Does pollination limit tolerance to browsing in Ipomopsis aggregata?
Ungulate browsing of flowering stalks of the semelparous herb Ipomopsis aggregata leads to regrowth of lateral inflorescences, a response that has been reported to yield overcompensation in some cases (browsed plants with higher reproductive success than unbrowsed), but undercompensation in others. Little is known about the mechanisms that cause such variable tolerance to herbivory. We explored one possible mechanism--variation in effects of browsing on pollination--by clipping I. aggregata inflorescences to mimic browsing, observing subsequent visits by pollinators and nectar-robbers, and adding pollen by hand to flowers of some clipped and unclipped plants. Clipping reduced floral display size and increased inflorescence branching, but neither hummingbirds, the primary pollinators, nor nectar-robbing bumblebees showed any preference for unclipped versus clipped plants. Clipping delayed flowering; this shift in phenology caused clipped plants to miss the peak of hummingbird activity and to have lower per-flower visitation rates than unclipped controls in one year, but to have greater overlap with birds and higher visitation rates in the subsequent year. In three sites and 2 years, clipped plants exposed to natural pollination suffered extreme undercompensation, producing on average only 16% as many seeds as unclipped controls. This was not directly attributable to clipping effects on pollination, however, because clipped plants were unable to increase fecundity when provided with supplemental pollen by hand. Taken altogether, our results suggest that compensation was constrained less by indirect effects of browsing on pollination than by its direct impacts on resource availability and hence on the ability of plants to regrow lost inflorescence tissue and to fill seeds. Exploring the physiological and developmental processes involved in regrowth of inflorescences and provisioning of seeds is a promising future direction for research designed to understand variation in browsing tolerance.


Arthur Schopenhauer and psychiatry 200 years after the publication of The World as Will and Representation (Idea).
In 2018 the academy will celebrate the 200th anniversary of the publication of the seminal work of Arthur Schopenhauer (1788-1860): The World as Will and Representation (Idea). Schopenhauer is known as the "philosopher of pessimism" and as the "psychologist of the will". His thinking is formally absent in the psychiatric education curricula, which could be enriched by the philosopher's work. Regarding psychiatry's theoretical foundations, Schopenhauer: a) anticipated several issues of species' origin and evolution, which are used in the contemporary understanding of disease development; b) anticipated some attributes of the psychodynamic and cognitive unconscious when referring to the irrational features of the will; c) foresaw the current concept of the embodied mind, which emphasizes the role of the body's structure and dynamics in cognition instead of that of a transcendental reason; d) proposed a simplified and heuristic model of mind, comprising the senses, understanding and reason; at a pragmatic level, particularly concerning psychotherapy, the philosopher e) stated that all human actions spring from three fundamental sources: egoism, malice and compassion; he also speculated about the role of unconscious repression in the genesis of mental illnesses; and finally, f) emphasized the ubiquity of suffering and the insatiability of desire, which unavoidably leads to egocentrism. In this regard he highly valued contemplation of art and nature as a way of dissociating knowledge from desire, and thus allowing the development of compassion and asceticism. This was considered by the philosopher to be "denial of the will", and a path for individual salvation and well-being. In contemporary psychiatry, this metaphysical proposal may be reformulated in terms of promoting cooperation and healthy austerity as a non-specific component of most psychotherapies and educational models. Schopenhauer's thinking may enrich psychiatric training and personal well-being.


High dose antioxidant supplementation to MS patients. Effects on glutathione peroxidase, clinical safety, and absorption of selenium.
High-dose antioxidant supplementation has recently been recommended for multiple sclerosis (MS) patients. This study tests the clinical safety, the glutathione peroxidase (GSH-px) activity, and the absorption of selenium during such supplementation. Eighteen MS patients were given 6 tablets especially made for this study, equivalent to 6 mg sodium selenite, 2 g vitamin C, and 480 mg vitamin E a day for five wk. GSH-px, which was lower than in non-MS controls before the start of treatment, increased fivefold during 5 wk of treatment. Side effects were scarce. Ten MS patients were subjected to a 24-h selenium absorption study after ingestion of 2 active tablets, equivalent to 2 mg sodium selenite. Selenium, which was low initially, increased 24% during the first 3 h and then stabilized. It is concluded that the tested antioxidant treatment seems to be safe and that MS patients have low GSH-px, which may be increased by the tested antioxidant treatment.


Hydroacoustic and hydrodynamic investigation of bio-inspired leading-edge tubercles on marine-ducted thrusters.
Underwater radiated noise (URN) has a negative impact on the marine acoustic environment where it can disrupt marine creature's basic living functions such as navigation and communication. To control the ambient ocean noise levels due to human activities, international governing bodies such as the International Maritime Organization (IMO) have issued non-mandatory guidelines to address this issue. Under such framework, the hydroacoustic performance of marine vehicles has become a critical factor to be evaluated and controlled throughout the vehicles' service life in order to mitigate the URN level and the role humankind plays in the ocean. This study aims to apply leading-edge (LE) tubercles of the humpback whales' pectoral fins to a benchmark ducted propeller to investigate its potential in noise mitigation. This was conducted using CFD, where the high-fidelity improved delayed detached eddy simulations (IDDES) in combination with the porous Ffowcs-Williams Hawkings (FW-H) acoustic analogy was used to solve the hydrodynamic flow field and propagate the generated noise to the far-field. It has been found that the LE tubercles have shown promising noise mitigation capabilities in the far-field, where the OASPL at J = 0.1 was reduced to a maximum of 3.4 dB with a maximum of 11 dB reduction in certain frequency ranges at other operating conditions. Based on detailed flow analysis researching the fundamental vortex dynamics, this noise reduction is shown to be due to the disruption of the coherent turbulent wake structure in the propeller slipstream causing the acceleration in the dissipation of turbulence and vorticity-induced noise.


