Aetiology of urethral discharge in Bangui, Central African Republic.
To determine the aetiology of urethritis in Bangui, Central African Republic. 410 men presenting with urethral discharge and 100 asymptomatic controls were enrolled. Urethral swabs were obtained and processed by gonococcal culture and polymerase chain reaction for the detection of Neisseria gonorrhoeae, Chlamydia trachomatis, Mycoplasma genitalium, Trichomonas vaginalis, and Ureaplasma urealyticum. In multivariate analyses, M genitalium and C trachomatis were significantly associated with urethral discharge when comparing cases of non-gonococcal urethritis (NGU) with controls. T vaginalis was also more common in cases than in controls, but this reached statistical significance only among cases in whom N gonorrhoeae was also detected. U urealyticum was not associated with urethritis. The gonococcus was found in 69% of cases of urethral discharge. M genitalium was the predominant pathogen in patients with NGU, being found in 42% (53/127) of such patients while C trachomatis was found in only 17% (22/127). T vaginalis was found in 18% (23/127) of patients with NGU, but also in 15% (43/283) of patients with gonococcal urethritis, and two thirds of patients with T vaginalis also had the gonococcus. Multiple infections were common. M genitalium caused a syndrome similar to chlamydial urethritis, with a less severe inflammation than in gonococcal infection. No behavioural or clinical characteristic could discriminate between the various aetiological agents. M genitalium is more prevalent than C trachomatis and is the most common cause of NGU in BANGUI: It causes a syndrome similar to chlamydial urethritis. T vaginalis is weakly associated with urethritis, and is often found along with other pathogens.


MK2: an unrecognized regulator of tumor promoting macrophages in colorectal cancer?
Colorectal cancer (CRC) is one of the most common malignancies and is associated closely with inflammation before and after development. Macrophages promote colitis and colitis-associated CRC. M1 macrophages contribute to colitis directly through the production of proinflammatory cytokines and through activation of proinflammatory immune cell phenotypes. In cancer, both M1 and M2 macrophages participate in tumor development and progression through cytokine production, changes in cell signaling and activation of T cells. We have identified the mitogen-activated protein kinase-activated protein kinase 2 (MK2) as a regulator of macrophages during colitis-associated CRC (CAC). MK2 is a proinflammatory kinase that promotes production of IL-1α, IL-1β, IL-6 and TNF-α. MK2-/- mice have decreases in macrophages, macrophage-associated chemokines, and proinflammatory cytokines. Most significantly, MK2-/- mice do not develop neoplasms in an inflammatory model of CRC. However, addition of MK2+/+ macrophages to MK2-/- mice increases production of proinflammatory cytokines. In wild type mice, both cytokines and tumor burdens increase upon addition of additional macrophages. These data support the importance of MK2 in macrophage regulation during inflammation-associated CRC.


Dielectric, haematological and biochemical studies of detergent toxicity in fish blood.
Blood characteristics in dielectric, haematological and biochemical terms of the fish Cyprinus carpio exposed to a sublethal concentration of sodium alkyl benzene sulphonate were compared with those from untreated control fish; recovery from the test solution was also checked. Trends of change in the majority of chosen parameters of blood with time of fish exposure to anionic detergent were significantly linear. A decline was noted in erythrocyte count, haematocrit, blood haemoglobin concentration, mean corpuscular haemoglobin concentration and mean corpuscular haemoglobin with the exception of mean cellular volume. An uptake of sodium into red blood cells and a rise of intracellular potassium were seen. Practical indicators of the presence of detergent in fish blood were obtained from dielectric beta dispersion measurements. It has been shown that dielectric parameters could be correlated with haematological parameters but not with a biochemical one. Results indicate that the changes in haematocrit induce corresponding variation of the maximum of the dielectric loss factor tan delta. An increase in the electrical conductivity and permittivity of the erythrocytes' interior in exposed fish was associated with a decline of mean corpuscular haemoglobin.


Statistical analysis of waste generation in healthcare services: a case study.
In the present study, the amounts of medical waste materials, sharps, liquid waste, hazardous waste, household waste and recyclables generated from 375 healthcare services including private hospitals, state hospitals, university hospitals, private medical centres, dialysis centres, cottage hospitals and private dentist surgeries were determined, and the relation between the amount of the waste and the bed capacities, inpatient and outpatient numbers were evaluated. The amount of regulated medical waste corresponded to 28.8% of the total waste streams collected from the healthcare services, and the major producers were private hospitals. The major producers of hazardous waste were state hospitals with a generation rate of 57.9%. The main results of the study indicate that the quantities of the waste streams generated from healthcare services in accordance with the outpatient number gave more appropriate results than the other evaluation methods. Furthermore, evaluation based on the bed capacities gave reasonable results except for recyclables and hazardous waste. As a result of the evaluation of the medical waste generation rate with bed capacities, the generation rate was determined as 2.11 ± 3.83 kg bed(-1) day(-1) and this rate was 1.45 ± 9.84 kg outpatient(-1) day(-1) for the evaluation by outpatient numbers. The observed significant P values (P > 0.05) indicate that the evaluation of the waste streams in healthcare services based upon outpatient numbers did not show any reasonable change according to service category.


The outcome of deep anterior lamellar keratoplasty in herpes simplex virus-related corneal scarring, complications and graft survival.
To determine the visual outcome, graft survival and complications after deep anterior lamellar keratoplasty (DALK) in patients with herpes simplex virus (HSV)-related corneal scarring. A retrospective analysis of the patients who had DALK for HSV-related corneal scarring between January 2004 and February 2007 was performed. Mean follow-up was 30 months (range 16-48 months). The statistical significance of host corneal vascularisation was determined using Fisher's exact test. There were 18 eyes from 18 patients and the mean age was 57 years. Preoperative visual acuity ranged from hand movements (HM) to 6/12. Fifty per cent of the eyes achieved visual acuity of 6/12 or better postoperatively. Six eyes (33%) had recurrence of HSV-related inflammation, eight eyes (including four eyes with recurrence of HSV-related inflammation) developed graft rejection and four eyes (including two eyes with recurrence of HSV-related inflammation) had bacterial keratitis. The graft survival rate was 83%. Three eyes developed glaucoma and one eye required trabeculectomy. Immunohistochemistry revealed that HSV was focally positive or equivocal in four recipient corneal buttons, and transmission electron microscopy showed intracellular HSV virions in two of them. This is the largest series of DALK for herpetic corneal scarring that shows a comparable visual outcome and better graft survival rate than penetrating keratoplasty. There is significant risk of recurrence of HSV-related inflammation and graft rejection that requires timely recognition and adequate management.


Differential expression of Q4 proteins (Qb-1) in fibroblasts and lymphocytes.
The Qb-1 protein is coded for by the Q4 gene. This gene appears to be widely transcribed in murine tissues. We have examined the subcellular localization and processing of Qb-1 in fibroblast cells. This protein has previously been reported to be secreted from activated lymphocytes. However, we report that high levels of Qb-1 are present on the surface of B10.P fibroblast cells. We also observed an unusual intracellular distribution for Qb-1. The protein appears to be highly concentrated in the endoplasmic reticulum, in addition to being on the surface. This distribution is not due to inefficient processing. The kinetics of Qb-1 processing and transport are not unusual for class I molecules. Complete resistance to endo-beta-N-acetylglucosaminidase H is acquired, indicating terminal processing. This unusual localization in fibroblast cells and the differential expression of this protein between cell types may reflect a specific role for Qb-1.


Versatile three-dimensional virus-based template for dye-sensitized solar cells with improved electron transport and light harvesting.
By genetically encoding affinity for inorganic materials into the capsid proteins of the M13 bacteriophage, the virus can act as a template for the synthesis of nanomaterial composites for use in various device applications. Herein, the M13 bacteriophage is employed to build a multifunctional and three-dimensional scaffold capable of improving both electron collection and light harvesting in dye-sensitized solar cells (DSSCs). This has been accomplished by binding gold nanoparticles (AuNPs) to the virus proteins and encapsulating the AuNP-virus complexes in TiO2 to produce a plasmon-enhanced and nanowire (NW)-based photoanode. The NW morphology exhibits an improved electron diffusion length compared to traditional nanoparticle-based DSSCs, and the AuNPs increase the light absorption of the dye-molecules through the phenomenon of localized surface plasmon resonance. Consequently, we report a virus-templated and plasmon-enhanced DSSC with an efficiency of 8.46%, which is achieved through optimizing both the NW morphology and the concentration of AuNPs loaded into the solar cells. In addition, we propose a theoretical model that predicts the experimentally observed trends of plasmon enhancement.


Repetitive, non-invasive imaging of neurodegeneration, and prevention of it with gene replacement, in mice with Sanfilippo syndrome.
Hampering assessment of treatment outcomes in gene therapy and other clinical trials in patients with childhood dementia is the lack of an objective, non-invasive measure of neurodegeneration. Optical coherence tomography (OCT) is a widely available, rapid, non-invasive, and quantitative method for examining the integrity of the neuroretina. Profound brain and retinal dysfunction occur in patients and animal models of childhood dementia, including Sanfilippo syndrome and we recently revealed a correlation between the age of onset and rate of progression of retinal and brain degeneration in sulfamidase-deficient Sanfilippo mice. The aim of the current study was to use OCT to visualise the discrete changes in retinal structure that occur during disease progression. A progressive decline in retinal thickness was readily observable in Sanfilippo mice using OCT, with differences seen in affected animals from 10-weeks of age. OCT applied to i.v. AAV9-sulfamidase-treated Sanfilippo mice enabled visualisation of improved retinal anatomy in living animals, an outcome confirmed via histology. Importantly, brain disease lesions were also ameliorated in treated Sanfilippo mice. The findings highlight the sensitivity, ease of repetitive use and quantitative capacity of OCT for detection of discrete changes in retinal structure and their prevention with a therapeutic. Combined with the knowledge that retinal and brain degeneration are correlated in Sanfilippo syndrome, OCT provides a window to the brain in this and potentially other childhood dementias.


