a smaller k' compared with low GCV-loaded microspheres. This was due to pores and microchannels created at the surface following the initial burst release, which increased water uptake and the dissolution and diffusion of GCV and degradation products from the matrix. The rate of hydrolytic degradation was also affected by the LA to GA ratio. For polymers of similar LA to GA ratio, those with a higher degree of blockiness had faster hydrolytic degradation rates irrespective of the initial molecular weight. The release profile had a biphasic pattern, which closely followed the degradation profile of the polymer. The time taken for the complete release of GCV was controlled by the diffusion phase and was dependent on the hydrolytic degradation rate of the polymers.


1-Year outcome of concomitant intracarpal lesions in patients with dislocated distal radial fractures: a systematic assessment of 78 distal radial fractures.
Ligamentous lesions are concomitant to dislocated distal radius fractures in a high percentage. The purpose of this study was to evaluate the relevance of intracarpal lesions. Seventy eight of an original cohort of 104 distal radius fractures (74%) were studied over a follow-up period of one year after surgery with complete data (X-rays, CT, MRI, follow-up X-rays and questionnaire). Most of our radius fractures (AO 23 type: A 39, B 9, C 30) present additional lesions: 97%. One-year evaluation showed an average Castaing score of 4.5 ± 2.5 points, means a "good" result of a scale of 0-27. Fifty five of seventy eight had an "excellent" or "good" result (<6 points). No patient had more than 12 points ("fair"). The dislocated distal radial fracture implies severe and complex injury to the whole wrist, mostly concerning intracarpal concomitant lesions (MRI). Surgical therapy of dislocated radius fractures followed by 6 weeks relief through thermoplastic splint seems to be sufficient to achieve good 1-year results. MRI-detectable carpal lesions at the time of the radial fracture are common, but only a few of them seem to decompensate later, give symptoms and became of therapeutic relevance.


Determination of phenolic compounds using spectral and color transitions of rhodium nanoparticles.
This work reports a new approach for the determination of phenolic compounds based on their interaction with citrate-capped rhodium nanoparticles. Phenolic compounds (i.e., catechins, gallates, cinnamates, and dihydroxybenzoic acids) were found to cause changes in the size and localized surface plasmon resonance of rhodium nanoparticles, and therefore, give rise to analyte-specific spectral and color transitions in the rhodium nanoparticle suspensions. Upon reaction with phenolic compounds (mainly dithydroxybenzoate derivatives, and trihydroxybenzoate derivatives), new absorbance peaks at 350 nm and 450 nm were observed. Upon reaction with trihydroxybenzoate derivatives, however, an additional absorbance peak at 580 nm was observed facilitating the speciation of phenolic compounds in the sample. Both absorbance peaks at 450 nm and 580 nm increased with increasing concentration of phenolic compounds over a linear range of 0-500 μM. Detection limits at the mid-micromolar levels were achieved, depending on the phenolic compound involved, and with satisfactory reproducibility (<7.3%). On the basis of these findings, two rhodium nanoparticles-based assays for the determination of the total phenolic content and total catechin content were developed and applied in tea samples. The obtained results correlated favorably with commonly used methods (i.e., Folin-Ciocalteu and aluminum complexation assay). Not the least, the finding that rhodium nanoparticles can react with analytes and exhibit unique localized surface plasmon resonance bands in the visible region, can open new opportunities for developing new optical and sensing analytical applications.


Parp1 deficient mice are protected from streptozotocin-induced diabetes but not caerulein-induced pancreatitis, independent of the induction of Reg family genes.
Poly(ADP-ribose) polymerase (Parp) 1 is a key regulator of cell death, its inhibition prevented streptozotocin-induced diabetes and attenuated caerulein-induced acute pancreatitis. Reg family proteins are significantly induced by Parp1 inhibitor, experimental diabetes and/or acute pancreatitis. We propose that Reg proteins are involved in the protection of pancreatic cells by Parp1 inhibition. To test this possibility, Parp1-/- and wild-type mice were injected with streptozotocin to induce diabetes. Separately, acute pancreatitis was induced with repeated injections of caerulein. Upon streptozotocin administration, Parp1-/- mice displayed much decreased hyperglycemia and preserved serum insulin level. The treatment induced similar levels of Reg1, -2, -3α and -3β genes in the pancreas of both wild-type and Parp1-/- mice, suggesting that the upregulation of Reg family genes during streptozotocin-induced diabetes was independent of Parp1 ablation. In caerulein-induced pancreatitis, unlike being reported, Parp1 knockout caused no relief on the severity of pancreatitis; the upregulation of pancreatic Reg1, -2, -3α and -3β genes upon caerulein was unaffected by Parp1 deletion. Our results reconfirmed the protective effect of Parp1 gene deletion on islet β-cells but questioned its effect on the acinar cells. In either case, the significant induction of Reg family genes seemed independent of Parp1-mediated cell death.


Lessons from the Organizer - an interview with Edward (Eddy) M. De Robertis.
In this interview, we talk with developmental biologist Eddy De Robertis about his wider scientific career and the history of developmental biology in Latin America. We discuss the early days of the homeobox, the discovery of the mechanism of the Spemann-Mangold organizer function in Xenopus embryos, and related Evo-Devo. De Robertis reflects on trends of how conducting biological research has changed over the years and he provides advice for young scientists.


Atherosclerosis--an immune disease: The Anitschkov Lecture 2007.
Atherosclerosis is an inflammatory disease. This article reviews the emergence of this concept from studies of patients and their lesions, experimental animal models, and epidemiological cohorts. Immunohistochemical studies identified immune cells and mediators and provided evidence for inflammatory activation in the atherosclerotic lesion. In parallel, cell culture studies demonstrated the capacity of vascular cells to interact with immune cells. Subsequent studies of clinical and epidemiological materials have identified inflammatory markers and immunoregulatory genes as contributors of risk for myocardial infarction and stroke. Finally, experiments using gene-targeted mice have provided mechanistic understanding of the disease process. It is now thought that the atherosclerotic process is initiated when low-density lipoproteins accumulate in the intima, activate the endothelium, and promote recruitment of monocytes and T cells. Monocytes differentiate into macrophages, internalize modified lipoproteins, and end up as foam cells. T cells in lesions recognize local antigens and mount T helper-1 responses that contribute to local inflammation and plaque growth. This atherogenic pathway is counterbalanced by anti-inflammatory signals provided by regulatory immunity. Intensified inflammatory activation may lead to local proteolysis, plaque rupture, thrombus formation, ischemia and infarction. Novel therapeutic opportunities may emerge from understanding the role of inflammation in atherosclerosis.