A novel patch-based procedure for estimating brain age across adulthood.
Aging is associated with structural alterations in many regions of the brain. Monitoring these changes contributes to increasing our understanding of the brain's morphological alterations across its lifespan, and could allow the identification of departures from canonical trajectories. Here, we introduce a novel and unique patch-based grading procedure for estimating a synthetic estimate of cortical aging in cognitively intact individuals. The cortical age metric is computed based on image similarity between an unknown (test) cortical label and known (training) cortical labels using machine learning algorithms. The proposed method was trained on a dataset of 100 cognitively intact individuals aged 19-61 years, within the 31 bilateral cortical labels of the Desikan-Killiany-Tourville parcellation, then tested on an independent test set of 78 cognitively intact individuals spanning a similar age range. The proposed patch-based framework yielded a R2 = 0.94, as well as a mean absolute error of 1.66 years, which compared favorably to the literature. These experimental results demonstrate that the proposed patch-based grading framework is a reliable and robust method to estimate brain age from image data, even with a limited training size.


Struggling at work--a qualitative study of working Danes with depressive symptoms.
Little is known on how employees at work with mental health problems experience their work environment. This study explores how a selected sample of Danish employees with depressive symptoms experience the interaction with their work environment and how they respond to and deal with problems at work. From a survey study on work and mental health in Denmark, we invited participants for in-depth interviews. Using grounded theory, we conducted 13 semi structured interviews with employees, at work, experiencing depressive symptoms. Work was pivotal for the informants who were in an on-going process that we conceptualised as struggling at work. Informants struggled with the negative experiences of work that led to emotional, cognitive and somatic symptoms. Relationships with supervisors and colleagues, work load and work pressure and their self-image as a good worker conditioned the struggle. The informants found themselves unable to change their problematic working situation. This gradually led to different strategies to endure work and take care of one-self. These strategies were as follows: tending to symptoms and altering prospects for their future. The consequence of the on-going struggle was that the informants distanced themselves from their work. This study provided insight to the process of struggling at work, which the interviewed employees with depressive symptoms experienced. Behaviour of supervisors is a key element for employees with depressive symptoms struggling at work. Practitioners and other health and rehabilitation practitioners working with people with depressive symptoms and other mental health problems could inquire about supervisor's behaviour and relation between supervisors and employees. Interventions that targets both the individual employee as well as work environment focused interventions at the organisational level could be beneficial for employees with mental health problems as well as the workplaces.


NTP Technical Report on the toxicity studies of trans-1,2-dichloroethylene (CAS no. 156-60-5) administered in microcapsules in feed to F344/N rats and B6C3F(1) mice.
1,2-Dichloroethylene exists in two isomeric states: trans-1,2-dichloroethylene and cis-1,2-dichloroethylene. The trans isomer is used more widely in industry than the cis isomer. trans-1,2-Dichloroethylene is used as a solvent for waxes, resins, and acetylcellulose. It is also used in the extraction of rubber, as a refrigerant, and in the manufacture of pharmaceuticals and artificial pearls. F344/N rats and B6C3F1 mice were administered trans-1,2-dichloroethylene in microcapsules in feed for 14 weeks. Animals were evaluated for clinical pathology, reproductive system effects, and histopathology. Genetic toxicity studies were conducted in vitro in Salmonella typhimurium and Chinese hamster ovary (CHO) cells, and in vivo in mouse bone marrow cells and peripheral blood erythrocytes. In the 14-week feed studies, groups of 10 male and 10 female rats and mice were fed diets containing microcapsules with a chemical load of 45% trans-1,2-dichloroethylene. Dietary concentrations of 3,125, 6,250, 12,500, 25,000, and 50,000 ppm microencapsulated trans-1,2-dichloroethylene resulted in average daily doses of 190, 380, 770, 1,540, and 3,210 mg/kg for male rats; 190, 395, 780, 1,580, and 3,245 mg/kg for female rats; 480, 920, 1,900, 3,850, and 8,065 mg/kg for male mice; and 450, 915, 1,830, 3,760, and 7,925 mg/kg for female mice. Additional groups of 10 male and 10 female rats and mice served as untreated and vehicle controls. There were no exposure-related deaths of rats or mice. Mean body weights of male rats and male and female mice in the 50,000 ppm groups were significantly less than those of the vehicle controls. The mean body weight gains of female mice in the 12,500 and 25,000 ppm groups were also significantly less than that of the vehicle controls. On day 21 and at week 14, there were mild decreases in hematocrit values, hemoglobin concentrations, and erythrocyte counts in groups of male and female rats in the 25,000 and 50,000 ppm groups. At week 14, these effects were seen in male rats exposed to 6,250 and 12,500 ppm. There were no exposure-related alterations in clinical chemistry parameters in rats or mice. The liver weights of female rats exposed to 6,250 ppm or greater were significantly greater than those of the vehicle controls. The absolute kidney weights of male rats exposed to 25,000 or 50,000 ppm were significantly decreased. No gross or microscopic lesions were observed in rats or mice that could be attributed to trans-1,2-dichloroethylene exposure. Neither cis-, trans-, nor cis,trans-1,2-dichloroethylene was mutagenic in S. typhimurium strain TA97 (cis isomer only), TA98, TA100, TA1535, or TA1537, with or without S9 metabolic activation enzymes. In CHO cells in vitro, cis- 1,2-dichloroethylene induced sister chromatid exchanges (SCEs) in the absence of S9; with S9, the single trial that was performed yielded equivocal results. The cis,trans isomer induced significant increases in SCEs in cultured CHO cells with and without S9. In contrast to these positive results, trans-1,2-dichloroethylene gave negative results in the SCE test, with and without S9. Neither cis-, trans-, nor cis,trans-1,2-dichloroethylene induced chromosomal aberrations (Abs) in cultured CHO cells, with or without S9. In vivo, no induction of SCEs or Abs was noted in bone marrow cells of male mice administered cis- or trans-1,2-dichloroethylene by intraperitoneal injection once, with sampling performed 23 hours (for SCE analyses) or 17 hours (for Abs analyses) after injection. In addition, negative results were obtained in a peripheral blood micronucleus test in male and female mice administered trans- 1,2-dichloroethylene in microcapsules in feed for 14 weeks. Very little toxicity was associated with ingestion of microencapsulated trans-1-2-dichloroethylene. Histopathology and clinical chemistry data, combined with body and organ weight data, revealed that the maximum tolerated dose was not reached in these studies.