Histiocytic necrotizing lymphadenitis (Kikuchi-Fujimoto's disease) mimicking systemic lupus erythematosus: a review of two cases.
Kikuchi-Fujimoto's disease (KFD), or histiocytic necrotizing lymphadenitis, is a benign and self-limited lymphadenitis commonly found in young women. It often shares clinical features with systemic lupus erythematosus (SLE), such as arthralgias, fever and leukopenia. The etiology of KFD remains unknown and controversial. Clinical course is favorable, with spontaneous remission in less than four months in almost all cases. Herein, we present two cases. The former is a 53-year old woman presenting with cervical lymphadenopathy, arthralgia, pancytopenia and positive antinuclear antibody (ANA). Lymph node biopsy revealed histopathological features compatible with Kikuchi-Fujimoto histiocytic necrotizing lymphadenitis. The latter patient was a 20-year old woman presenting with left cervical lympadenopathy, a butterfly rash that was reminiscent of SLE, and a positive antinuclear antibody. Based upon clinical, histological and laboratory findings, the diagnosis of SLE was excluded. Careful attention should be paid to differentiating between KFD and SLE, because of their similar presentations, yet different clinical courses and therapeutic requirements.


GIPR Agonism Enhances TZD-Induced Insulin Sensitivity in Obese IR Mice.
Recent studies have found that GIPR agonism can enhance the metabolic efficacy of GLP-1R agonist treatment by promoting both weight-dependent and -independent improvements on systemic insulin sensitivity. These findings have prompted new investigations aimed at better understanding the broad metabolic benefit of GIPR activation. Herein, we determined whether GIPR agonism favorably influenced the pharmacologic efficacy of the insulin sensitizing thiazolidinedione, rosiglitazone in obese insulin resistant (IR) mice. Genetic and pharmacological approaches were employed to examine the role of GIPR signaling on rosiglitazone-induced weight gain, hyperphagia, and glycemic control. RNA-sequencing was conducted to uncover potential mechanisms by which GIPR activation influences energy balance and insulin sensitivity. In line with previous findings, treatment with rosiglitazone induced the mRNA expression of the GIPR in white and brown fat. However, obese GIPR null mice dosed with rosiglitazone displayed equivalent weight gain to that of wild-type (WT) animals. Strikingly, chronic treatment of obese IR WT animals with a long-acting GIPR agonist (LAGIPRA) prevented rosiglitazone-induced weight-gain and hyperphagia, and it enhanced the insulin-sensitivity effect of this thiazolidinedione. The systemic insulin sensitization was accompanied by increased glucose disposal in brown adipose tissue (BAT), which was underlined by the recruitment of metabolic and thermogenic genes. These findings suggest that GIPR agonism can counter the negative consequences of rosiglitazone treatment on body weight and adiposity, while at the same time improving its insulin sensitizing efficacy.


Influenza virus and its mucoprotein substrate in the chorioallantoic membrane of the chick embryo. I. Characterization and quantitative assay of soluble substrate and studies on its relation to allantoic cells.
As a preliminary to a study of the fate of mucoprotein substrate in tissues infected with influenza virus, some characteristics of soluble hemagglutination inhibitors (HI) extracted from chorioallantoic membranes (CAM) have been investigated. The inhibitory material was found to be heat-stable, precipitable with cold ethanol, and subject to progressive inactivation by active viruses or by receptor-destroying enzyme (RDE). Certain changes in the slope of titration curves obtained with precipitated and non-precipitated fractions upon alcohol fractionation suggested that the HI in heated CAM extracts was heterogeneous. Alcohol in low concentration precipitated preferentially the more efficient (longer?) HI leaving the "weak" component in the non-precipitated fraction. With higher concentrations of alcobol, "strong" HI were converted to "weak" ones, either by denaturation or as result of reduced solubility. These changes in slope of titration curves were reflected in significant discrepancies when densitometric titers (HI(50)) of fractions were compared with their titers in pattern tests. The action of active viruses on HI, on the other hand, did not induce qualitative changes in the composition of the inhibitory principle: Titration curves retained parallel slopes even when their position was markedly displaced from that of control curves. In its essential properties, the HI from the CAM appeared to be similar to inhibitors isolated from various other biological sources which have been identified as mucoprotein in nature. Standards for reproducibility of inhibitory titers obtained by the densitometric method of Hirst and Pickels have been presented. The relation of HI to the allantoic epithelium has been analyzed. It has been concluded that the HI is a normal constituent and secretion product of these cells. Under physiological conditions, i.e. in the intact egg, the HI contained in the mucoid outer layer of allantoic cells appears to be protected from enzymatic action from without, although adsorption of viral particles may be temporarily impeded. In deembryonated eggs, or in excised membranes, a reduction in total inhibitory substrate as a result of the action of RDE has been observed. It has been shown in experiments on adsorption of active or heat-inactivated virus on the allantoic membrane that prevention of adsorption by RDE may require the synergistic action of the active viral enzyme itself. It has been concluded that the maintenance or restoration of a normal supply of mucoprotein substrate is a function of the ability of allantoic cells to maintain homeostatic conditions under stress.


Population-Based Estimation of the Preterm Birth Rate in Lilongwe, Malawi: Making Every Birth Count.
Objective The objective of this study was to perform a population-based estimation of the preterm birth (PTB) rate in regions surrounding Lilongwe, Malawi. Study Design We partnered with obstetrician specialists, community health workers, local midwives, and clinicians in a 50 km region surrounding Lilongwe, Malawi, to perform a population-based estimation of the PTB rate during the study period from December 1, 2012 to May 19, 2015. Results Of the 14,792 births captured, 19.3% of births were preterm, including preterm early neonatal deaths. Additional PTB risk factors were similarly prevalent including domestic violence, HIV, malaria, anemia, and malnutrition. Conclusion When performing a population-based estimation of the rate of PTB, including women without antenatal care and women delivering at home, the 19.3% rate of PTB is among the highest recorded globally. This is accompanied by a high rate of risk factors and comorbid conditions.


What are the outcomes of core decompression in patients with avascular necrosis? Protocol for a systematic review.
Background: Core decompression is a hip preserving surgical procedure that is used to treat avascular necrosis (AVN) of the femoral head. The eventual clinical and radiological outcome following this procedure is varied in literature. Also, the time to a total hip replacement (THR) from the index procedure and the percentage of patients subsequently undergoing a THR is controversial. Furthermore, there are multiple surgical methods along with multiple augmentation techniques and various classification and staging systems described. The purpose of this systematic review, therefore, is to analyse the outcomes following decompression only, excluding any augmentation techniques for non-traumatic AVN of the femoral head. Methods: This protocol is being developed in line with the PRISMA-P guidelines. The search strategy includes articles from Medline, Embase, Google Scholar, CINHAL and Cochrane library. The review and screening will be done by two independent reviewers. Review articles, editorials and correspondences will be excluded. Articles including patients with sickle cell disease and with core decompression where augmentation is used will be excluded. The risk of bias and quality of articles will be assessed using the Joanna Briggs Institute Critical Appraisal Checklist for the different study designs included. Discussion: This study will be a comprehensive review on all published articles having patients with AVN of the femoral head and undergoing core decompression surgery only. The systematic review will then define the outcomes of the core decompression surgery based on clinical and radiological outcomes. Each outcome will include the different stages within it and finally, the total mean time to THR will be calculated. This will then be followed by assessing the cumulative confidence in evidence from all the data collected using the GRADE tool. Registration: This systematic review is registered in the International Prospective Register for Systematic Reviews and Meta-analysis (PROSPERO) under the registration number: CRD42018100596.


Regional impact of climate on Japanese encephalitis in areas located near the three gorges dam.
In this study, we aim to identify key climatic factors that are associated with the transmission of Japanese encephalitis virus in areas located near the Three Gorges Dam, between 1997 and 2008. We identified three geographical regions of Chongqing, based on their distance from the Three Gorges Dam. Collectively, the three regions consisted of 12 districts from which study information was collected. Zero-Inflated Poisson Regression models were run to identify key climatic factors of the transmission of Japanese encephalitis virus for both the whole study area and for each individual region; linear regression models were conducted to examine the fluctuation of climatic variables over time during the construction of the Three Gorges Dam. Between 1997 and 2008, the incidence of Japanese encephalitis decreased throughout the entire city of Chongqing, with noticeable variations taking place in 2000, 2001 and 2006. The eastern region, which is closest to the Three Gorges Dam, suffered the highest incidence of Japanese encephalitis, while the western region experienced the lowest incidence. Linear regression models revealed that there were seasonal fluctuations of climatic variables during this period. Zero-Inflated Poisson Regression models indicated a significant positive association between temperature (with a lag of 1 and 3 months) and Japanese encephalitis incidence, and a significant negative association between rainfall (with a lag of 0 and 4 months) and Japanese encephalitis incidence. The spatial and temporal trends of Japanese encephalitis incidence that occurred in the City of Chongqing were associated with temperature and rainfall. Seasonal fluctuations of climatic variables during this period were also observed. Additional studies that focus on long-term data collection are needed to validate the findings of this study and to further explore the effects of the Three Gorges Dam on Japanese encephalitis and other related diseases.


Developmental exposure of zebrafish (Danio rerio) to 17α-ethinylestradiol affects non-reproductive behavior and fertility as adults, and increases anxiety in unexposed progeny.
Exposure to estrogenic endocrine disruptors (EDCs) during development affects fertility, reproductive and non-reproductive behavior in mammals and fish. These effects can also be transferred to coming generations. In fish, the effects of developmental EDC exposure on non-reproductive behavior are less well studied. Here, we analyze the effects of 17α-ethinylestradiol (EE2) on anxiety, shoaling behavior and fertility in zebrafish after developmental treatment and remediation in clean water until adulthood. Zebrafish embryos were exposed from day 1 to day 80 post fertilization to actual concentrations of 1.2 and 1.6ng/L EE2. After remediation for 82days non-reproductive behavior and fertilization success were analyzed in both sexes. Males and females from the 1.2ng/L group, as well as control males and females, were bred, and behavior of the untreated F1 offspring was tested as adults. Developmental treatment with 1.2 and 1.6ng/L EE2 significantly increased anxiety in the novel tank test and increased shoaling intensity in both sexes. Fertilization success was significantly reduced by EE2 in both sexes when mated with untreated fish of opposite sex. Progeny of fish treated with 1.2ng/L EE2 showed increased anxiety in the novel tank test and increased light avoidance in the scototaxis test compared to control offspring. In conclusion, developmental exposure of zebrafish to low doses of EE2 resulted in persistent changes in behavior and fertility. The behavior of unexposed progeny was affected by their parents' exposure, which might suggest transgenerational effects.


Partnering with Patients to Enhance Access to Kidney Transplantation and Living Kidney Donation.
Kidney transplantation gives many patients with kidney failure a longer and healthier life. Unfortunately, some transplant-eligible patients will never receive one. In this paper, we describe how patients and researchers collaborated on new strategies and programs to enhance access to kidney transplantation and living kidney donation. These efforts led to the creation of the Transplant Ambassador Program (TAP). TAP is a patient-led program that helps connect patients who have kidney failure to individuals who have successfully received a kidney transplant or donated a kidney. We also detail barriers, facilitators and lessons learned from engaging patients in research.