Convective heat transfer around vertical jet fires: an experimental study.
The convection heat transfer phenomenon in vertical jet fires was experimentally analyzed. In these experiments, turbulent propane flames were generated in subsonic as well as sonic regimes. The experimental data demonstrated that the rate of convection heat transfer increases by increasing the length of the flame. Assuming the solid flame model, the convection heat transfer coefficient was calculated. Two equations in terms of adimensional numbers were developed. It was found out that the Nusselt number attains greater values for higher values of the Rayleigh and Reynolds numbers. On the other hand, the Froude number was analyzed only for the subsonic flames where the Nusselt number grows by this number and the diameter of the orifice.


Quantitation of human serum antithyroglobulin antibodies by a two-site radioimmunoassay.
A two-site solid-phase radioimmunoassay for measuring serum antithyroglobulin antibodies applicable to human serum is described. The sequential steps of the procedure include the adsorption of thyroglobulin (Tg) on polystyrene tubes and the binding of the antithyroglobulin antibody to solid phase followed by the fixation of labelled thyroglobulin. The optimal experimental conditions for the adsorption of unlabelled Tg, the uptake of the antibodies and the fixation of labelled Tg have been defined. The test is specific for antithyroglobulin antibody and its reproducibility and precision are satisfactory. The radioassay showed a good correlation with the hemagglutination method and, also, was found to be more sensitive. Levels of antithyroglobulin IgG in positive sera ranged from 0.3 microgram/ml to several mg/ml. In contrast to the double antibody radioimmunoassay for antithyroglobulin antibodies, this solid-phase radioassay is easier to perform; moreover, it is relatively independent of the quality, the purity and the specific activity of the tracer.


S434F in NrdE generates the thermosensitive phenotype of corynebacterium ammoniagenes CH31 and enhances thermolability by increasing the surface hydrophobicity of the NrdE(Ts) protein.
The thermosensitive phenotype of strain CH31, a derivative of Corynebacterium ammoniagenes ATCC 6872, was allocated by cloning, sequencing, and genetic complementation to a single C-->T exchange in the nrdE (nucleotide reduction) gene at nucleotide 1301. Protein modeling indicates the impaired surface hydrophobicity of NrdE(Ts) due to the S434F transition.


Synthesis of chitin nanocrystals supported Zn2+ with high activity against tobacco mosaic virus.
Chitin is a kind of natural nitrogenous organic polysaccharide. It contains antibacterial and antiviral properties, and it can induce plant disease resistance and promote plant growth. However, its application is constrained due to its insolubility and intricate molecular structure. Tobacco mosaic disease is caused by tobacco mosaic virus (TMV) infection, which seriously harms tobacco production. Zinc-containing chemical agents are commonly used to control tobacco mosaic disease, but overuse of chemical agents will cause serious environmental pollution. In this study, a novel nanomaterial (ChNC@Zn) was prepared by using chitin nanocrystals loaded with Zn2+, which has the function of inducing disease resistance to plants and reducing virus activity. When the Zn2+ concentration of ChNC@Zn is 105.6 μg/mL, it shows higher resistance to TMV than Lentinan (LNT). ChNC@Zn can improve the enzymes activities of peroxidase (POD) and catalase (CAT) in tobacco, and reduce the damage of reactive oxygen species (ROS) caused by TMV infection, thereby inducing resistance to TMV in tobacco. Besides, it can promote the growth of tobacco. As a result, ChNC@Zn can exhibit strong antiviral activity at low Zn2+ concentration and minimize the pollution of Zn2+ to the environment, which has high potential application value in the control of virus disease.


Adapting the layered learning model to a virtual international exchange program.
The layered learning model (LLM) is a well-established teaching approach designed for attending preceptors to train post-graduate learners and to precept students. The adaptation of a LLM to a virtual exchange program has not been previously described. The purpose of this study was to evaluate the effectiveness of the longitudinal virtual international exchange program in applying principles of the LLM to multiple levels of learners and instructors at West Virginia University (WVU) School of Pharmacy and Kitasato University (KU) School of Pharmacy. The online survey piloted the impact of applying the LLM to virtual international exchange sessions on improving participant knowledge in pharmacy practice, pharmacy education, cultural practices, and cultural awareness. The survey questions assessed the program's structure and effectiveness in achieving learning outcomes related to pharmacy residency topics and cultural competency using a five-point Likert scale. Median scores of the effectiveness of the virtual international exchange program structure were high (≥ 4.0). Two questions evaluating the use of the LLM had median scores of 4.0. All nine residency-related questions were rated ≥3.0. The median scores for three questions evaluating small group discussions and the use of the LLM were rated significantly higher by WVU participants than KU participants. There were no significant differences in program structure and learning outcome ratings between participant groups (student vs. resident/fellow vs. preceptor/faculty). Application of the LLM to the virtual international exchange program was positively received by participants, particularly by United States participants.


Limited contribution of health behaviours to expanding income-related chronic disease disparities based on a nationwide cross-sectional study in China.
This study estimated the association of income and prevalence of cardiovascular diseases (CVD) and hypertension, and then quantified the contribution of health behaviors to the association in China. Using the 2013 survey of the China Health and Retirement Longitudinal Study (CHARLS), a logit model was applied to examine income-related health disparities in relation to CVD and hypertension. A four-step regression method was then constructed to measure the role of health behaviors in income-related health disparities. Using indirect effects, mediation by health behaviors was examined. Income-related health disparities in chronic diseases were found to exist in China. Specifically, individuals in the high-income group had a 14% (OR = 0.86; 95% CI 0.73-1.02) and 14% (OR = 0.86; 95% CI 0.76-0.97) lower odds of suffering from CVD and hypertension than those in the low-income group. However, limited evidence shows this association was mediated by health behaviors. The Heaviness of Smoking Index (HSI), heavy drinking, irregular eating, and nap time did not significantly mediate the association of income and prevalence of CVD and hypertension. To curb the rising prevalence of CVD and hypertension in China, policies should focus on the low-income subpopulation. However, healthy behaviors interventions targeting smoking, heavy drinking, unhealthy napping and irregular eating habits among low-income people may be ineffective in reduction of income-related disparities in prevalence of CVD and hypertension.