Dose-dense FEC followed by dose-dense ixabepilone as neoadjuvant treatment for breast cancer patients: a feasibility study.
Ixabepilone is an effective chemotherapy in metastatic breast cancer that has been pretreated with anthracyclines and is resistant or refractory to taxanes. Adjuvant dose-dense (DD) chemotherapy is more effective than regimens administered every 3 weeks, especially in hormonal receptor (HR)-negative tumors. A feasibility study of neoadjuvant DD ixabepilone was conducted in breast cancer patients with tumors measuring at least 2 cm. Patients received 5-fluorouracil 600 mg/m(2), epirubicin 90 mg/m(2), and cyclophosphamide 600 mg/m(2) ("FEC" in combination) administered intravenously on day 1 every 14 days with granulocyte-colony stimulating factor (filgrastim) followed by ixabepilone 40 mg/m(2) administered intravenously on day 1 every 14 days with granulocyte-colony stimulating factor. The study's primary endpoint was feasibility, and the secondary endpoint was pathologic complete response. A two-stage Simon's design was adopted. Forty-seven patients were enrolled, and 42 were evaluable. For 10 of 42 patients, DD ixabepilone was not feasible. Six (14%) required ixabepilone interruption, and four (9.5%) required ixabepilone dose reduction of 25%. One toxic death occurred. Hematologic grade 3-4 toxicities included anemia (9.5%), grade 4 neutropenia (2.4%), febrile neutropenia (4.8%), and thrombocytopenia (2.4%). Nonhematologic grade 3-4 toxicities consisted of fatigue (14.3%), mucositis (14.3%), sensory neuropathy (7.1%), onychopathy (7.1%), and liver toxicity (4.8%). Grade 2 sensory neuropathy lasting longer than 7 days was recorded in 11.9% of patients. Pathologic complete response was observed in 16 of 42 patients (38.1%), including 11 of 23 (47.8%) with HR-negative tumors and 5 of 19 (26.3%) with HR-positive tumors. Despite high activity, DD ixabepilone after DD FEC is poorly tolerated.


The safety of controlled hypotension for shoulder arthroscopy in the beach-chair position.
The safety of controlled hypotension during arthroscopic shoulder procedures with the patient in the beach-chair position is controversial. Current practice for the management of intraoperative blood pressure is derived from expert opinion among anesthesiologists, but there is a paucity of clinical data validating their practice. The purpose of this study was to evaluate the effect of controlled hypotension on cerebral perfusion with use of continuous electroencephalographic monitoring in patients undergoing shoulder arthroscopy in the beach-chair position. Fifty-two consecutive patients who had undergone shoulder arthroscopy in the beach-chair position were enrolled prospectively in this study. All patients underwent preoperative blood pressure measurements, assignment of an American Society of Anesthesiologists (ASA) grade, and a preoperative and postoperative neurological and Mini-Mental State Examination (MMSE). The target systolic blood pressure for all patients was 90 to 100 mm Hg during surgery. Continuous intraoperative monitoring was performed with standard ASA monitors and a ten-lead portable electroencephalography monitor. Real-time electroencephalographic monitoring was performed by an attending-level neurophysiologist. All patients violated at least one recommended limit for blood pressure reduction. The average decrease in systolic blood pressure and mean arterial pressure from baseline was 36% and 42%, respectively. Three patients demonstrated ischemic changes on electroencephalography that resolved with an increase in blood pressure. No adverse neurological sequelae were observed in any patient on the basis of the MMSE. This study provides the first prospective data on global cerebral perfusion during shoulder arthroscopy in the beach-chair position with use of controlled hypotension. Our study suggests that patients may be able to safely tolerate a reduction in blood pressure greater than current recommendations. In the future, intraoperative cerebral monitoring may play a role in preventing neurological injury in patients undergoing shoulder arthroscopy in the beach-chair position.