Mapping of homozygous deletions in verified esophageal adenocarcinoma cell lines and xenografts.
Human esophageal adenocarcinoma (EAC) cell lines and xenografts are powerful tools in the search for genetic alterations because these models are composed of pure human cancer cell populations without admixture of normal human cells. In particular detection of homozygous deletions (HDs) is easier using these pure populations of cancer cells. Identification of HDs could potentially lead to the subsequent identification of new tumor suppressor genes (TSGs) involved in esophageal adenocarcinogenesis. Genome wide single nucleotide polymorphism (SNP) arrays were used to identify HDs in 10 verified EAC cell lines and nine EAC xenografts. In total, 61 HDs (range 1-6 per sample) were detected and confirmed by polymerase chain reaction. Besides HDs observed in common fragile genomic regions (n = 26), and gene deserts (n = 8), 27 HDs were located in gene-containing regions. HDs were noted for known TSGs, including CDKN2A, SMAD4 and CDH3/CDH1. Twenty-two new chromosomal regions were detected harboring potentially new TSGs involved in EAC carcinogenesis. Two of these regions of homozygous loss, encompassing the ITGAV and RUNX1 gene, were detected in multiple samples indicating a potential role in the carcinogenesis of EAC. To exclude culturing artifacts, these last two deletions were confirmed by fluorescent in situ hybridization in the primary tumors of which the involved cell lines and xenografts were derived. In summary, in this report we describe the identification of HDs in a series of verified EAC cell lines and xenografts. The deletions documented here are a step forward identifying the key genes involved in EAC development.


[Ultrasound mammography:special applications (author's transl)].
Clinical observations on more than 700 patients between September 1979 and October 1980 are reported. If cysts are suspected clinically, ultrasound mammography provides the most reliable diagnosis and is superior to all other methods for localization, fine-needle biopsy and follow-up. Since it is difficult to assess (due to summation effects), the radiologically dense breast (DY) is a further indication for sonography. In case of excentrically located palpatory findings, pregnant or immobile patients, ultrasound mammography can provide valuable diagnostic information.


Vitamin D absorption in healthy subjects and in patients with intestinal malabsorption syndromes.
We developed a test procedure for the clinical evaluation of the absorption of vitamin D. Serum vitamin D concentrations were evaluated in seven patients with intestinal fat malabsorption syndromes and in seven healthy, normal subjects, after being given a single oral dose of 50,000 IU (1.25 mg) vitamin D2. In the normal subjects, serum vitamin D concentrations rose from a baseline of less than 5 ng/ml to a peak of over 50 ng/ml by 12 h, gradually falling to baseline levels by 3 days. In five of the seven patients with intestinal fat malabsorption, oral administration of 50,000 IU vitamin D2 did not raise serum vitamin D concentrations above 10 ng/ml. Two patients with severe inflammatory bowel disease had a normal absorption pattern, however. These findings suggest that an oral vitamin D absorption test may be of value for determination of patients at risk for development of vitamin D deficiency. They also raise questions about the efficacy of oral vitamin D preparations in patients with intestinal fat malabsorption.


Comparison of Eucalyptus cinerea essential oils produced by hydrodistillation and supercritical carbon dioxide extraction.
The essential oil of Eucalyptus cinerea is reported to possess a higher 1,8-cineole content than other Eucalyptus species. Variations in the quantitative and qualitative characteristics of E. cinerea oil produced by hydrodistillation (HD) and supercritical carbon dioxide extraction (SCE) techniques and a comparison between glycoside-bound and free volatile constituents produced by HD have been studied. It was found that HD produced higher oil (free volatiles) content (3.1%) as compared with SCE (1.1%), whereas bound volatiles constituted only about 0.4%. Gas chromatographic (GC) analysis of the oil samples revealed significant difference in their chemical composition. The essential oil (free volatiles) produced by HD contained 1,8-cineole (85.1%) as the major constituent, followed by a-terpineol (7.2%) and limonene (4.4%). In the bound volatile fraction produced by HD, 1,8 cineole (20.6%), alpha-terpineol (7.6%), p-cymene (6.3%), and limonene (4.5%) were found as major constituents. The extract produced by SCE was dominated by 1,8-cineole (70.4%), a-terpineol (8.6%), globulol (3.1%), aromadendrene (2%), citronellal (1.7%), viridiflorol (1.3%), phytol (1.1%) and terpinen-4-ol (1%). Although HD produced higher oil yields, SCE produced better extract in terms of the number of components detected.


Computational fluid dynamics modeling of mass-transfer behavior in a bioreactor for hairy root culture. II. Analysis of ultrasound-intensified process.
Recently, cichoric acid production from hairy roots of Echinacea purpurea was significantly improved by ultrasound stimulation in an airlift bioreactor. In this article, the possible mechanism on ultrasound-intensified hairy root culture of E. purpurea in the bioreactor was elucidated with the help of computational fluid dynamics (CFD) simulation, membrane permeability detection, dissolved oxygen concentration detection, confocal laser-scanning microscopy (LSM) observation, and phenylalanine ammonium lyase (PAL) activity analysis. The CFD model developed in Part I was used to simulate the hydrodynamics and oxygen mass transfer in hairy root bioreactor culture stimulated by ultrasound. A dynamic mesh model combined with a changing Schmidt number method was used for the simulation of the ultrasound field. Simulation results and experimental data illustrated that ultrasound intensified oxygen mass transfer in the hairy root clump, which subsequently stimulated root growth and cichoric acid biosynthesis. Ultrasound increased the hairy root membrane permeability, and a high root membrane permeability of 0.359 h(-1) was observed at the bottom region in the bioreactor. LSM observation showed that the change in the membrane permeability recovered to normal in the further culture after ultrasound stimulation. PAL activity in the hairy roots was stimulated by ultrasound increase and was correlated well to cichoric acid accumulation in the hairy roots of E. purpurea.


Neuroinflammatory responses after experimental diffuse traumatic brain injury.
Little is known about microglial activation and macrophage localization after diffuse brain injury (DBI). DBI-mediated perisomatic traumatic axonal injury (TAI) was recently identified within the neocortex, hippocampus, and thalamus, providing an opportunity to characterize immune cell responses within diffusely injured brain loci uncomplicated by contusion. By using moderate midline/central fluid percussion injury, microglial/macrophage responses were examined with antibodies targeting immune cell phenotypes and amyloid precursor protein, a marker of TAI. Parallel assessments of blood-brain barrier alterations were also performed. Within 6 to 48 hours postinjury, microglial activation within injured loci was observed, whereas microglia within non-TAI-containing regions maintained a resting phenotype. Microglial activation shared a spatiotemporal relationship with TAI though no clear interactions were observed. By 7 to 28 days postinjury, activated microglia contained myelin debris, yet revealed limited aggregation. Immunophenotypic macrophages were also localized to injured loci. Select macrophages approximated somatic membranes of perisomatically axotomized neurons with evidence of bouton disruption. No causality was established between blood-brain barrier alterations and these inflammatory responses. These findings indicate rapid, yet initially nonspecific, and persistent microglial/macrophage responses to DBI. DBI-mediated inflammatory responses suggest further expansion of traumatic brain injury histopathologic evaluations to identify neuroinflammation indicative of diffuse pathology.


Qualitative study of depression management in primary care: GP and patient goals, and the value of listening.
Guidelines for depression management have been developed but little is known about GP and patient goals, which are likely to influence treatment offers, uptake, and adherence. To identify issues of importance to GPs, patients, and patients' supporters regarding depression management. GP and patient goals for depression management became a focus of the study. Grounded theory-based qualitative study. GPs were drawn from 28 practices. The majority of patients and supporters were recruited from 10 of these practices. Sixty-one patients (28 depressed, 18 previously depressed, 15 never depressed), 18 supporters, and 32 GPs were interviewed. GPs described encouraging patients to view depression as separate from the self and 'normal' sadness. Patients and supporters often questioned such boundaries, rejecting the notion of a medical cure and emphasising self-management. The majority of participants who were considering depression-management strategies wanted to 'get out' of their depression. However, a quarter did not see this as immediately relevant or achievable. They focused on getting by from day to day, which had the potential to clash with GP priorities. GP frustration and uncertainty could occur when depression was resistant to cure. Participants identified the importance of GPs listening to patients, but often felt that this did not happen. Physicians need greater awareness of the extent to which their goals for the management of depression are perceived as relevant or achievable by patients. Future research should explore methods of negotiating agreed strategies for management.


[Transcription of Drosophila MDG4 mobile element under hyperthermic conditions].
The Drosophila melanogaster cultured cells were subjected to stable transformation by cotransfection with two plasmids, one of which conferred G418 resistance and the second contained the Drosophila retrotransposon MDG4 (gypsy) under control of different promoter fragments of the heat shock protein gene hsp70. Transcription of these constructs as well as of the endogenous gypsy was examined in the conditions of heat shock. Active degradation of preexisting MDG4 transcripts is observed after heat shock. Transcription of MDG4 is restored during recovery but its termination and/or 3' end processing becomes aberrant.


A 3q gene signature associated with triple negative breast cancer organ specific metastasis and response to neoadjuvant chemotherapy.
Triple negative breast cancers (TNBC) are aggressive tumors, with high rates of metastatic spread and targeted therapies are critically needed. We aimed to assess the prognostic and predictive value of a 3q 19-gene signature identified previously from lung cancer in a collection of 4,801 breast tumor gene expression data. The 3q gene signature had a strong association with features of aggressiveness such as high grade, hormone receptor negativity, presence of a basal-like or TNBC phenotype and reduced distant metastasis free survival. The 3q gene signature was strongly associated with lung metastasis only in TNBC (P < 0.0001, Hazard ratio (HR) 1.44, 95% confidence interval (CI), 1.31-1.60), significantly associated with brain but not bone metastasis regardless of TNBC status. The association of one 3q driver gene FXR1 with distant metastasis in TNBC (P = 0.01) was further validated by immunohistochemistry. In addition, the 3q gene signature was associated with better response to neoadjuvant chemotherapy in TNBC (P < 0.0001) but not in non-TNBC patients. Our study suggests that the 3q gene signature is a novel prognostic marker for lung and/or brain metastasis and a predictive marker for the response to neoadjuvant chemotherapy in TNBC, implying a potential role for 3q genes in the mechanism of organ-specific metastasis.