Low levels of 25(OH)D and insulin-resistance: 2 unrelated features or a cause-effect in PCOS?
Recent investigations have identified low vitamin D status as a hypothetical mechanism of insulin-resistance in Polycystic Ovary Syndrome (PCOS). Instead, some authors supported the hypothesis that low vitamin D levels and insulin-resistance are 2 unrelated features of body size in PCOS. Hence, we aimed to explore the association of 25-hydroxyvitamin D (25(OH)D) with anthropometric, metabolic and hormonal features in PCOS. We assessed the association of low 25(OH)D levels with endocrine parameters, insulin-sensitivity evaluated by hyperinsulinemic euglycemic clamp (HEC) and body composition measured by DEXA in 38 women affected by PCOS. Low 25(OH)D (25(OH)D < 50 nmo/L) was detected in 37% of the entire cohort of patients. Body Mass Index (BMI), in particular total fat mass (p < 0.001), resulted to be the most predictor factor of 25(OH)D levels whereas Sex Hormone Binding Globulin (SHBG), Free Androgen Index (FAI), glucose uptake and fat free mass were not. Our data demonstrated that in PCOS low 25(OH)D levels are significantly determined by the degree of adiposity.


Prognostic implications of protein S-100beta serum levels in the clinical outcome of high-risk melanoma patients.
It was the aim of this study to analyze the clinical value of the determination of serum S-100beta protein in high-risk melanoma patients. Patients were tested for serum S-100beta protein by luminoimmunometric assay after melanoma surgical excision, before starting interferon-alpha2b and every 3 months thereafter, until treatment was completed. Ninety-seven patients were included in the study. Median follow-up was 62.9 months (range 32.7-87.4). High baseline S-100beta levels were associated with positive lymph node status (p = 0.02). High S-100beta levels (during therapy) showed a relation with positive lymph node status (p = 0.014), number of positive lymph nodes (p = 0.01), macroscopic lymph node involvement (p = 0.002) and second melanoma diagnosis at study entry (p = 0.001). By univariate analysis, high baseline S-100beta levels were associated with disease-free survival (p = 0.004) and overall survival (p = 0.0007). Similarly, high S-100beta levels during therapy were associated with disease-free survival (p < 0.0001) and overall survival (p < 0.0001). In the multivariate analysis, high S-100beta levels during therapy (hazard ratio 1.017, 95% CI 1.008-1.026; p < 0.0001) and high baseline S-100beta levels (hazard ratio 3.31, 95% CI 1.10-9.89; p = 0.032) were independent prognostic factors for overall survival when compared with low levels while on therapy and low baseline S-100beta levels, respectively. These results provide evidence of the clinical usefulness of serum S-100beta level determination in high-risk melanoma patients. S-100beta serum determination should be considered to be included in clinical trials that test adjuvant therapies in melanoma patients.


Caregivers' experience of seeking care for adolescents with sickle cell disease in a tertiary care hospital in Bahrain.
This study aimed to determine caregivers' perspectives on difficulties encountered while seeking care for adolescents with sickle cell disease (SCD). It explored the social, emotional, and financial impact of caring for an adolescent with SCD on their caregivers. A mixed-method study in a major tertiary care hospital in Bahrain was conducted between June and August 2019. Cross-sectional questionnaires and thematic analyzed interviews were performed with 101 and 18 Bahraini caregivers of adolescents with SCD (aged 10-18 years), respectively. Lack of parking lots (52.5%) and traffic jams (27%) were identified as the most common challenges in seeking hospital care for adolescents with SCD. These difficulties, including prolonged waiting in the emergency room, discouraged more than half of the caregivers who preferred to seek care from smaller healthcare centers. Most caregivers reported receiving a high degree of support from their families, who emotionally encouraged them to facilitate patient care (73.3%). Therefore, their relationships with their friends, colleagues, and relatives were not significantly affected. Catastrophic health expenditure occurred in 14.8% of caregivers. Qualitative themes that emerged were A) the intricacy of caring for adolescents with SCD, B) dissatisfaction with hospital facilities, and C) insufficient healthcare services, wherein caregivers reported adolescents' experiences with services during hospital visits. Subthemes for the intricacy of caring for adolescents with SCD were 1) the psychological tragedy, summarizing the initial caregivers' feelings after the confirmed diagnosis, 2) caregiving hardships that described the caregivers' emotional and health burden while accepting and adjusting to the disease, and 3) the cost of care on families, which highlights the financial burden of the disease on families. The caregivers of adolescents with SCD experienced several overwhelming challenges, including problems in accessing healthcare and receiving medical services, in addition to influences on the emotional, financial, and social aspects of their lives.


Mites and related disease.
Parasitic mites cause a variety of dermatoses in domestic animals. The clinical signs, diagnosis, and treatment of canine and feline demodicosis, canine scabies, notoedric mange, cheyletiellosis, otodectic mange, and other mite infestations are discussed.


Relationship between oral health and physical frailty in patients with cardiovascular disease.
Oral health is important for maintaining general health and is associated with components of physical frailty among the elderly. Oral health problems are common in hospitalized patients; however, no reports on oral health problems pertain to patients with cardiovascular diseases (CVD). The present study aimed to evaluate the association between oral health and physical frailty in these patients. In this retrospective cohort study, we included consecutive patients admitted for CVD to our hospital between May 2014 and December 2018. Physical frailty was assessed using the Short Physical Performance Battery (SPPB). Oral health characteristics, such as the number of remaining teeth, denture use, occlusal support, and periodontal status, were assessed. In our cohort (n = 457), 111 (24.3%) patients had physical frailty. Univariate linear regression showed that the number of teeth present and the prevalence of occlusal support were significantly lower in patients with than without physical frailty. Pearson correlation indicated that the number of teeth significantly correlated with the nutritional status (r = 0.27) and SPPB score (r = 0.24), grip strength (r = 0.33), and 6-minute walking distance (r = 0.26). Multiple linear regression analysis showed that the number of teeth was independently associated with physical frailty after adjusting for confounders. Oral health was closely associated with physical frailty, and nutritional status in patients with CVD; thus, it could be an important screening marker for early frailty symptoms and a predictor of future malnutrition risk.


The structure of Ap(4)A hydrolase complexed with ATP-MgF(x) reveals the basis of substrate binding.
Ap(4)A hydrolases are Nudix enzymes that regulate intracellular dinucleoside polyphosphate concentrations, implicating them in a range of biological events, including heat shock and metabolic stress. We have demonstrated that ATP x MgF(x) can be used to mimic substrates in the binding site of Ap(4)A hydrolase from Lupinus angustifolius and that, unlike previous substrate analogs, it is in slow exchange with the enzyme. The three-dimensional structure of the enzyme complexed with ATP x MgF(x) was solved and shows significant conformational changes. The substrate binding site of L. angustifolius Ap(4)A hydrolase differs markedly from the two previously published Nudix enzymes, ADP-ribose pyrophosphatase and MutT, despite their common fold and the conservation of active site residues. The majority of residues involved in substrate binding are conserved in asymmetrical Ap(4)A hydrolases from pathogenic bacteria, but are absent in their human counterparts, suggesting that it might be possible to generate compounds that target bacterial, but not human, Ap(4)A hydrolases.