Association between obesity and therapeutic goal attainment in patients with concomitant hypertension and dyslipidemia.
Obesity is associated with cardiovascular risk factors such as hypertension, dyslipidemia, and diabetes mellitus, as well as cardiovascular diseases. To evaluate demographic, diagnostic, and treatment characteristics of patients with concomitant hypertension and dyslipidemia, stratified by body mass index and the attainment of blood pressure (BP) and lipid targets in obese versus nonobese patients. This retrospective study used data from GE Centricity Electronic Medical Records database (2004-2011) of a primary care physician group. Patients aged ≥ 18 years and having concomitant hypertension and dyslipidemia were categorized based on their body mass index: normal weight (≤ 24.9 kg/m2), overweight (25.0-29.9 kg/m2), and obese (≥ 30.0 kg/m2). Blood pressure and lipid goal attainments were based on Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure and National Cholesterol Education Program Adult Treatment Panel III guidelines, respectively. A total of 9086 patients with concomitant hypertension and dyslipidemia were identified and categorized as normal weight (n = 1256), overweight (n = 3058) and obese (n = 4772). Patients who were obese were younger (< 65 years); were more likely to have diabetes mellitus (P < 0.001); had higher baseline BP and triglyceride levels and lower levels of high-density lipoprotein cholesterol (P < 0.05); and were more likely to be prescribed antihypertensives and antilipemic agents (P < 0.001). In multivariate analyses, obese patients were significantly more likely to fail to attain BP (odds ratio = 1.562, P < 0.001) and dual BP and low-density lipoprotein cholesterol (odds ratio = 1.193, P = 0.023) goals. Obesity appears to be an independent risk factor for the failure to attain BP and dual BP and low-density lipoprotein cholesterol goals in patients with concomitant hypertension and dyslipidemia. These findings suggest that future research is needed to determine the underlying link between obesity and failure to attain these goals.


A study of dysmenorrhea during menstruation in adolescent girls.
What is the prevalence of dysmenorrhea severity and its associated symptoms among adolescent girls? (1) To study the prevalence of dysmenorrhea in high school adolescent girls of Gwalior. (2) To study the evidence of severity of the problem with associated symptoms and general health status. An explorative survey technique with a correlational approach. Nine hundred and seventy adolescent girls of age 15 to 20 years, studying in the higher secondary schools (Pre-University Colleges) of Gwalior. Percentages, Chi-square test, and Test-Retest Method. The prevalence of dysmenorrhea in adolescent girls was found to be 79.67%. Most of them, 37.96%, suffered regularly from dysmenorrhea severity. The three most common symptoms present on both days, that is, day before and first day of menstruation were lethargy and tiredness (first), depression (second) and inability to concentrate in work (third), whereas the ranking of these symptoms on the day after the stoppage of menstruation showed depression as the first common symptoms. Negative correlation had found between dysmenorrhea and the General Health Status as measured by the Body surface area.


Improving social behaviour in schizophrenia patients using an integrated virtual reality programme: a case study.
Social skills training programmes are among the treatments of choice in schizophrenia. Virtual reality (VR) can improve the results obtained with traditional social skills programmes by helping to generalize the acquired responses to patients' daily lives. We present the results of a case study involving the application of an integrated VR programme for social skills training. A 30-year-old woman with a well-established diagnosis of schizophrenia was enrolled in the study. She completed four baseline sessions, 16 treatment sessions and four follow-up sessions three months after the end of the treatment. Using a multiple baseline across-behaviours design, three target behaviours were analysed: facial emotion recognition, social anxiety and conversation time. Symptoms and social function variables were also assessed. The results showed a positive change in the three target behaviours and improvements in interpersonal communication, assertiveness and negative symptoms. The VR programme proved useful for training the patient's social behaviour and, consequently, for improving her performance.


Virus removal efficiency of Cambodian ceramic pot water purifiers.
Virus removal efficiency is described for three types of silver-impregnated, ceramic water filters (CWFs) produced in Cambodia. The tests were completed using freshly scrubbed filters and de-ionized (DI) water as an evaluation of the removal efficiency of the virus in isolation with no other interacting water quality variables. Removal efficiencies between 0.21 and 0.45 log are evidenced, which is significantly lower than results obtained in testing of similar filters by other investigators utilizing surface or rain water and a less frequent cleaning regime. Other experiments generally found virus removal efficiencies greater than 1.0 log. This difference may be because of the association of viruses with suspended solids, and subsequent removal of these solids during filtration. Variability in virus removal efficiencies between pots of the same manufacturer, and observed flow rates outside the manufacturer's specifications, suggest tighter quality control and consistency may be needed during production.