Cytogenetic analysis of epithelial renal-cell tumors: relationship with a new histopathological classification.
Renal-cell carcinomas (RCC) are clinically, histologically and cytogenetically very heterogeneous. The present histological WHO classification shows no clear correlation between histologic subtypes and specific chromosomal abnormalities. In 1986, a new classification was proposed by Thoenes and Störkel based on the cell type from which the tumor arises. They distinguish 5 cell types: clear-cell, chromophilic, chromophobic, ductus Bellini and oncocytic. Results of 105 primary tumors show that, in this new classification, there is a correlation between different subtypes of renal-cell tumor and specific chromosomal abnormalities at a microscopic and/or molecular level. The clear-cell compact type shows structural aberrations of chromosomes I, 3, 4, 5q, 6, 10q, 11q and 12q, together with polysomy of chromosomes X, 4, 5, 7, 10, 12, 15, 16, 19, 20, 21 and 22, monosomy of chromosomes 3, 8, 9, 13, 14, and loss of Y. The main characteristics of the chromophilic tubulo-papillary type are trisomies 7 and 17, and loss of the Y-chromosome. Chromophobic carcinoma seems to be correlated with, inter alia, polysomy 7, trisomies 12, 16, 18, 19, structural abnormalities of 11q, and telomeric associations. Oncocytomas do not reveal any specific chromosomal anomaly, except for trisomy 7. Loss of heterozygosity on 3p is only found in the clear-cell compact type. Some specific chromosomal abnormalities correlate with a particular grade of the tumor. These correlations support the hypothesis that specific chromosomal abnormalities play a role in the histogenesis and oncogenesis of RCC. They may be important for tumor diagnosis and clinical prognosis.


Dietary iodine deficiency as a tumor promoter and carcinogen in male F344/NCr rats.
Groups of 6-wk-old male F344/NCr rats received a single i.v. injection of either vehicle or N-nitrosomethylurea (Cas: 684-93-5) (MNU) at a dose of 41.2 mg/kg body weight. Two wk later, groups of rats were placed on iodine-deficient, iodine-adequate, or commercial (Wayne Lab Blox) diets, or one of these diets and without previous MNU injection. Animals were sacrificed at either 52 or 77 wk, or when they became moribund. Carcinogen-treated rats on the iodine-deficient diet for up to 52 wk had significantly increased thyroid gland weights and increased incidences of both thyroid follicular cell carcinoma (90%) and diffuse pituitary thyrotroph hyperplasia (90%) at 52 wk. The majority of the follicular carcinomas were transplantable and invasive into the mammary fat pad of weanling F344/NCr rats. No other tumors induced by MNU were affected by the iodine-deficient diets. Rats fed the iodine-deficient diet without MNU injection had a 40% incidence of thyroid follicular adenomas at 52 wk and 60% at 77 wk, and a 10% incidence of follicular carcinomas at 77 wk. Thus this experiment provided evidence that the iodine-deficient diet is a potent promoter of thyroid tumors initiated by MNU and carcinogenic by itself. In addition, pituitary tumors were found in 29 of the 58 rats treated with the carcinogen alone, compared to only 3 of the 20 rats in the control groups. The vast majority of these pituitary tumors contained prolactin that was demonstrable by the avidin:biotin:peroxidase complex immunocytochemical technique.


Regeneration of intervertebral disc by mesenchymal stem cells: potentials, limitations, and future direction.
Over the past few years, substantial progress has been made in the field of stem cell regeneration of the intervertebral disc. Autogenic mesenchymal stem cells in animal models can arrest intervertebral disc degeneration or even partially regenerate it and the effect is suggested to be dependent on the severity of degeneration. Mesenchymal stem cells (MSCs) are able to escape alloantigen recognition which is an advantage for allogenic transplantation. A number of injectable scaffolds have been described and various methods to pre-modulate MSCs' activity have been tested. In future, work will need to address the use of mesenchymal stem cells in large animal models and the fate of the implanted mesenchymal stem cells, particularly in the long term, in animals. This review examines the state-of-the-art in the field of stem cell regeneration of the intervertebral disc, and critically discusses, with scientific support, the issues involved, before stem cells could be used in human subjects.


Analysis of Factors Contributing to the Severity of Large Truck Crashes.
Crashes that involved large trucks often result in immense human, economic, and social losses. To prevent and mitigate severe large truck crashes, factors contributing to the severity of these crashes need to be identified before appropriate countermeasures can be explored. In this research, we applied three tree-based machine learning (ML) techniques, i.e., random forest (RF), gradient boost decision tree (GBDT), and adaptive boosting (AdaBoost), to analyze the factors contributing to the severity of large truck crashes. Besides, a mixed logit model was developed as a baseline model to compare with the factors identified by the ML models. The analysis was performed based on the crash data collected from the Texas Crash Records Information System (CRIS) from 2011 to 2015. The results of this research demonstrated that the GBDT model outperforms other ML methods in terms of its prediction accuracy and its capability in identifying more contributing factors that were also identified by the mixed logit model as significant factors. Besides, the GBDT method can effectively identify both categorical and numerical factors, and the directions and magnitudes of the impacts of the factors identified by the GBDT model are all reasonable and explainable. Among the identified factors, driving under the influence of drugs, alcohol, and fatigue are the most important factors contributing to the severity of large truck crashes. In addition, the exists of curbs and medians and lanes and shoulders with sufficient width can prevent severe large truck crashes.


The exocyst component Sec5 is present on endocytic vesicles in the oocyte of Drosophila melanogaster.
The exocyst is an octameric complex required for polarized secretion. Some components of the exocyst are found on the plasma membrane, whereas others are recruited to Golgi membranes, suggesting that exocyst assembly tethers vesicles to their site of fusion. We have found that in Drosophila melanogaster oocytes the majority of the exocyst component Sec5 is unexpectedly present in clathrin-coated pits and vesicles at the plasma membrane. In oocytes, the major substrate for clathrin-dependent endocytosis is the vitellogenin receptor Yolkless. A truncation mutant of Sec5 (sec5(E13)) allows the formation of normally sized oocytes but with greatly reduced yolk uptake. We find that in sec5(E13) oocytes Yolkless accumulates aberrantly in late endocytic compartments, indicating a defect in the endocytic cycling of the receptor. An analogous truncation of the yeast SEC5 gene results in normal secretion but a temperature-sensitive defect in endocytic recycling. Thus, the exocyst may act in both Golgi to plasma membrane traffic and endocytic cycling, and hence in oocytes is recruited to clathrin-coated pits to facilitate the rapid recycling of Yolkless.


The development of awareness of the carcinogenic hazard of inhaled iron.
Numerous studies have observed that workers in ferriferous industries have an elevated risk of respiratory tract neoplasia. Research at the cellular and animal model levels indicates that iron compounds, per se, are carcinogenic. However, some investigators have suggested that inhaled iron compounds are merely carriers of other carcinogens. Evidence is presented that iron apparently is a principal carcinogenic hazard in inhalation of silicon dioxide, asbestos, and tobacco smoke. Included in the discussion are unresolved questions concerning the precise role of inhaled iron as a carcinogen.


[Use of tobacco among Norwegian pupils in secondary school 1975-2005].
The proportion of daily smokers in the adult Norwegian population is gradually decreasing. We have examined changes in smoking among secondary school students (1975 - 2005) and changes in snus use (smokeless tobacco) from 1985 through 2005. The data stem from a series of nationwide surveys carried out by the Norwegian Directorate of Health every fifth year since 1975. The present analyses are based on samples of students born on the 6 th day of any month (n = 32669) in the period 1975 - 2005. The proportion of daily smokers among 15-year-olds was highest in 1975 (22.6 % among males and 28.4 % among females) and lowest in 2005 (8.5 % among males and 9.5 % among females). There were periods with no decrease during the 1980s and 1990s, and even an increase in smoking. From 2000 to 2005, the proportion of smokers decreased markedly irrespective of how smoking is defined - in all three grades - and for both sexes. The proportion of 15-year-old boys who used snus daily dropped markedly from 1985 to 1990, and increased steadily thereafter (7.9 % in 2005). The marked decrease in smoking among secondary school students from 2000 to 2005 may result in that fewer of these students will ever start smoking.


A 3-D active shape model driven by fuzzy inference: application to cardiac CT and MR.
Manual quantitative analysis of cardiac left ventricular function using Multislice CT and MR is arduous because of the large data volume. In this paper, we present a 3-D active shape model (ASM) for semiautomatic segmentation of cardiac CT and MR volumes, without the requirement of retraining the underlying statistical shape model. A fuzzy c-means based fuzzy inference system was incorporated into the model. Thus, relative gray-level differences instead of absolute gray values were used for classification of 3-D regions of interest (ROIs), removing the necessity of training different models for different modalities/acquisition protocols. The 3-D ASM was evaluated using 25 CT and 15 MR datasets. Automatically generated contours were compared to expert contours in 100 locations. For CT, 82.4% of epicardial contours and 74.1% of endocardial contours had a maximum error of 5 mm along 95% of the contour arc length. For MR, those numbers were 93.2% (epicardium) and 91.4% (endocardium). Volume regression analysis revealed good linear correlations between manual and semiautomatic volumes, r(2) >/= 0.98. This study shows that the fuzzy inference 3-D ASM is a robust promising instrument for semiautomatic cardiac left ventricle segmentation. Without retraining its statistical shape component, it is applicable to routinely acquired CT and MR studies.


Methotrexate for psoriasis in the era of biological therapy.
Methotrexate's traditional role as a first line agent for moderate to severe psoriasis is being challenged by the rapid and growing use of biological therapies. A recent study comparing adalimumab with methotrexate showed significantly superior efficacy of adalimumab over methotrexate over 16 weeks. Although it is inexpensive, the future use of methotrexate may be compromised by its unpredictable response and toxicity, and by the introduction of newer, more effective biological therapies. However, recent advances in the screening of liver fibrosis by monitoring serum levels of the aminoterminal peptide fragment of type III procollagen have reduced the need for liver biopsy. Furthermore, the potential for personalized methotrexate use by application of modern pharmacogenetics and pharmacokinetics may ensure its place as a first-line agent for the treatment of psoriasis for the foreseeable future.