"The communication and support from the health professional is incredibly important": A qualitative study exploring the processes and practices that support parental decision-making about postmortem examination.
Consent rates for postmortem (PM) examination in the perinatal and paediatric setting have dropped significantly in the United Kingdom, the United States, and the Western Europe. We explored the factors that act as facilitators or barriers to consent and identified processes and practices that support parental decision-making. A qualitative study conducted with bereaved parents, parent advocates, and health care professionals in the United Kingdom. Analysis was conducted on 439 free-tect comments within a cross-sectional survey, interviews with a subset of 20 survey respondents and 25 health professionals, and a focus group with five parent advocates. Three broad parental decision-making groups were identified: 1, "Not open to postmortem examination"; 2, "Consent regardless of concerns"; and 3, "Initially undecided." Decisional drivers that were particularly important for this "undecided" group were "the initial approach," "adjustment and deliberation," "detailed discussion about the procedure," and "formal consent." The way in which these were managed by health care staff significantly impacted whether those parents' consented to PM, particularly for those who are ambivalent about the procedure. We propose a set of recommendations to improve the way PM counselling and consent is managed. Adopting such measures is likely to lead to improved family experience and more consistent and high-quality discussion regarding PM.


A methodological framework for coastal development assessment: A case study of Fujian Province, China.
Decision-makers often have to make trade-offs between economic growth and environmental conservation when developing and managing coastal environments. Coastal development and management need to be subject to rigorous assessments to determine if they are sustainable over time. We propose a methodological framework - the Coastal Development Index (CDI) for the assessment of the changes in sustainability of coastal development over time. CDI is a modified version of the Ocean Health Index (OHI) but with two new indicators - ecological and environmental indicators (EEI), and social and economic indicators (SEI), both of which comprise three sub-indicators (coastal protection, clean waters and species protection for EEI, and food provision, coastal livelihoods and economies and tourism and recreation for SEI). The six sub-indicators represent key aspects of coastal development and the level of exploitation of natural resources that have previously been missing in other conceptual frameworks. We demonstrate the value of CDI with a detailed case study of Fujian Province in China, 2000-2013. The scores of CDI decreased from 1.01 in 2000 to 0.42 in 2013 suggesting that the Fujian coastal zone has experienced unsustainable development in that time. Meanwhile, the scores of EEI decreased from 22.1 to 20.4 while the scores of SEI increased from 21.9 to 48.1 suggesting that environmental values have been eroded by economic growth. Analysis of the scores of sub-indicators reveals a need to integrate economic growth and social development with environmental conservation on Fujian coastal management. Our case study highlights the potential value of the CDI for improving the ecological sustainability of coastal zone management and development practices.


Anatomy of the middle rectal artery: a review of the historical literature.
The middle rectal artery is a very important anatomical structure in rectal cancer surgery. It is the only vessel that penetrates through the proper rectal fascia into the pelvic cavity, and therefore threatens the integrity of total mesorectal excision. Moreover, it is very closely related to the lateral lymphatic drainage root. The definition of the middle rectal artery is ambiguous, and different frequencies, origins, and trajectories have been reported in various papers. The frequency of the middle rectal artery is reported to range from 12 to 97 %. Traditionally, the middle rectal artery is described as an artery that penetrates the pelvic plexus from the lateral side along with the lateral ligament; the frequency of this lateral type of middle rectal artery ranges from 20 to 30 %. However, the reports that describe higher frequency values also consider another type of middle rectal artery, which penetrates the neuro-vascular bundle from the antero-lateral direction; this antero-lateral type of middle rectal artery tends to be a small vessel, and frequently forms a common trunk with the prostatic artery. With advancements in endoscopic surgery, the knowledge of the precise anatomy of this structure is becoming more crucial for optimal rectal cancer surgery.


Perinatal infection and vaginal flora.
Vaginal cultures were obtained from 1, 083 mothers on admission to the labor floor. The additional bacteriologic information gained from this survey was not sufficient to warrant continued use of the admission vaginal culture as a screening procedure.


Arthroscopic assistance during open reduction and fixation for complex acetabular fractures.
Achieving an anatomical reduction in acetabular fracture is essential but may also be challenging. Most of complex fractures are treated with anterior approaches without direct visualization of the acetabular surface. In this paper, we present the surgical technique for arthroscopic assistance during open reduction and fixation for complex acetabular fractures. To our knowledge, this technique has not been described in the literature yet.


Fusobacterium nucleatum biofilm induces epithelial migration in an organotypic model of dento-gingival junction.
Effects of Fusobacterium nucleatum (F. nucleatum) biofilm on epithelial cell proliferation, apoptotic cell death, and basement membrane constituent collagen IV production were examined in an organotypic dento-epithelial (OD-E) model. The OD-E model was constructed by seeding keratinocytes on fibroblast-containing collagen gels and by placing tooth pieces on top. A 3-day-old biofilm either a laboratory strain (American Type Culture Collection [ATCC] 25586) or a clinical strain (Anaerobe Helsinki Negative [AHN] 9508) of F. nucleatum was placed on the top of the model. The coculture was incubated ≤24 hours. The expression and localization of Ki-67, caspase-3, and collagen IV were examined by immunohistochemistry. Hematoxylin and eosin staining showed epithelial migration and lateral sprouting into the connective tissue matrix in F. nucleatum OD-E cocultures. The proliferation pattern of the in vitro dento-epithelial junction was changed. In controls without bacterial challenge, the Ki-67 expression was abundant in the cells attached to the tooth, whereas in F. nucleatum biofilm-treated cultures, the Ki-67-expressing cells were more often in the connective tissue-facing side of the epithelium. An apoptotic marker caspase-3 was expressed in controls and in F. nucleatum laboratory strain ATCC cocultures throughout the epithelium, in contrast to cultures treated with F. nucleatum clinical strain AHN, in which caspase-3 was absent. Collagen IV stainings were negative in both controls and F. nucleatum cocultures. F. nucleatum biofilm coculture with OD-E model causes lateral sprouting of the epithelium with an altered epithelial proliferation pattern, resembling the histologic changes seen in vivo in the early pathogenesis of periodontal disease.