Characterization of fructose-1,6-bisphosphate aldolase during anoxia in the tolerant turtle, Trachemys scripta elegans: an assessment of enzyme activity, expression and structure.
One of the most adaptive facultative anaerobes among vertebrates is the freshwater turtle, Trachemys scripta elegans. Upon a decrease in oxygen supply and oxidative phosphorylation, these turtles are able to reduce their metabolic rate and recruit anaerobic glycolysis to meet newly established ATP demands. Within the glycolytic pathway, aldolase enzymes cleave fructose-1,6-bisphosphate to triose phosphates facilitating an increase in anaerobic production of ATP. Importantly, this enzyme exists primarily as tissue-specific homotetramers of aldolase A, B or C located in skeletal muscle, liver and brain tissue, respectively. The present study characterizes aldolase activity and structure in the liver tissue of a turtle whose survival greatly depends on increased glycolytic output during anoxia. Immunoblot and mass spectrometry analysis verified the presence of both aldolase A and B in turtle liver tissue, and results from co-immunoprecipitation experiments suggested that in the turtle aldolase proteins may exist as an uncommon heterotetramer. Expression levels of aldolase A protein increased significantly in liver tissue to 1.59±0.11-fold after 20 h anoxia, when compared to normoxic control values (P<0.05). A similar increase was seen for aldolase B expression. The overall kinetic properties of aldolase, when using fructose-1,6-bisphosphate as substrate, were similar to that of a previously studied aldolase A and aldolase B heterotetramer, with a Km of 240 and 180 nM (for normoxic and anoxic turtle liver, respectively). Ligand docking of fructose-1,6-bisphosphate to the active site of aldolase A and B demonstrated minor differences in both protein:ligand interactions compared to rabbit models. It is likely that the turtle is unique in its ability to regulate a heterotetramer of aldolase A and B, with a higher overall enzymatic activity, to achieve greater rates of glycolytic output and support anoxia survival.


Optical particle-sizing method that provides optical isolation of the sampling volume.
We have constructed and tested a novel particle sizer that employs particle counting (the time-domain approach) rather than the ensemble-diffraction approach that currently dominates the market in atmospheric-dust particle sizers. The method does not depend on mechanical devices to restrict particles within the sampling volume but instead allows for optical isolation of the sampling volume. This technique is useful for atmospheric-dust measurements for which nonobtrusive measurement is often desirable.


White matter hyperintensities in progranulin-associated frontotemporal dementia: A longitudinal GENFI study.
Frontotemporal dementia (FTD) is a heterogeneous group of neurodegenerative disorders with both sporadic and genetic forms. Mutations in the progranulin gene (GRN) are a common cause of genetic FTD, causing either a behavioural presentation or, less commonly, language impairment. Presence on T2-weighted images of white matter hyperintensities (WMH) has been previously shown to be more commonly associated with GRN mutations rather than other forms of FTD. The aim of the current study was to investigate the longitudinal change in WMH and the associations of WMH burden with grey matter (GM) loss, markers of neurodegeneration and cognitive function in GRN mutation carriers. 336 participants in the Genetic FTD Initiative (GENFI) study were included in the analysis: 101 presymptomatic and 32 symptomatic GRN mutation carriers, as well as 203 mutation-negative controls. 39 presymptomatic and 12 symptomatic carriers, and 73 controls also had longitudinal data available. Participants underwent MR imaging acquisition including isotropic 1 mm T1-weighted and T2-weighted sequences. WMH were automatically segmented and locally subdivided to enable a more detailed representation of the pathology distribution. Log-transformed WMH volumes were investigated in terms of their global and regional associations with imaging measures (grey matter volumes), biomarker concentrations (plasma neurofilament light chain, NfL, and glial fibrillary acidic protein, GFAP), genetic status (TMEM106B risk genotype) and cognition (tests of executive function). Analyses revealed that WMH load was higher in both symptomatic and presymptomatic groups compared with controls and this load increased over time. In particular, lesions were seen periventricularly in frontal and occipital lobes, progressing to medial layers over time. However, there was variability in the WMH load across GRN mutation carriers - in the symptomatic group 25.0% had none/mild load, 37.5% had medium and 37.5% had a severe load - a difference not fully explained by disease duration. GM atrophy was strongly associated with WMH load both globally and in separate lobes, and increased WMH burden in the frontal, periventricular and medial regions was associated with worse executive function. Furthermore, plasma NfL and to a lesser extent GFAP concentrations were seen to be associated with increased lesion burden. Lastly, the presence of the homozygous TMEM106B rs1990622 TT risk genotypic status was associated with an increased accrual of WMH per year. In summary, WMH occur in GRN mutation carriers and accumulate over time, but are variable in their severity. They are associated with increased GM atrophy and executive dysfunction. Furthermore, their presence is associated with markers of WM damage (NfL) and astrocytosis (GFAP), whilst their accrual is modified by TMEM106B genetic status. WMH load may represent a target marker for trials of disease modifying therapies in individual patients but the variability across the GRN population would prevent use of such markers as a global outcome measure across all participants in a trial.