[Service expectations facing Saxony's newly established social psychiatric services. Attitudes of established neurologists, physicians in psychiatric clinics and social psychiatry service staff].
In the wake of the disintegration of the policlinical system which had prevailed in the former German Democratic Republic, far-reaching restructuring has become necessary in the "new" German laender in the field of complementary psychiatric care. Establishment throughout the state of Saxony of a uniform outreach-based ambulatory service ranks as a first component towards building regionalized community psychiatric networks. In light of some twenty years of experience in the old laender, this function is considered a task of the Social Psychiatric Services ("Sozialpsychiatrische Dienste", SPDIs). The present study had been directed at a state-wide investigation of the expectations community-practice psychiatrists (n = 165), physicians in psychiatric clinics (n = 95) and staff working in SPDIs (n = 138) in Saxony hold regarding service programmes and operating methods of these newly established service delivery structures. Given the high return rates in this anonymous postal questionnaire study, the findings presented are considered near-representative. A concurrent finding for all of the groups interviewed, expectations concerning the client population to be serviced by the SPDIs focus on the group of persons with chronic mental illness. Also, the expectations expressed concerning major care/therapeutic services to be rendered by the SPDIs concur in their emphasis on a core area of immediately client-oriented SPDI activities. Between the two medical groups, a major difference found is that community-practice psychiatrists more frequently expect high SPDI commitment regarding sociotherapeutic programmes at an institutional level, whereas clinical physicians expect them to focus on taking over medical therapies in the narrower sense. The expectations SPDI staff hold relative to the therapeutic services to be rendered by themselves go beyond the scope of what has so far been implemented in their current activity, and qualitative content analyses are presented in the article for each of the areas concerned. Along with better staffing levels, removal of in-service organizational and further education deficits are identified by SPDI staff as the two main requirements for stabilizing their operations. In order to counter undue burdening of the SPDI with service expectations and to enable a more clear-cut positioning of its programme structures within a complex psychosocial service delivery system, it is necessary--at least in the state of Saxony--that further needs-oriented establishment and/or extension of community-based psychiatric services and agencies take place.


Effect of incorporating fat into a liquid test meal on the relation between intragastric distribution and gastric emptying in human volunteers.
The relation between gastric emptying and the intragastric distribution of 300 ml radiolabelled beef consommé with and without 60 g margarine was investigated by performing randomised, paired gammacamera studies in seven healthy male volunteers (aged 20-22 years). The low calorie bland meal emptied rapidly from both the proximal and distal stomach after a short lag period (4-6 min), during which 24-50% of the liquid passed into the distal stomach. Addition of margarine to the liquid test meal increased the lag period (median 32 min, range 7-60 min; p less than 0.01) and decreased the slope of emptying (T1/2 lag period 88 min, 49-146 min v 15 min, 10-57 min; p less than 0.01). During the lag period there was an initial filling of the distal stomach, similar to that with the bland liquid, followed by a redistribution of between 19% and 61% (median 46%) of the distal stomach contents back into the proximal stomach. At the onset of emptying, the distal stomach filled (median 30%, range 16-34%) and during this time the proximal stomach emptied twice as fast as the whole stomach (p less than 0.05). Thereafter, the distal stomach capacity remained relatively constant while both the proximal and whole stomach emptied at similar rates. This study shows that the delay in gastric emptying of a liquid that has a high fat content is due in part to a redistribution of distal stomach contents back into the proximal stomach.


Effects of parathyroid hormone on net proton flux from neonatal mouse calvariae.
Bone mineral buffers protons during acute metabolic acidosis; whether parathyroid hormone (PTH) augments proton buffering is controversial. To determine whether PTH augments proton buffering by bone, we cultured neonatal mouse calvariae with or without PTH (10(-8) M) for 3 h in medium that was physiologically acid (pH approximately 7.20), neutral (pH approximately 7.40), or alkaline (pH approximately 7.60). Over the entire pH range studied there was less influx of protons into calvariae treated with PTH than into control calvariae, indicating that PTH does not augment but instead inhibits proton buffering by bone. To determine whether chronic exposure to PTH is necessary to augment proton buffering, calvariae were incubated with PTH for 24 h before a 3-h culture. Calcium efflux from calvariae exposed to PTH (10(-8) M) for 24 h exceeded that of controls. When these same calvariae were recultured for 3 h in fresh medium, PTH-treated and control calvariae behaved similarly, with net efflux of protons into acid, neutral, and alkaline media. Regardless of whether PTH is added at the time of exposure to acid medium or 24 h before calvariae cultured with PTH do not buffer protons to a greater extent than controls.


Anion and cation permeability of a chloride channel in rat hippocampal neurons.
The ionic permeability of a voltage-dependent Cl channel of rat hippocampal neurons was studied with the patch-clamp method. The unitary conductance of this channel was approximately 30 pS in symmetrical 150 mM NaCl saline. Reversal potentials interpreted in terms of the Goldman-Hodgkin-Katz voltage equation indicate a Cl:Na permeability ratio of approximately 5:1 for conditions where there is a salt gradient. Many anions are permeant; permeability generally follows a lyotropic sequence. Permeant cations include Li, Na, K, and Cs. The unitary conductance does not saturate for NaCl concentrations up to 1 M. No Na current is observed when the anion Cl is replaced by the impermeant anion SO4. Unitary conductance depends on the cation species present. The channel is reversibly blocked by extracellular Zn or 9-anthracene carboxylic acid. Physiological concentrations of Ca or Mg do not affect the Na:Cl permeability ratio. The permeability properties of the channel are consistent with a permeation mechanism that involves an activated complex of an anionic site, an extrinsic cation, and an extrinsic anion.


Epicardial fat thickness is associated with non-dipper blood pressure pattern in patients with essential hypertension.
Epicardial fat tissue reflects visceral adiposity and is a suggested cardiometabolic risk factor. Patients with abdominal obesity have an increased prevalence of the non-dipper blood pressure (BP) pattern, but it is unclear whether the same is true of patients with increased epicardial fat thickness (EFT). The association between EFT and circadian BP changes in patients with recently diagnosed essential hypertension was examined. Sixty hypertensive patients underwent echocardiography, treadmill stress testing, and 24 hours of ambulatory BP monitoring. Epicardial fat thickness and left ventricular mass (LVM) index were measured by using transthoracic echocardiography. The patients were categorized into two groups according to their BP pattern (group 1, non-dippers; group 2, dippers). The mean EFT and LVM of patients in group 1 (n = 24) (EFT, 7.6 ± 2.1 mm; LVM, 130 ± 31.2 g/m(2)) were significantly greater than those of group 2 (n = 36) (EFT, 5.5 ± 1.2 mm, P = .0001; LVM, 107 ± 23.7 g/m(2), P = .002). The average systolic BP over 24 hours (BP(s) 24) and average diastolic BP over 24 hours (BP(d) 24) of group 1 (BP(s) 24, 151.1 ± 17.6 mm Hg; BP(d) 24, 94.1 ± 16.5 mm Hg) were significantly higher than those of group 2 (BP(s) 24, 136.7 ± 11.9 mm Hg, P = .0001; BP(d) 24, 84.6 ± 10.6 mm Hg; P = .008). Multivariate backward logistic regression analysis demonstrated that the non-dipper BP pattern was associated with EFT (standardized β coefficient = 0.87, P = .005) and LVM (standardized β coefficient = 0.43, P = .016). An EFT ≥ 7 mm was associated with the non-dipper BP pattern with 44% sensitivity and 94% specificity (receiver operating characteristic area under curve of 0.72, 95% CI [0.59-0.83], P = .0007). Epicardial fat thickness was above average in newly diagnosed, untreated hypertensive patients with non-dipper BP pattern. The echocardiographic measurement of EFT may be used to indicate increased risk of hypertension-related adverse cardiovascular events.


Effect of spinal manipulation thrust magnitude on trunk mechanical activation thresholds of lateral thalamic neurons.
High-velocity low-amplitude spinal manipulation (HVLA-SM), as performed by doctors who use manual therapy (eg, doctors of chiropractic and osteopathy), results in mechanical hypoalgesia in clinical settings. This hypoalgesic effect has previously been attributed to alterations in peripheral and/or central pain processing. The objective of this study was to determine whether thrust magnitude of a simulated HVLA-SM alters mechanical trunk response thresholds in wide dynamic range (WDR) and/or nociceptive specific (NS) lateral thalamic neurons. Extracellular recordings were carried out in the thalamus of 15 anesthetized Wistar rats. Lateral thalamic neurons having receptive fields, which included the lumbar dorsal-lateral trunk, were characterized as either WDR (n=22) or NS (n=25). Response thresholds to electronic von Frey (rigid tip) mechanical trunk stimuli were determined in 3 directions (dorsal-ventral, 45° caudalward, and 45° cranialward) before and immediately after the dorsal-ventral delivery of a 100-millisecond HVLA-SM at 3 thrust magnitudes (control, 55%, 85% body weight). There was a significant difference in mechanical threshold between 85% body weight manipulation and control thrust magnitudes in the dorsal-ventral direction in NS neurons (P=.01). No changes were found in WDR neurons at either HVLA-SM thrust magnitude. This study is the first to investigate the effect of HVLA-SM thrust magnitude on WDR and NS lateral thalamic mechanical response threshold. Our data suggest that, at the single lateral thalamic neuron level, there may be a minimal spinal manipulative thrust magnitude required to elicit an increase in trunk mechanical response thresholds.


Curcumin as Add-On to Antipsychotic Treatment in Patients With Chronic Schizophrenia: A Randomized, Double-Blind, Placebo-Controlled Study.
Introduction of old and new generations of antipsychotics leads to significant improvements in the positive symptoms of schizophrenia. However, negative symptoms remain refractory to conventional trials of antipsychotic therapy. Recently, there were several open clinical human trials with curcumin. Curcumin is a natural polyphenol, which has a variety of pharmacological activities, including antioxidative and neuroprotective effects. The studies showed that curcumin improved the negative symptoms of schizophrenia. The purpose of our study was to examine the efficacy of curcumin as an add-on agent to regular antipsychotic medications in patients with chronic schizophrenia. Thirty-eight patients with chronic schizophrenia were enrolled in a 24-week, double-blind, randomized, placebo-controlled study. The subjects were treated with either 3000 mg/d curcumin or placebo combined with antipsychotics from January 2015 to February 2017. The outcome measures were the Positive and Negative Symptoms Scale (PANSS) and the Calgary Depression Scale for Schizophrenia. Analysis of variance showed significant positive changes in both groups from baseline to the end of the study in all scales of measurement. There was a significant response to curcumin within 6 months in total PANSS (P = 0.02) and in the negative symptoms subscale (P = 0.04). There were no differences in the positive and general PANSS subscales, and the Calgary Depression Scale for Schizophrenia scores between the treatment and placebo groups. No patient complained of any adverse effect. The promising results of curcumin as an add-on to antipsychotics in the treatment of negative symptoms may open a new and safe therapeutic option for the management of schizophrenia. However, these results should be replicated in further studies.ClinicalTrials.gov Identifier: NCT02298985.