Variability in the P1 gene helps to refine phylogenetic relationships among leek yellow stripe virus isolates from garlic.
Nucleotide sequences from the P1 gene and the 5' untranslated region of leek yellow stripe virus (LYSV), collected from several locations, were used to refine the phylogenetic relationships among the isolates. Multiple alignments revealed three distinct regions of insertions and deletions to classify LYSVs. In our phylogenetic analyses, the LYSV isolates separated into two major groups (N-type and S-type). S-type viruses had two large deletions compared to N-type viruses. Considering that the outgroup, onion yellow dwarf virus (OYDV) also has the sequences corresponding to the deletions in the S-type viruses, our study shows that the sequences missing in the S-type were present in the common ancestor of the N-type and S-type. In the phylogenetic trees, we found three distinct clades of isolates, from Uruguay (U), Okinawa (O) and Spain (Sp), suggesting that LYSVs have unique evolutionary histories depending on their garlic origins. The P1 gene of LYSV is thus quite suited to reflecting viral evolution, as recently suggested for other potyviruses.


A minor transplantation antigen detected by MHC-restricted cytotoxic T lymphocytes during graft-versus-host disease.
Transplantation of bone marrow can give rise to graft-versus-host disease when donor T lymphocytes, mismatched with the host for major histocompatability (MHC) antigens, become sensitized and attack host tissues. However, graft-versus-host disease can also arise between donor and host with compatible MHC antigens but mismatched for a minor histocompatability antigen. We report here on the occurrence of severe acute graft-versus-host disease in a male patient with acute myeloid leukaemia who had received bone marrow matched for MHC (HLA) antigens from his sister. Strong cytotoxicity of the posttransplantation (that is, donor) lymphocytes against the patient's pretransplantation lymphocytes was found. Thus, the transplanted lymphocytes differed in a non-HLA antigen from the patient. The possible role of this strong cytotoxic minor histocompatability antigen in the development of graft-versus-host disease in man is being evaluated. Furthermore, with the use of cytotoxic T-cell lines, derived from the patient's 6 day effector cells, we are now able to type for it before grafting.


Measurement of tendon reflexes by surface electromyography in normal subjects.
A simple method for measuring the tendon reflexes was developed. A manually operated, electronic reflex hammer was applied that enabled measurement of the strength of tendon taps. Reflex responses were recorded by surface electromyography. Stimulus-response relations and latencies of tendon reflexes in the biceps, triceps, quadriceps and triceps surae were examined in 40 healthy subjects. A characteristic relation between stimulus strength and response amplitude was found which could be described by an empirical function. Latencies of both arm and leg reflexes were linearly related to the height of the subjects. Variations of reflex amplitudes within and between subjects were comparable with previous results obtained with more complicated techniques. Although repeatability of measurement of the amplitude is limited by the variability of reflexes, significant agreement was found between repeated measurements. Most reflex amplitudes were diminished during repeated examination after a short interval. Both measurement and clinical examination showed the frequent occurrence of left-right asymmetry of reflex amplitudes. These left-right differences were reproducible to a significant degree on repeated measurements after more than 2 years.


An improved synthesis of 6beta-hydroxy-5beta-pregnane-3,20-dione.
6beta-Hydroxy-5beta-pregnane-3,20-dione, formerly prepared by hydroboration method, has been obtained in greatly improved yield by a simpler irradiation-hydrogenation procedure.


Kinetic Analysis of Ultrasound-Induced Oil Exchange in Oil-in-Water Emulsions through Contrast Variation Time-Resolved Small-Angle Neutron Scattering.
Ultrasound is one of the most commonly used methods for synthesizing and processing emulsion systems. In this study, the kinetics of acoustically induced emulsion oil exchange was examined using contrast variation time-resolved small-angle neutron scattering (CV-SANS). A custom-built sample environment was used to deliver acoustic forces while simultaneously performing CV-SANS experiments. It was observed that the oil exchange rate was significantly accelerated when sonicating at high acoustic pressures, where violent cavitation events can induce droplet coalescence and breakup. No significant oil exchange occurred at acoustic pressures below the cavitation threshold within the short time scales of the experiments. It was also observed that the oil exchange kinetics was deterred when emulsions were stabilized by surfactants. In addition, oil exchange rates varied nonlinearly with the concentration of surfactant, and exchange was slowest when the emulsions were stabilized by an intermediate concentration. It is hypothesized that emulsion size, electrostatic repulsion, and Gibbs elasticity of the oil-water interface play significant roles in the observed trends. The observed trends in oil exchange rates versus surfactant concentration coincide well with theoretical models for the fluctuation of the elasticity of the interface. Acoustically induced oil exchange was most inefficient when the interfacial elasticity was at its maximum value.


Optimization of RiPCA for the Live-Cell Detection of Pre-MicroRNA-Protein Interactions.
Advancements in methods for identifying RNA-protein interactions (RPIs) on a large scale has necessitated the development of assays for validation of these interactions, particularly in living cells. We previously reported the development of RiPCA (RNA interaction with protein-mediated complementation assay) to enable the cellular detection of the well-characterized interaction between the pre-microRNA, pre-let-7, and its RNA-binding protein (RBP) partner Lin28. In this study, the applicability of RiPCA for the detection of putative pre-miRNA-protein interactions was explored using an improved RiPCA protocol, termed RiPCA 2.0. RiPCA 2.0 was adapted to detect the sequence specificity of the RBPs hnRNP A1, Msi1, and Msi2 for reported pre-microRNA binding partners. Additionally, the ability of RiPCA 2.0 to detect site-specific binding was explored. Collectively, this work highlights the versatility of RiPCA 2.0 in detecting cellular RPIs.


Review: Antibacterial components of the Bivalve's immune system and the potential of freshwater bivalves as a source of new antibacterial compounds.
Antibacterial research is reaching new heights due to the increasing demand for the discovery of new substances capable of inhibiting bacteria, especially to respond to the appearance of more and more multi-resistant strains. Bivalves show enormous potential for the finding of new antibacterial compounds, although for that to be further explored, more research needs to be made regarding the immune system of these organisms. Beyond their primary cellular component responsible for bacterial recognition and destruction, the haemocytes, bivalves have various other antibacterial units dissolved in the haemolymph that intervene in the defense against bacterial infections, from the recognition factors that detect different bacteria to the effector molecules carrying destructive properties. Moreover, to better comprehend the immune system, it is important to understand the different survival strategies that bacteria possess in order to stay alive from the host's defenses. This work reviews the current literature regarding the components that intervene in a bacterial infection, as well as discussing the enormous potential that freshwater bivalves have in the discovery of new antibacterial compounds.