Heart Valve Replacements with Regenerative Capacity.
The incidence of severe valvular dysfunctions (e.g., stenosis and insufficiency) is increasing, leading to over 300,000 valves implanted worldwide yearly. Clinically used heart valve replacements lack the capacity to grow, inherently requiring repetitive and high-risk surgical interventions during childhood. The aim of this review is to present how different tissue engineering strategies can overcome these limitations, providing innovative valve replacements that proved to be able to integrate and remodel in pre-clinical experiments and to have promising results in clinical studies. Upon description of the different types of heart valve tissue engineering (e.g., in vitro, in situ, in vivo, and the pre-seeding approach) we focus on the clinical translation of this technology. In particular, we will deepen the many technical, clinical, and regulatory aspects that need to be solved to endure the clinical adaptation and the commercialization of these promising regenerative valves.


Cytotoxic and larvicidal activities of Stemona alkaloids from the aerial parts and roots of Stemona curtisii Hook.f.
A new Stemona alkaloid glycoside derivative, 6-hydroxy-5,6-seco-stemocurtisinoside (4), was isolated from the ethanolic extract of the aerial parts of Stemona curtisii Hook.f., together with stemocurtisine (1), (11Z)-1',2'-didehydrostemofoline (2) and 6-hydroxy-5,6-seco-stemocurtisine (3). Whereas, stemocurtisine (1), stemocurtisinol (5) and oxyprotostemonine (6) were isolated from the roots. Their structures were elucidated using 1D and 2D NMR spectroscopy as well as MS experiments. The extract and the pure isolated compounds were evaluated for their cytotoxicities and their larvicidal activities against the dengue vector, Aedes aegypti. The alkaloid 2 showed the strongest larvicidal activity with a LC50 value of 2.44 µM. While the alkaloid 3 exhibited cytotoxicity against MCF-7 and KB cells (IC50 values of 62.52 and 18.82 µM, respectively) and showed no significant cytotoxicity against Vero cells. Additionally, quantitative analysis of the most active compounds; 2 and 3 in the crude extracts was also performed by HPLC.


Real-time, multidimensional in vivo imaging used to investigate blood flow in mouse pancreatic islets.
The pancreatic islets of Langerhans are highly vascularized micro-organs that play a key role in the regulation of blood glucose homeostasis. The specific arrangement of endocrine cell types in islets suggests a coupling between morphology and function within the islet. Here, we established a line-scanning confocal microscopy approach to examine the relationship between blood flow and islet cell type arrangement by real-time in vivo imaging of intra-islet blood flow in mice. These data were used to reconstruct the in vivo 3D architecture of the islet and time-resolved blood flow patterns throughout the islet vascular bed. The results revealed 2 predominant blood flow patterns in mouse islets: inner-to-outer, in which blood perfuses the core of beta cells before the islet perimeter of non-beta cells, and top-to-bottom, in which blood perfuses the islet from one side to the other regardless of cell type. Our approach included both millisecond temporal resolution and submicron spatial resolution, allowing for real-time imaging of islet blood flow within the living mouse, which has not to our knowledge been attainable by other methods.


Noise exposures and perceptions of hearing conservation programs among wildland firefighters.
Wildland firefighters are exposed to numerous noise sources that may be hazardous to their hearing. This study examined the noise exposure profiles for 264 wildland firefighters across 15 job categories. All 264 firefighters completed questionnaires to assess their use of hearing protection devices, enrollment in hearing conservation programs, and their overall perception of their noise exposure. Roughly 54% of firefighters' noise exposures exceeded the National Institute for Occupational Safety and Health recommended exposure limit of 85 decibels, A-weighted, over 8 hr, and 32% exceeded the Occupational Safety and Health Administration permissible exposure limit of 90 decibels, A-weighted, over 8 hr. Questionnaire results indicated good agreement between noise exposures and firefighters' perceptions of the noise hazard. Approximately 65% reported that they used some form of hearing protection; however, only 19% reported receiving any proper training regarding the use of hearing protection devices, with the majority of those firefighters relying on earplugs, including electronic and level-dependent earplugs, over earmuffs or other forms of hearing protectors. The results also suggest that improved communication and situational awareness play a greater role in the consistent use of hearing protection devices than other factors such as risk of developing noise-induced hearing loss. The study highlighted the challenges facing wildland firefighters and their management and the need for a comprehensive wildland fire agencies' hearing conservation program especially for firefighters who were exempt based on their occupational designations.