Brainstem manifestations in neuromyelitis optica: a multicenter study of 258 patients.
Neuromyelitis optica (NMO) is a severe autoimmune disease of the central nervous system characterized by spinal cord and optic nerve involvement. Brainstem manifestations have recently been described. To evaluate the time of occurrence, the frequency and the characteristics of brainstem symptoms in a cohort of patients with NMO according to the ethnic background and the serologic status for anti-aquaporin-4 antibodies (AQP4-abs). We performed a multicenter study of 258 patients with NMO according to the 2006 Wingerchuk criteria and we evaluated prospectively the frequency, the date of onset and the duration of various brainstem signs in this population. Brainstem signs were observed in 81 patients (31.4%). The most frequently observed signs were vomiting (33.1%), hiccups (22.3%), oculomotor dysfunction (19.8%), pruritus (12.4%), followed by hearing loss (2.5%), facial palsy (2.5%), vertigo or vestibular ataxia (1.7%), trigeminal neuralgia (2.5%) and other cranial nerve signs (3.3%). They were inaugural in 44 patients (54.3%). The prevalence was higher in the non-Caucasian population (36.6%) than in the Caucasian population (26%) (p<0.05) and was higher in AQP4-ab-seropositive patients (32.7%) than in seronegative patients (26%) (not significant). This study confirms the high frequency of brainstem symptoms in NMO with a majority of vomiting and hiccups. The prevalence of these manifestations was higher in the non Caucasian population.


The Susceptibilities of Respiratory Syncytial Virus to Nucleolin Receptor Blocking and Antibody Neutralization are Dependent upon the Method of Virus Purification.
Respiratory Syncytial Virus (RSV) that is propagated in cell culture is purified from cellular contaminants that can confound experimental results. A number of different purification methods have been described, including methods that utilize fast protein liquid chromatography (FPLC) and gradient ultracentrifugation. Thus, the constituents and experimental responses of RSV stocks purified by ultracentrifugation in sucrose and by FPLC were analyzed and compared by infectivity assay, Coomassie stain, Western blot, mass spectrometry, immuno-transmission electron microscopy (TEM), and ImageStream flow cytometry. The FPLC-purified RSV had more albumin contamination, but there was less evidence of host-derived exosomes when compared to ultracentrifugation-purified RSV as detected by Western blot and mass spectrometry for the exosome markers superoxide dismutase [Cu-Zn] (SOD1) and the tetraspanin CD63. Although the purified virus stocks were equally susceptible to nucleolin-receptor blocking by the DNA aptamer AS1411, the FPLC-purified RSV was significantly less susceptible to anti-RSV polyclonal antibody neutralization; there was 69% inhibition (p = 0.02) of the sucrose ultracentrifugation-purified RSV, 38% inhibition (p = 0.03) of the unpurified RSV, but statistically ineffective neutralization in the FPLC-purified RSV (22% inhibition; p = 0.30). The amount of RSV neutralization of the purified RSV stocks was correlated with anti-RSV antibody occupancy on RSV particles observed by immuno-TEM. RSV purified by different methods alters the stock composition and morphological characteristics of virions that can lead to different experimental responses.


Risk of myocardial infarction in men and women with type 2 diabetes in the UK: a cohort study using the General Practice Research Database.
Our primary aim was to establish reliable and generalisable estimates of the risk of myocardial infarction (MI) for men and women with type 2 diabetes in the UK compared with people without diabetes. Our secondary aim was to investigate how the MI risk associated with diabetes differs between men and women. A cohort study using the General Practice Research Database (1992-1999) was carried out, selecting 40,727 patients with type 2 diabetes and 194,913 age and sex-matched patients without diabetes. Rates of MI in men and women with and without diabetes were derived, as were hazard ratios for MI adjusted for known risk factors. The rate of MI in men with type 2 diabetes was 19.74 (95% CI 18.83-20.69) per 1,000 person-years compared with 16.18 (95% CI 15.33-17.08) per 1,000 person-years in women with type 2 diabetes. The overall adjusted relative risk of MI in diabetes versus no diabetes was 2.13 (95% CI 2.01-2.26) in men and 2.95 (95% CI 2.75-3.17) in women and decreased with age in both sexes. Women with type 2 diabetes aged 35 to 54 years were at almost five times the risk of MI compared with women of the same age without diabetes (HR 4.86 [95% CI 2.78-8.51]). This study has demonstrated that women with type 2 diabetes are at a much greater relative risk of MI than men even when adjusted for risk factors.


FOXP3+ regulatory T cells in normal prostate tissue, postatrophic hyperplasia, prostatic intraepithelial neoplasia, and tumor histological lesions in men with and without prostate cancer.
The tumor promoting or counteracting effects of the immune response to cancer development are thought to be mediated to some extent by the infiltration of regulatory T cells (Tregs ). In the present study we evaluated the prevalence of Treg populations in stromal and epithelial compartments of normal, post atrophic hyperplasia (PAH), prostatic intraepithelial neoplasia (PIN), and tumor lesions in men with and without prostate cancer. Study subjects were 102 men consecutively diagnosed with localized prostate cancer undergoing radical prostatectomy and 38 men diagnosed with bladder cancer undergoing cystoprostatectomy without prostate cancer at the pathological examination. Whole mount sections from all patients were evaluated for the epithelial and stromal expression of CD4+ Tregs and CD8+ Tregs in normal, PAH, PIN, and tumor lesions. A Friedmańs test was used to investigate differences in the mean number of Tregs across histological lesions. Logistic regression was used to estimate crude and adjusted odds ratios (OR) for prostate cancer for each histological area. In men with prostate cancer, similarly high numbers of stromal CD4+ Tregs were identified in PAH and tumor, but CD4+ Tregs were less common in PIN. Greater numbers of epithelial CD4+ Tregs in normal prostatic tissue were positively associated with both Gleason score and pT-stage. We observed a fourfold increased risk of prostate cancer in men with epithelial CD4+ Tregs in the normal prostatic tissue counterpart. Our results may suggest a possible pathway through which PAH develops directly into prostate cancer in the presence of CD4+ Tregs and indicate that transformation of the anti-tumor immune response may be initiated even before the primary tumor is established.


In vitro translation of poliovirus RNA: utilization of internal initiation sites in reticulocyte lysate.
The translation of poliovirus RNA in rabbit reticulocyte lysate was examined. Translation of poliovirus RNA in this cell-free system resulted in an electrophoretic profile of poliovirus-specific proteins distinct from that observed in vivo or after translation in poliovirus-infected HeLa cell extract. A group of proteins derived from the P3 region of the polyprotein was identified by immunoprecipitation, time course, and N-formyl-[35S]methionine labeling studies to be the product of the initiation of protein synthesis at an internal site(s) located within the 3'-proximal RNA sequences. Utilization of this internal initiation site(s) on poliovirus RNA was abolished when reticulocyte lysate was supplemented with poliovirus-infected HeLa cell extract. Authentic P1-1a was also synthesized in reticulocyte lysate, indicating that correct 5'-proximal initiation of translation occurs in that system. We conclude that the deficiency of a component(s) of the reticulocyte lysate necessary for 5'-proximal initiation of poliovirus protein synthesis resulted in the ability of ribosomes to initiate translation on internal sequences. This aberrant initiation could be corrected by factors present in the HeLa cell extract. Apparently, under certain conditions, ribosomes are capable of recognizing internal sequences as authentic initiation sites.


Graded Ca²⁺/calmodulin-dependent coupling of voltage-gated CaV1.2 channels.
In the heart, reliable activation of Ca(2+) release from the sarcoplasmic reticulum during the plateau of the ventricular action potential requires synchronous opening of multiple CaV1.2 channels. Yet the mechanisms that coordinate this simultaneous opening during every heartbeat are unclear. Here, we demonstrate that CaV1.2 channels form clusters that undergo dynamic, reciprocal, allosteric interactions. This 'functional coupling' facilitates Ca(2+) influx by increasing activation of adjoined channels and occurs through C-terminal-to-C-terminal interactions. These interactions are initiated by binding of incoming Ca(2+) to calmodulin (CaM) and proceed through Ca(2+)/CaM binding to the CaV1.2 pre-IQ domain. Coupling fades as [Ca(2+)]i decreases, but persists longer than the current that evoked it, providing evidence for 'molecular memory'. Our findings suggest a model for CaV1.2 channel gating and Ca(2+)-influx amplification that unifies diverse observations about Ca(2+) signaling in the heart, and challenges the long-held view that voltage-gated channels open and close independently.


A chromatin-regulated biphasic circuit coordinates IL-1β-mediated inflammation.
Inflammation is characterized by a biphasic cycle consisting initially of a proinflammatory phase that is subsequently resolved by anti-inflammatory processes. Interleukin-1β (IL-1β) is a master regulator of proinflammation and is encoded within the same topologically associating domain (TAD) as IL-37, which is an anti-inflammatory cytokine that opposes the function of IL-1β. Within this TAD, we identified a long noncoding RNA called AMANZI, which negatively regulates IL-1β expression and trained immunity through the induction of IL37 transcription. We found that the activation of IL37 occurs through the formation of a dynamic long-range chromatin contact that leads to the temporal delay of anti-inflammatory responses. The common variant rs16944 present in AMANZI augments this regulatory circuit, predisposing individuals to enhanced proinflammation or immunosuppression. Our work illuminates a chromatin-mediated biphasic circuit coordinating expression of IL-1β and IL-37, thereby regulating two functionally opposed states of inflammation from within a single TAD.


Becoming a general practitioner--which factors have most impact on career choice of medical students?
In Germany, there is a shortage of young physicians in several specialties, the situation of general practitioners (GP) being especially precarious. The factors influencing the career choice of German medical students are poorly understood. This study aims to identify factors influencing medical students' specialty choice laying a special focus on general practice. The study was designed as a cross-sectional survey. In 2010, students at the five medical schools in the federal state of Baden-Wuerttemberg (Germany) filled out an online-questionnaire. On 27 items with 5-point Likert scales, the students rated the importance of specified individual and occupational aspects. Furthermore, students were asked to assign their intended medical specialty. 1,299 students participated in the survey. Thereof, 1,114 students stated a current choice for a specialty, with 708 students choosing a career in one of the following 6 specialties: internal medicine, surgery, gynaecology and obstetrics, paediatrics, anaesthetics and general practice. Overall, individual aspects ('Personal ambition', 'Future perspective', 'Work-life balance') were rated as more important than occupational aspects (i.e. 'Variety in job', 'Job-related ambition') for career choice. For students favouring a career as a GP individual aspects and the factor 'Patient orientation' among the occupational aspects were significantly more important and 'Job-related ambition' less important compared to students with other specialty choices. This study confirms that future GPs differ from students intending to choose other specialties particularly in terms of patient-orientation and individual aspects such as personal ambition, future perspective and work-life balance. Improving job-conditions in terms of family compatibility and work-life balance could help to increase the attractiveness of general practice. Due to the shortage of GPs those factors should be made explicit at an early stage at medical school to increase the number of aspirants for general practice.