Increased cancer mortality among Japanese individuals with hyperinsulinemia.
To evaluate the effect of hyperinsulinemia on cancer death, we clarified the association between hyperinsulinemia and cancer mortality among Japanese individuals. All the participants (5586 men and 6652 women) lived in Hiroshima City, underwent a 75 g oral glucose tolerance test between 1994 and 2012, and were followed for mortality until August 2013. A systematic review of death certificates was used to confirm the cause of death. During the follow-up period (median, 10.0 years), 587 participants died of cancer. Lung cancer was the most common cause of organ-specific death. We divided the participants into 3 groups according to the tertiles of fasting immunoreactive insulin (FIRI) levels (low, middle, and high groups). The high group had the highest mortality rate (5.5 per 1000 person-years). The hazard ratio (HR) for cancer mortality of the high group after adjustment for possible confounders, such as age, sex, body mass index, smoking status, alcohol intake, and radiation effects (model 1), was significantly higher than that of the low group (HR, 1.55; 95% confidence interval (CI), 1.23-1.95). In model 2 (model 1 plus fasting plasma glucose) and model 3 (model 1 plus HbA1c), the multivariate HRs for cancer mortality were 1.46 (95% CI, 1.15-1.85) and 1.48 (95% CI, 1.17-1.87), respectively.The HR for cancer death at high FIRI levels (per 1 μU/mL) was 1.04 (95% CI, 1.02-1.05) in all participants after adjusting for fasting plasma glucose level and other confounders. In the subgroup analysis, the HRs were 1.03 (95% CI, 0.98-1.09), 1.05 (95% CI, 1.02-1.08), and 1.04 (95% CI, 1.02-1.06) in the normal, prediabetes, and diabetes group, respectively. Hyperinsulinemia was associated with a high risk of cancer mortality and may be an important link between cancer mortality and diabetes or prediabetes.


Electronic surveillance and using administrative data to identify healthcare associated infections.
Traditional surveillance of healthcare associated infections (HCAI) is time consuming and error-prone. We have analysed literature of the past year to look at new developments in this field. It is divided into three parts: new algorithms for electronic surveillance, the use of administrative data for surveillance of HCAI, and the definition of new endpoints of surveillance, in accordance with an automatic surveillance approach. Most studies investigating electronic surveillance of HCAI have concentrated on bloodstream infection or surgical site infection. However, the lack of important parameters in hospital databases can lead to misleading results. The accuracy of administrative coding data was poor at identifying HCAI. New endpoints should be defined for automatic detection, with the most crucial step being to win clinicians' acceptance. Electronic surveillance with conventional endpoints is a successful method when hospital information systems implemented key changes and enhancements. One requirement is the access to systems for hospital administration and clinical databases.Although the primary source of data for HCAI surveillance is not administrative coding data, these are important components of a hospital-wide programme of automated surveillance. The implementation of new endpoints for surveillance is an approach which needs to be discussed further.


Glutathione peroxidase expression and activity in barley root tip after short-term treatment with cadmium, hydrogen peroxide and t-butyl hydroperoxide.
The purpose of this study was to analyse the alterations of glutathione peroxidase (GPX) expression and activity during the recovery period after a short-term treatment of barley root tip with cadmium (Cd) and hydrogen peroxide (H(2)O(2)). The transcript level of GPX increased as early as 1 h and GPX activity 3 h after short-term treatment independently of Cd concentration. In 15 μM Cd-treated roots, its expression reached a peak within 2 h and sustained until 3 h, after which it gradually declined. After 6 h of short-term Cd treatment, the activity of GPX was the highest in the 15-μM Cd-treated roots. At higher Cd concentrations, the activity of GPX was lower than in 15 μM Cd-treated roots, but still higher than in control roots. A considerable increase in H(2)O(2) production was observed even after only 1 h of short-term exposure of roots to 30 and 60 μM Cd, while after 15 μM Cd exposure, its production increased 3 h after the treatment. Lipid peroxidation increased even 1 h after short-term treatment in a Cd concentration-dependent manner. A considerable decrease of GPX activity was observed after the exposure of roots to H(2)O(2) or t-butyl hydroperoxide in a concentration-dependent manner despite that its expression increased even 1 h after short-term treatment. Presumable, under high acute Cd stress, rapid accumulation of H(2)O(2) leads to the disturbance of basal metabolic processes affecting also GPX activity. In contrast, high GPX activity under moderate Cd stress maintains cell function despite the high rate of H(2)O(2) metabolism in root tip.


Differentiation of cultured epidermal keratinocytes related to sterol metabolism and its retardation by chemical carcinogens.
The amount of 5 beta-cholest-7-en-3 beta-ol of mouse dorsal skin was increased after parturition until 10 days of age, reaching a maximum 5 beta-cholest-7-en-3 beta-ol/5-cholesten-3 beta-ol ratio of 0.43. [2-14C]Acetate was incorporated almost exclusively into 5-cholesten-3 beta-ol in the basal cell culture of epidermal keratinocytes. However, when the concentration of calcium was changed from 0.07 to 1.9 mM to induce terminal differentiation of keratinocytes, a definite amount of radioactive acetate was incorporated into 5 beta-cholest-7-en-3 beta-ol. The extent of the incorporation was increased at least until 72 h after changing medium, and the ratio of radioactive 5 beta-cholest-7-en-3 beta-ol/radioactive 5-cholesten-3 beta-ol was constantly increased in this period, indicating that the accumulation of 5 beta-cholest-7-en-3 beta-ol in the cell is concomitant with the differentiation of the cell. Pretreatment with chemical carcinogens such as 7,12-dimethylbenz[a]anthracene and 20-methylcholanthrene inhibited the incorporation of radioactive acetate into 5 beta-cholest-7-en-3 beta-ol in the high calcium medium at least for the initial 24 h. After that, the incorporation was gradually restored to the normal level. Pretreatment with a tumor promoter, such as 12-O-tetradecanoyl-phorbol 13-acetate, however, did not inhibit the incorporation. Thus, sterol metabolism is suggested to be a useful indicator for differentiation of epidermal keratinocytes.