The kinematic alignment technique for TKA reliably aligns the femoral component with the cylindrical axis.
Kinematic alignment (KA) technique is an alternative technique for positioning a TKA, which aims a patient-specific implant positioning in order to reproduce the pre-arthritic knee anatomy. Because reliability in implant positioning is of interest to obtain reproducible good functional results, our study tests the hypothesis that the medial and lateral distal and posterior positions of the planned and surgically implanted kinematically aligned femoral component are similar. Preoperative knee magnetic resonance imaging (MRI) and postoperative knee computed tomography (CT) of 13 patients implanted with a KA Persona® TKA (Zimmer, Warsaw, USA) using manual instrumentation (kinematically-aligned TKA procedure pack®, Zimmer Biomet, Warsaw, USA) were segmented to create 3D femoral models. The kinematic alignment position of the femoral component was planned on the 3D model created from the preoperative MRI. Differences in the positions of the planned and surgically implanted kinematically-aligned femoral component were determined with in-house analysis software. The average differences between the medial and lateral distal and posterior positions of the planned and surgically implanted kinematically-aligned femoral component were inferior to 1mm and no statistically significant. In terms of variability, 62% (8/13) of performed implants matched all four positions within 1.5mm, and the maximum difference was 3mm. In this small series, intraoperative kinematic positioning of the femoral component with the specific manual instrumentation closely matched the planned position, which suggests that this technique reliably aligned the flexion-extension axis of the femoral component to the cylindrical axis. Level 3.


A randomised controlled trial of the effect of providing online risk information and lifestyle advice for the most common preventable cancers: study protocol.
Cancer is a leading cause of mortality and morbidity worldwide. Prevention is recognised by many, including the World Health Organization, to offer the most cost-effective long-term strategy for the control of cancer. One approach that focuses on individuals is the provision of personalised risk information. However, whether such information motivates behaviour change and whether the effect is different with varying formats of risk presentation is unclear. We aim to assess the short-term effect of providing information about personalised risk of cancer in three different formats alongside lifestyle advice on health-related behaviours, risk perception and risk conviction. In a parallel group, randomised controlled trial 1000 participants will be recruited through the online platform Prolific. Participants will be allocated to either a control group receiving cancer-specific lifestyle advice alone or one of three intervention groups receiving the same lifestyle advice alongside their estimated 10-year risk of developing one of the five most common preventable cancers, calculated from self-reported modifiable behavioural risk factors, in one of three different formats (bar chart, pictograph or qualitative scale). The primary outcome is change from baseline in computed risk relative to an individual with a recommended lifestyle at three months. Secondary outcomes include: perceived risk of cancer; anxiety; cancer-related worry; intention to change behaviour; and awareness of cancer risk factors. This study will provide evidence on the short-term effect of providing online information about personalised risk of cancer alongside lifestyle advice on risk perception and health-related behaviours and inform the development of interventions. ISRCTN17450583. Registered 30 January 2018.


Social class, anxieties and mothers' foodwork.
In the context of concerns about childhood obesity, mothers are placed at the forefront of responsibility for shaping the eating behaviour and consequently the health of their young children. This is evident in a multitude of diverse sites such as government reports, health promotion materials, reality TV shows and the advice of childcare nurses and preschools. These sites produce a range of resources available to mothers to draw on to constitute themselves as mothers in terms of caring for their children's health. Drawing on a qualitative study of mothers recruited through three Australian preschool centres, this article examines how the working-class and middle-class mothers of preschool-aged children engage with knowledge about motherhood, children and health and how those engagements impact on their mothering, their foodwork and their children. We argue that, unlike the working-class mothers pathologised in some literature on obesity, these working-class mothers demonstrated a no-nonsense (but still responsibilised) approach to feeding their children. The middle-class mothers, on the other hand, were more likely to engage in practices of self-surveillance and to demonstrate considerable anxieties about the appropriateness of their practices for their children's current and future health.


African-American sexual minority adolescents and sexual health disparities: An exploratory cross-sectional study.
To better understand sexual health disparities among African-American sexual minority adolescents. African-American adolescents (N = 1120; mean age = 15.24 years) were recruited from 4 cities (Columbia, SC; Macon, GA; Providence, RI; Syracuse, NY) to a larger trial. The current analyses used data from the 18-month follow-up when adolescents reported on their sexual partnerships, condom use knowledge, self-efficacy and outcome expectancies for condom use, sexual risk behavior, and STI testing history. Compared with heterosexual adolescents, sexual minority adolescents reported more concerns about potential relationship harms resulting from safer sex negotiation. Sexual minority adolescents were also more likely to engage in riskier sexual behaviors, with females reporting more sexual partners and drug use prior to sex, and males reporting inconsistent condom use and higher rates of HIV. African-American sexual minority adolescents evidence disparities in sexual risk behavior and STI history that appear to result from interpersonal and relationship concerns. These concerns need to be targeted in sexual health interventions for sexual minority adolescents.


Mapping diabetic sensory neuropathy by current perception threshold testing.
Detailed clinical neurological examinations were conducted on 44 nondiabetic volunteers and 59 diabetic subjects. The examinations focused particularly on sensory symptomatic and physical evaluation. Standardized assessment of symptoms and physical testing of light touch, pain, vibratory, and thermal sensation was performed at the hand, wrist, elbow, foot, ankle, and knee. A total symptom score and physical score were defined by summing test scores at each site. Current perception threshold (CPT) testing that used constant sine-wave-alternating current was conducted at the same anatomic sites. CPT correlations with the physical score gave r values of .55 for 5 Hz, .60 for 250 Hz, and .62 for 2000 Hz (n = 618). Correlations with the symptom score were not as strong: r = .45 for 5 Hz, .46 for 250 Hz, and .51 for 2000 Hz. The correlation with symptom score was due primarily to a strong relationship for the symptom of numbness (r = .53 for all 3 frequencies). Correlations with pain and paresthesia were much lower. CPTs for diabetic subjects at the three frequencies were higher at most locations than for the nondiabetic volunteers. However, CPTs were no different from normal values in diabetic subjects without evidence of neuropathy. CPT testing appears to be a useful technique for assessment of diabetic sensory neuropathy.