Ab initio molecular dynamics: concepts, recent developments, and future trends.
The methodology of ab initio molecular dynamics, wherein finite-temperature dynamical trajectories are generated by using forces computed "on the fly" from electronic structure calculations, has had a profound influence in modern theoretical research. Ab initio molecular dynamics allows chemical processes in condensed phases to be studied in an accurate and unbiased manner, leading to new paradigms in the elucidation of microscopic mechanisms, rationalization of experimental data, and testable predictions of new phenomena. The purpose of this work is to give a brief introduction to the technique and to review several important recent developments in the field. Several illustrative examples showing the power of the technique have been chosen. Perspectives on future directions in the field also will be given.


SHP-1 negatively regulates neuronal survival by functioning as a TrkA phosphatase.
Nerve growth factor (NGF) mediates the survival and differentiation of neurons by stimulating the tyrosine kinase activity of the TrkA/NGF receptor. Here, we identify SHP-1 as a phosphotyrosine phosphatase that negatively regulates TrkA. SHP-1 formed complexes with TrkA at Y490, and dephosphorylated it at Y674/675. Expression of SHP-1 in sympathetic neurons induced apoptosis and TrkA dephosphorylation. Conversely, inhibition of endogenous SHP-1 with a dominant-inhibitory mutant stimulated basal tyrosine phosphorylation of TrkA, thereby promoting NGF-independent survival and causing sustained and elevated TrkA activation in the presence of NGF. Mice lacking SHP-1 had increased numbers of sympathetic neurons during the period of naturally occurring neuronal cell death, and when cultured, these neurons survived better than wild-type neurons in the absence of NGF. These data indicate that SHP-1 can function as a TrkA phosphatase, controlling both the basal and NGF-regulated level of TrkA activity in neurons, and suggest that SHP-1 regulates neuron number during the developmental cell death period by directly regulating TrkA activity.


Birth technology and maternal roles in birth: knowledge and attitudes of canadian women approaching childbirth for the first time.
To describe Canadian nulliparous women's attitudes to birth technology and their roles in childbirth. A large convenience sample of low-risk women expecting their first birth was recruited by posters in laboratories, at the offices of obstetricians, family physicians, and midwives, at prenatal classes, and through web-based advertising and invited to complete a paper or web-based questionnaire. Of the 1318 women completing the questionnaire, 95% did so via the web-based method; 13.2% of respondents were in the first trimester, 39.8% were in the second trimester, and 47.0% in the third. Overall, 42.6% were under the care of an obstetrician, 29.3% a family physician, and 28.1% a registered midwife. The sample included mainly well-educated, middle-class women. The planned place of giving birth ranged from home to hospital, and from rural centres to large city hospitals. Eighteen percent planned to engage a doula. Women attending obstetricians reported attitudes more favourable to the use of birth technology and less supportive of women's roles in their own delivery, regardless of the trimester in which the survey was completed. Those women attending midwives reported attitudes less favourable to the use of technology at delivery and more supportive of women's roles. Family practice patients' opinions fell between the other two groups. For eight of the questions, "I don't know" (IDK) responses exceeded 15%. These IDK responses were most frequent for questions regarding risks and benefits of epidural analgesia, Caesarean section, and episiotomy. Women in the care of midwives consistently used IDK options less frequently than those cared for by physicians. Regardless of the type of care provider they attended, many women reported uncertainty about the benefits and risks of common procedures used at childbirth. When grouped by the type of care provider, in all trimesters, women held different views across a range of childbirth issues, suggesting that the three groups of providers were caring for different populations with different attitudes and expectations.


Individual factors explain neighbourhood variations in accidents to children under 5 years of age.
Previous studies have identified possible neighbourhood-level influences on the risk of injuries to preschool children, but none have had sufficient data at both household and area level to explain these neighbourhood effects. We used data from the Avon Longitudinal Study of Parents and Children, which recruited over 14,062 children at birth in the former county of Avon, UK, and collected information about accidents, as well as extensive social, health and developmental data throughout the first 5 years of life. This information was combined with census and geographical data in order to identify neighbourhood influences on accident risks and then attempt to explain these using multilevel regression modelling. A small but statistically significant amount of between-neighbourhood variance in accident risk was found, with neighbourhood intraclass correlation coefficients of 0.82% for any accident, and 0.84% for accidents resulting in injury requiring medical attention. This was entirely accounted for by a variety of child, parental and household level variables. Independent risk factors for both outcomes were children who were developmentally more advanced or displayed greater conduct and behavioural problems, mothers who were of younger age, who were without work, who were smokers, whose partners were unemployed or drank alcohol excessively, and households in which there had recently been adverse life events, or which were under financial stress. The mother's perceptions of neighbourhood quality also explained some of the risks for any accident, but not for medically attended accidents, and this was a variable that operated at the level of individual households rather than at the level of neighbourhoods. The implications of this study are that differences in accident risk between neighbourhoods are explained by geographical clustering of similar types of children, families and households. Interventions should focus more on parental factors and household social circumstances than on the physical environment or community based risks. However, many of these factors are those most resistant to modification without broader societal change.


Cobalt protoporpyhrin reduces caspase-3,-7 enzyme activity in neonatal porcine islets, but does not inhibit cell death induced by TNF-alpha.
Apoptotic phenomena observed in vitro following isolation and following transplantation contribute significantly to islet graft loss. Strategies to reduce apoptosis of islet tissue prior to and posttransplantation may improve graft survival and function and reduce the amount of tissue necessary to achieve insulin independence. The expression of cytoprotective proteins is one such strategy that may prolong islet survival. In this light, heme-oxygenase 1 (HO-1) upregulation has been studied in both allo- and xenotransplantation models. In this study, the effect of HO-1 on apoptosis in neonatal porcine islet-like cell clusters (NPICC) was assessed. In in vitro assessments of NPICC apoptosis, NPICC showed a high sensitivity to apoptotic stimulation using a combination of TNF-alpha and cycloheximide. Stimulation with TNF-alpha alone was sufficient to induce reproducible apoptotic responses as demonstrated by caspase-3,-7 activation and subdiploid DNA analysis. Dose-dependent, high-level HO-1 protein expression was achieved following culture of NPICC in medium containing either cobalt protoporphyrin (CoPP) or cobalt mesoporphyrin (CoMP). CoPP treatment resulted in the reduction of caspase-3,-7 enzyme activity following TNF-alpha stimulation. However, such an effect was not associated with a reduction in the levels of cell death. Indeed, the inhibition of caspase enzyme activity resulted in decreased PARP-1 cleavage, which may lead to heightened levels of necrosis in treated NPICC cultures, possibly explaining the observed commitment of NPICC to the death pathway.


MRI appearance of placenta percreta and placenta accreta.
The purpose of this paper is to describe the magnetic resonance imaging (MR) features of placenta accreta and percreta. We retrospectively reviewed MRI findings in four cases of placenta accreta/percreta to determine features which assist in identifying the presence and extent of placental implantation abnormality. All patients had ultrasound (US) examinations. Pathologic correlation was available in all cases. There were two cases of placenta percreta and two cases of placenta accreta. All cases were treated by hysterectomy. In the two cases of placenta percreta, the placenta demonstrated transmural extension through the uterus (percreta) on MRI. In the two cases of placenta accreta, the location of thinning in the uterine wall correlated with the location of placental invagination into the myometrium at pathology. US correlation was available in all four cases. Gray scale US did not demonstrate placental invasion in any of the four cases of placenta accreta/percreta, however, in two of three cases in which color Doppler was performed, there was flow at the uterine margin suspicious for implantation abnormality. In conclusion, MRI is useful for identifying the presence and extent of placenta accreta/percreta.


Subcellular location of secretory proteins retained in the liver during the ethanol-induced inhibition of hepatic protein secretion in the rat.
Ethanol administration inhibits the secretion of proteins by the liver, resulting in their hepatocellular retention. Experiments were designed in this study to determine the subcellular location of the retained secretory proteins. Ethanol was administered acutely to nonfasted rats by gastric intubation, whereas control animals received an isocaloric dose of glucose. Two hours after intubation, when maximum blood ethanol levels (45 mM) were observed, [3H]leucine and [14C]fucose were injected simultaneously into the dorsal vein of the penis. The labelling of secretory proteins was determined in the liver and plasma at various time periods after label injection. Ethanol treatment decreased the secretion of both leucine- and fucose-labeled proteins into the plasma. This inhibition of secretion was accompanied by a corresponding increase in the hepatic retention of both leucine- and fucose-labeled immunoprecipitable secretory proteins. At the time of maximum inhibition of secretion, leucine labeled secretory proteins located in the Golgi apparatus represented about 50% of the accumulated secretory proteins in the livers of the ethanol-treated rats, whereas the remainder was essentially equally divided among the rough and smooth endoplasmic reticulum and cytosol. Because fucose is incorporated into secretory proteins almost exclusively in the Golgi complex, fucose-labeled proteins accumulated in the livers of the ethanol-treated rats mainly in the Golgi apparatus, with the remainder located in the cytosol. These results show that ethanol administration causes an impaired movement of secretory proteins along the secretory pathway, and that secretory proteins accumulate mainly, but not exclusively, in the Golgi apparatus.


[The former knackers yard in Zurich-Albisrieden: pathological findings in excavated animal bones].
During archaeological excavations in the former knackers yard in Zurich-Albisrieden bones and joints of 8 horses and 1 mule were found and examinedfor pathological lesions. Degenerative changes (arthropathies, spondylosis and spondylarthrosis) as well as tooth irregularities were most often seen. One horse had a discospondylitis and spondylitis of C7 and Th1.