A review of comparative responses of men and women to heat stress.
Most of our present knowledge regarding human responses to thermal stress is primarily a result of research conducted on male subjects. Recently, as women have moved into the industrial workplace and forefront of athletic activity, attention has turned to comparative responses of men and women. Very limited research on preadolescent children suggests no physiological thermoregulatory sex differences except for a slightly higher sweat rate in lean boys as compared to lean girls of a similar age. Boys also tended to be more tolerant of higher temperatures. Current beliefs regarding men and women are: Women, as a population, are less tolerant to a given imposed heat stress; however, if cardiovascular fitness level, body size, and acclimation state are standardized, the differences tend to disappear; women have a lower sweat rate than men of equal fitness, size, and acclimation which is disadvantageous in hot-dry environments, but advantageous in hot-wet environments; and menstrual cycle effects are minimal. It is concluded that aerobic capacity, surface area-to-mass ratio, and state of acclimation are more important than sex in determining physiological responses to heat stress.


The effect of temperature on size and development in three species of benthic copepod.
The effect of temperature on the size and development times of three benthic cyclopoid copepods, Acanthocyclops viridis, A. vernalis and Macrocyclops albidus were investigated within the normal environmental temperature range (5°C-20°C). Adult weight decreased as temperature increased. All three species complete their development at 5°C and development times at all temperatures are presented as curvilinear logarithmic temperature functions. The duration of development decreases as temperature rises. The results are compared with those reported else-where for benthic and planktonic species and the ecological implications are discussed.


Single cuprous oxide films synthesized by radical oxidation at low temperature for PV application: notice of redundant publication.
This is a notice of redundant publication regarding Opt. Express21, 11448 (2013)10.1364/OE.21.011448.


Eukaryotic Transcription Turns 50.
This year we celebrate the 50th anniversary of the discovery of the three eukaryotic RNA polymerases. Ever since this seminal event in 1969, researchers have investigated the intricate mechanisms of gene transcription with great dedication. The transcription field continues to influence developmental, stem cell, and cancer biology.


Impacts of climate and land use/cover changes on streamflow at Kibungo sub-catchment, Tanzania.
The impacts of changing climate and land use/cover on streamflow in the Kibungo sub-catchment were evaluated using the Soil and Water Assessment Tool (SWAT). Rainfall, minimum, and maximum temperature data for six stations from the ensemble mean of the RCMs (RCA4, RACMO22T, CCLM4-8-17) were used under RCP 4.5 and RCP 8.5. The homogeneity and trend test were used to detect the change point and identify the pattern in the annual time series, respectively. Land Change Modeler (LCM) was used to predict land use maps of 2040 and 2070 from historical maps. Streamflow was simulated for 2021-2040 and 2041-2070 based on the homogeneity test results. The model calibration (2009-2016) and validation (2009-2016) for streamflow were successful. The homogeneity test detects a change point in 2040. A significant decrease in annual rainfall by 22.9 mm/yr (RCP 4.5) and 57 mm/yr (RCP 8.5) for 2021-2040 and an insignificant decrease was obtained during 2041-2070 under both emission scenarios. The annual temperature increased insignificantly by 0.004 °C/yr under RCP 4.5 while a significant increase of 0.21 °C/yr under RCP 8.5 was observed for 2021-2040. For 2041-2070, a significant increase of 0.016 °C/yr (RCP 4.5) and 0.045 °C/yr (RCP 8.5) was observed. The change in land use/cover resulted in increasing the build-up area (84%), agricultural fields (55.6%), and a decrease in the forest area (10.5%) during 2021-2040. During 2041-2070, the build-up area increased by 32.1%, the agricultural field by 36%, and the forest area decreased by 11%. Streamflow decreased significantly by 65.4 m3/yr (RCP 4.5) and 195.9 m3/yr (RCP 8.5) from 2021 to 2040. An insignificant decrease of 13.7 m3/s (RCP 4.5) and 7.63 m3/s (RCP 8.5) was observed during 2041-2070. This study provides an insight to the managers, planners, and policymakers on environmental protection/conservation for sustainable utilization of water resources at the Kibungo sub-catchment.


Before the next storm: some evidence-based reminders about temporary release.
This article offers a long overdue comprehensive review of the literature on the effectiveness of temporary release programs for prisoners. Following an account of how the public and criminal justice workers view temporary release, and against the "nothing works" proposition, it is shown that while in the community, prisoners tend to spend their time constructively and comply with the rules and regulations of temporary release; both home leave and work release schemes can be effective in reducing recidivism rates, and work release in particular may also enhance postrelease employment prospects.


Chemically identifying single adatoms with single-bond sensitivity during oxidation reactions of borophene.
The chemical interrogation of individual atomic adsorbates on a surface significantly contributes to understanding the atomic-scale processes behind on-surface reactions. However, it remains highly challenging for current imaging or spectroscopic methods to achieve such a high chemical spatial resolution. Here we show that single oxygen adatoms on a boron monolayer (i.e., borophene) can be identified and mapped via ultrahigh vacuum tip-enhanced Raman spectroscopy (UHV-TERS) with ~4.8 Å spatial resolution and single bond (B-O) sensitivity. With this capability, we realize the atomically defined, chemically homogeneous, and thermally reversible oxidation of borophene via atomic oxygen in UHV. Furthermore, we reveal the propensity of borophene towards molecular oxygen activation at room temperature and phase-dependent chemical properties. In addition to offering atomic-level insights into the oxidation of borophene, this work demonstrates UHV-TERS as a powerful tool to probe the local chemistry of surface adsorbates in the atomic regime with widespread utilities in heterogeneous catalysis, on-surface molecular engineering, and low-dimensional materials.


C-terminal domains within human MT1 and MT2 melatonin receptors are involved in internalization processes.
Melatonin, a molecule implicated in a variety of diseases, including cancer, often exerts its effects through G-protein-coupled melatonin receptors, MT(1) and MT(2). In this study, we sought to understand further the domains involved in the function and desensitization patterns of these receptors through site-directed mutagenesis. Two mutations were constructed in the cytoplasmic C-terminal tail of each receptor subtype: (i) a cysteine residue in the C-terminal tail was mutated to alanine, thus removing a putative palmitoylation site, and a site possibly required for normal receptor function (MT(1)C7.72A and MT(2)C7.77A) and (ii) the C-terminal tail in the MT(1) and MT(2) receptors was truncated, removing the putative phosphorylation and beta-arrestin binding sites (MT(1)Y7.64 and MT(2)Y7.64). These mutations did not alter the affinity of 2-[(125)I]-iodomelatonin binding to the MT(1) or MT(2) receptors. Using confocal microscopy, it was determined that the putative palmitoylation site (cysteine residue) did not play a role in receptor internalization; however, this residue was essential for receptor function, as determined by 3',5'-cyclic adenosine monophosphate (cAMP) accumulation assays. Truncation of the C-terminal tail of both receptors (MT(1)Y7.64 and MT(2)Y7.64) inhibited internalization as well as the cAMP response, suggesting the importance of the C-terminal tail in these receptor functions.


Effect of childhood maltreatment on cardiovascular response habitation to repeated psychosocial stress.
Childhood maltreatment as an early-life stress leads to cardiovascular stress response dysregulation manifested by either exaggerated or blunted stress responses. However, little is known how childhood maltreatment affects cardiovascular response habituation to recurrent stress, which implicated in the long-term health effects of chronic stress. The scale of Childhood Trauma Questionnaire (CTQ) was administered to 192 healthy undergraduates who underwent continuous cardiovascular monitoring [heart rate (HR), blood pressure (BP), cardiac output (CO) and total peripheral resistance (TPR)] while facing two consecutive psychosocial stress exposures (public speaking tasks). Results showed that childhood maltreatment was negatively associated with HR and CO reactivity to the first stress exposure and HR reactivity to the second stress exposure. Even after controlling for depression symptoms, both high and low childhood maltreatment groups (upper and lower 27% of total CTQ scores) exhibited HR and CO response habituation to repeated stress exposures, but high childhood maltreatment group showed blunted HR and CO reactivity to the first stress exposure compared with low childhood maltreatment group. These findings suggest that the observed cardiovascular response habituation to repeated stress following initial blunted (i.e., inadequate) reactivity among individuals with high childhood maltreated experiences might be maladaptive, which would lead to cardiovascular disease risk.


Photocarcinogenicity of psoralens used in PUVA treatment: present status in mouse and man.
There is good evidence that 8-methoxypsoralen is photocarcinogenic in psoriatic patients undergoing long-term photochemotherapy (PUVA) in the U.S.A. However, this conclusion has not been supported by two major European studies which have indicated that PUVA is a tumour promoter of damage initiated by other agents. Variation in PUVA treatment protocols in the U.S.A. and Europe may partly account for the different conclusions. There is much interest in the therapeutic potential of monofunctional psoralens. It is hoped that these may reduce long-term risk. Monofunctional and cross-linking psoralens have been shown to be photocarcinogenic in mouse skin. The relative risk of different compounds may be assessed in the mouse, but it is important to base comparisons on dose protocols that have been shown to be therapeutically effective.


Lobular breast cancer: pathology, biology, and options for clinical intervention.
Lobular carcinoma is a breast cancer subtype comprising approximately 15 % of all breast cancer cases. Clinical diagnosis of this subtype is difficult due to a characteristic growth pattern that inhibits detection using palpation or standard X-ray mammography. While clinical intervention based on hormone antagonists has proven an effective strategy, hormone receptor negative or nonresponsive disease cannot be treated successfully, indicating the need for alternative curative approaches. In contrast to its well-defined histopathological characteristics that were first recognized a century ago, the surface of the underlying biology has only recently been scratched. Progress was made in understanding the biology of the disease, which will hopefully have its impact on future treatment modalities and initiate development of novel intervention strategies. Here, we review the pathological and molecular features of lobular breast cancer and report on the currently known mechanisms that control disease development and progression. Finally we will reflect on past, present, and future treatment options.


The timing of TNF and IFN-gamma signaling affects macrophage activation strategies during Mycobacterium tuberculosis infection.
During most infections, the population of immune cells known as macrophages are key to taking up and killing bacteria as an integral part of the immune response. However, during infection with Mycobacterium tuberculosis (Mtb), host macrophages serve as the preferred environment for mycobacterial growth. Further, killing of Mtb by macrophages is impaired unless they become activated. Activation is induced by stimulation from bacterial antigens and inflammatory cytokines derived from helper T cells. The key macrophage-activating cytokines in Mtb infection are tumor necrosis factor-alpha (TNF) and interferon (IFN)-gamma. Due to differences in cellular sources and secretion pathways for TNF and IFN-gamma, the possibility of heterogeneous cytokine distributions exists, suggesting that the timing of macrophage activation from these signals may affect activation kinetics and thus impact the outcome of Mtb infection. Here we use a mathematical model to show that negative feedback from production of nitric oxide (the key mediator of mycobacterial killing) that typically optimizes macrophage responses to activating stimuli may reduce effective killing of Mtb. Statistical sensitivity analysis predicts that if TNF and IFN-gamma signals precede infection, the level of negative feedback may have a strong effect on how effectively macrophages kill Mtb. However, this effect is relaxed when IFN-gamma or TNF+IFN-gamma signals are received coincident with infection. Under these conditions, the model suggests that negative feedback induces fast responses and an initial overshoot of nitric oxide production for given doses of TNF and IFN-gamma, favoring killing of Mtb. Together, our results suggest that direct entry of macrophages into a granuloma site (and not distal to it) from lung vascular sources represents a preferred host strategy for mycobacterial control. We examine implications of these results in establishment of latent Mtb infection.


Sex differences in long-term kidney fibrosis following neonatal nephron loss during ongoing nephrogenesis.
Clinical studies suggest that female sex plays a protective role in the development and progression of kidney disease. Recent experimental studies indicate that in male rats early nephron loss under ongoing nephrogenesis is accompanied by severe long-term sequelae. In humans, nephron formation occurs mainly in the third trimester, ceasing with 36 weeks of gestation. Due to perinatal complications, preterm infants delivered during this vulnerable period may undergo acute nephron loss. In rats nephrogenesis persists until postnatal day 10, reflecting the situation of human preterms with persisting nephrogenesis. In our animal model of neonatal uninephrectomy, female and male rats were uninephrectomized at day 1 of life. Hypothesizing sex-dependent differences, long-term renal outcome was assessed after 1 year. In both sexes, neonatal uninephrectomy was not followed by arterial hypertension at 1 year of age. Compensatory weight gain and glomerular hypertrophy of the remaining kidney occurred in uninephrectomized female and male animals. Selected markers of interstitial inflammation and fibrosis were regulated sex-dependently. The expression of monocyte chemoattractant protein-1 was increased in females, while tubulointerstitial infiltration by M1 macrophages was significantly higher in males after neonatal uninephrectomy. Neonatally uninephrectomized male rats had more glomerulosclerosis and podocyte damage compared to females, which was assessed by a semiquantitative score and desmin staining. RT-PCR revealed that after neonatal uninephrectomy in the remaining contralateral kidney of female rats the expression of candidate genes of renal development and function, i.e., wt-1, nephrin, synaptopodin, gdnf, and itga8 was higher than in males. Based on these observations we conclude that female sex is protective in the long-term response of the kidney to acute nephron loss under active nephrogenesis.