[The role of the interaction of serotonin- and noradrenergic systems in regulating behavior].
A review of the data concerning the role of 5-hydroxytriptamine (5HT)-ergic and noradrenergic (NA) system in the regulation of behavior. Reciprocal effects of cerebral 5HT-ergic and NA-ergic systems on brain morphogenesis and on behavior suggest that normal brain ontogenesis is mediated by the steady state of 5HT and NA. The disbalance between 5HT-ergic and NA-ergic systems in brain structures results in abnormal brain development and behavioral pathologies. The concept of reciprocal effects of 5HT-ergic and NA-ergic brain systems may serve as a basis for new principles of pharmacological correction of pathologies resulting from inborn or acquired disbalance of monoaminergic systems.


Evaluation of roots, root canal morphology, and bilateral symmetry of maxillary first molars in a Syrian subpopulation using cone beam computed tomography.
Successful endodontic treatments require a comprehensive knowledge of the root canal anatomy, so this study aimed to investigate the number of roots, configurations of root canals, and their bilateral symmetry of maxillary first molars in the Syrian subpopulation, and also the effect of gender on this symmetry. The study sample consisted of 250 cone beam computed tomography images (140 for females; and 110 for males), including 500 maxillary first molars. Images were investigated by two endodontists. Root number and canal configuration in each root were recorded, according to Vertucci classification, by studying the image at all levels (axial, coronal, sagittal, oplique, and three-dimensional) to assess the bilateral symmetry and its relation to gender. Statistical analysis was performed with SPSS and the χ2 test was used to compare the bilateral symmetry in males and females. The most common shape of the maxillary first molars was three roots (97.6%). All the roots are symmetrical by 100% in both genders. The root canal configuration was mainly Vertucci type I classification in the distobuccally (73.6%), and palatal root (98%). While the most common types in mesial root were type II (33.3%), this root showed all different types of Vertucci classifications except type VIII, and the proportion of symmetry was (37.2%) without significant difference between the gender (p = .441). Most maxillary first molars in a Syrian population were three-rooted with four root canals (type II), the numbers of roots achieved perfect symmetry 100%, and higher than symmetry ratios in the number of canals and canals configurations (37.2%).


Primate cognition.
As the cognitive revolution was slow to come to the study of animal behavior, the vast majority of what we know about primate cognition has been discovered in the last 30 years. Building on the recognition that the physical and social worlds of humans and their living primate relatives pose many of the same evolutionary challenges, programs of research have established that the most basic cognitive skills and mental representations that humans use to navigate those worlds are already possessed by other primates. There may be differences between humans and other primates, however, in more complex cognitive skills, such as reasoning about relations, causality, time, and other minds. Of special importance, the human primate seems to possess a species-unique set of adaptations for "cultural intelligence," which are broad reaching in their effects on human cognition.


Escherichia coli Shiga toxins induce apoptosis in epithelial cells that is regulated by the Bcl-2 family.
Human intestinal cells lack globotriaosylceramide (Gb(3)), the receptor for Shiga toxin-1 (Stx1) and Shiga toxin-2 (Stx2). Therefore, the role of these toxins in mediating intestinal disease during infection with Shiga toxin-producing Escherichia coli is unclear. The aims of this study were to determine whether Stx1 and Stx2 induce apoptosis in epithelial cells expressing (HEp-2, Caco-2) or lacking (T84) Gb(3) and to characterize the role of the Bcl-2 family. Stx1 (12.5 ng/ml) induced apoptosis in both HEp-2 (21.9 +/- 7.9% vs. 0.8 +/- 0.3%, P = 0.01) and Caco-2 (10.1 +/- 1.2% vs. 3.1 +/- 0.4%, P = 0.006) cells but not in Gb(3)-deficient T84 cells. Toxin-mediated apoptosis of HEp-2 cells was associated with enhanced expression of the proapoptotic protein Bax. Inhibition of caspase activation prevented toxin-stimulated apoptosis. In addition, overexpression of Bcl-2 by transient transfection blocked Stx1-stimulated cell death. These findings indicate that Shiga toxins produced by E. coli signal Gb(3)-expressing epithelial cells to undergo apoptosis in association with enhanced Bax expression, thereby resulting in activation of the caspase cascade.


Bochdalek's flower basket: applied neuroimaging morphometry and variants of choroid plexus in the cerebellopontine angles.
Protrusions of fourth ventricular choroid plexus through the foramina of Luschka are called 'Bochdalek's flower basket' (BochFB). The bulbous terminal expansions (cornucopiae) extend into the cerebellopontine angle (CPA) cisterns. We studied and reviewed the normal imaging anatomy, morphometry and anatomical variants of BochFB. We retrospectively analysed normal brain imaging findings on axial pre- and post-contrast CT scans and enhanced axial T1-weighted MRIs of 200 patients. We assessed BochFB for: (a) calcification, (b) lateral extension, (c) enhancement pattern, (d) cornucopiae shape, (e) symmetry and (f) proximity to tortuous vertebral arteries and morphometry of cornucopiae size and length of BochFB limbs. BochFB calcification was found in 38 % of patients aged over 51 years. Lateral extension of BochFB into the CPA cistern was prominent in 75 % on CT and 96 % on MRI. The mean length of these extensions was 23.6 mm. BochFB enhanced strongly in 47 % on CT and 66 % on MRI. The BochFB cornucopiae were bulbous in 51 % on CT and 54 % on MRI. The mean width of bulbous cornucopiae was 3.5 mm. Bilateral BochFB symmetry was found in 71 % on CT and 80 % on MRI. Six to 8 % of tortuous left vertebral arteries were close to BochFB. The cornucopiae are particularly well demonstrated on post-contrast MRI. However several sources of error in image interpretation may arise when imaging the normal BochFB on routine head CT and MRI. Difficulties in analysis arise especially on CT because of physiologic calcification, asymmetry, and the bulbous cornucopiae being mistaken for aneurysms.


The global methane cycle: recent advances in understanding the microbial processes involved.
The global budget of atmospheric CH4 , which is on the order of 500-600 Tg CH4 per year, is mainly the result of environmental microbial processes, such as archaeal methanogenesis in wetlands, rice fields, ruminant and termite digestive systems and of microbial methane oxidation under anoxic and oxic conditions. This review highlights recent progress in the research of anaerobic CH4 oxidation, of CH4 production in the plant rhizosphere, of CH4 serving as substrate for the aquatic trophic food chain and the discovery of novel aerobic methanotrophs. It also emphasizes progress and deficiencies in our knowledge of microbial utilization of low atmospheric CH4 concentrations in soil, CH4 production in the plant canopy, intestinal methanogenesis and CH4 production in pelagic water.


Role of steroid receptor and coregulator mutations in hormone-dependent cancers.
Steroid hormones mediate critical lineage-specific developmental and physiologic responses. They function by binding their cognate receptors, which are transcription factors that drive specific gene expression programs. The requirement of most prostate cancers for androgen and most breast cancers for estrogen has led to the development of endocrine therapies that block the action of these hormones in these tumors. While initial endocrine interventions are successful, resistance to therapy often arises. We will review how steroid receptor-dependent genomic signaling is affected by genetic alterations in endocrine therapy resistance. The detailed understanding of these interactions will not only provide improved treatment options to overcome resistance, but, in the future, will also be the basis for implementing precision cancer medicine approaches.


Insulin binding and glucose uptake differences in rodent skeletal muscles.
Insulin binding and 2-deoxy-d-glucose uptake were compared in the soleus, plantaris, and extensor digitorum longus (EDL) muscles, in vitro, since the known biochemical profile of the soleus differs markedly from the other two. The present study showed that insulin binding increased in all three muscles with increasing concentrations of insulin in the range of 0.2-30 nM. However, the increase in binding of insulin to soleus at each insulin concentration exceeded that observed in the other two muscles (P less than 0.05). Differences between the plantaris and EDL were not significant. The quantity of insulin bound at each concentration also increased more rapidly in the soleus than in either the plantaris (P less than 0.05) or EDL (P less than 0.05). Basal and insulin-stimulated uptake of 2-deoxy-d-glucose was also greater in the soleus than in the other muscles (P less than 0.05). Maximal 2-deoxy-d-glucose uptake occurred at 1 nM insulin in each of the three muscles. These results indicate that in metabolically distinct types of skeletal muscles glucose uptake can differ markedly, and this is related to differences in the insulin binding capacities of these muscles.


Diabetes-induced osteoarthritis: from a new paradigm to a new phenotype.
Several epidemiological and experimental data support the hypothesis that diabetes could be an independent risk factor for osteoarthritis (OA), at least in some patients, leading to the concept of a diabetes-induced OA phenotype. If confirmed, this new paradigm will have a dramatic impact on prevention of OA initiation and progression.


Endothelial Activation and Blood-Brain Barrier Disruption in Neurotoxicity after Adoptive Immunotherapy with CD19 CAR-T Cells.
Lymphodepletion chemotherapy followed by infusion of CD19-targeted chimeric antigen receptor-modified T (CAR-T) cells can be complicated by neurologic adverse events (AE) in patients with refractory B-cell malignancies. In 133 adults treated with CD19 CAR-T cells, we found that acute lymphoblastic leukemia, high CD19+ cells in bone marrow, high CAR-T cell dose, cytokine release syndrome, and preexisting neurologic comorbidities were associated with increased risk of neurologic AEs. Patients with severe neurotoxicity demonstrated evidence of endothelial activation, including disseminated intravascular coagulation, capillary leak, and increased blood-brain barrier (BBB) permeability. The permeable BBB failed to protect the cerebrospinal fluid from high concentrations of systemic cytokines, including IFNγ, which induced brain vascular pericyte stress and their secretion of endothelium-activating cytokines. Endothelial activation and multifocal vascular disruption were found in the brain of a patient with fatal neurotoxicity. Biomarkers of endothelial activation were higher before treatment in patients who subsequently developed grade ≥4 neurotoxicity.Significance: We provide a detailed clinical, radiologic, and pathologic characterization of neurotoxicity after CD19 CAR-T cells, and identify risk factors for neurotoxicity. We show endothelial dysfunction and increased BBB permeability in neurotoxicity and find that patients with evidence of endothelial activation before lymphodepletion may be at increased risk of neurotoxicity. Cancer Discov; 7(12); 1404-19. ©2017 AACR.See related commentary by Mackall and Miklos, p. 1371This article is highlighted in the In This Issue feature, p. 1355.


A new resource for managing malpractice risks in managed care.
The risk of malpractice liability faced by physicians is exacerbated by third-party intrusions such as those encountered in today's managed care environment. The likelihood that a malpractice action will be brought is increased by the interaction among patients, families, or physicians who are at high risk for litigation and situations (eg, denial of treatment benefits by the managed care organization) that create adversity. To prevent the ready translation of resource adversity into an adversarial physician-patient-family relationship, a forensic psychiatric consultation is recommended.