The anatomical basis for transcutaneous auricular vagus nerve stimulation.
The array of end organ innervations of the vagus nerve, coupled with increased basic science evidence, has led to vagus nerve stimulation (VNS) being explored as a management option in a number of clinical disorders, such as heart failure, migraine and inflammatory bowel disease. Both invasive (surgically implanted) and non-invasive (transcutaneous) techniques of VNS exist. Transcutaneous VNS (tVNS) delivery systems rely on the cutaneous distribution of vagal afferents, either at the external ear (auricular branch of the vagus nerve) or at the neck (cervical branch of the vagus nerve), thus obviating the need for surgical implantation of a VNS delivery device and facilitating further investigations across a wide range of uses. The concept of electrically stimulating the auricular branch of the vagus nerve (ABVN), which provides somatosensory innervation to several aspects of the external ear, is relatively more recent compared with cervical VNS; thus, there is a relative paucity of literature surrounding its operation and functionality. Despite the increasing body of research exploring the therapeutic uses of auricular transcutaneous VNS (tVNS), a comprehensive review of the cutaneous, intracranial and central distribution of ABVN fibres has not been conducted to date. A review of the literature exploring the neuroanatomical basis of this neuromodulatory therapy is therefore timely. Our review article explores the neuroanatomy of the ABVN with reference to (1) clinical surveys examining Arnold's reflex, (2) cadaveric studies, (3) fMRI studies, (4) electrophysiological studies, (5) acupuncture studies, (6) retrograde tracing studies and (7) studies measuring changes in autonomic (cardiovascular) parameters in response to auricular tVNS. We also provide an overview of the fibre composition of the ABVN and the effects of auricular tVNS on the central nervous system. Cadaveric studies, of which a limited number exist in the literature, would be the 'gold-standard' approach to studying the cutaneous map of the ABVN; thus, there is a need for more such studies to be conducted. Functional magnetic resonance imaging (fMRI) represents a useful surrogate modality for discerning the auricular sites most likely innervated by the ABVN and the most promising locations for auricular tVNS. However, given the heterogeneity in the results of such investigations and the various limitations of using fMRI, the current literature lacks a clear consensus on the auricular sites that are most densely innervated by the ABVN and whether the brain regions secondarily activated by electrical auricular tVNS depend on specific parameters. At present, it is reasonable to surmise that the concha and inner tragus are suitable locations for vagal modulation. Given the therapeutic potential of auricular tVNS, there remains a need for the cutaneous map of the ABVN to be further refined and the effects of various stimulation parameters and stimulation sites to be determined.


Is epigenetics an important link between early life events and adult disease?
Epigenetic mechanisms provide one potential explanation for how environmental influences in early life cause long-term changes in chronic disease susceptibility. Whereas epigenetic dysregulation is increasingly implicated in various rare developmental syndromes and cancer, the role of epigenetics in complex chronic diseases, such as cardiovascular disease, type 2 diabetes and obesity, remains largely uncharacterized. Extensive work in animal models is required to develop specific hypotheses that can be practicably tested in humans. We have developed a mouse model showing that methyl donor supplementation prevents transgenerational amplification of obesity, suggesting a role for DNA methylation in the developmental establishment of body weight regulation. Coupling such models with recently developed epigenomic technologies should ultimately enable us to determine if epigenetics is an important link between early life events and adult disease.


Development and health care needs of lesbians.
Lesbians have complained about the lack of awareness and sensitivity of their health care providers, resulting in unnecessary examinations and inappropriate focus on reproductive issues. This study attempted to identify psychosocial and health care needs of lesbians, to assess relationships with primary care providers and disclosure of sexual orientation, and to describe the chronologic features of a sexual identity and lifestyle. An anonymous, self-administered written questionnaire was distributed through a campus lesbian organization. Fifty-three women (median age 23 years) completed the questionnaire. Whereas 60% had disclosed their sexual orientation to their parents, only 31% had "come out" to their health care provider. Of participants who had disclosed their sexual preference to a provider, 27% reported a negative effect on their health care, 57% of participants who never had penile intercourse had annual Papanicolaou smears, and 16% felt pressured in the past to accept birth control from a physician. Lesbian sexuality was associated with several risk factors, such as childhood abuse (20%), alcohol or drug problems (39%), suicide attempts (27%), depression (49%), and physical or verbal abuse at school (34%). Average age of awareness of sexual orientation was 15 years, and average age of first homosexual activity was 17 years. Lesbians are at risk for depression, substance abuse, and suicide attempts. Although most would like to confide in their physician, few do because of fears of negative reactions. Communication must be improved to better address their specific health care needs.


Do children derive exact meanings pragmatically? Evidence from a dual morphology language.
Number words allow us to describe exact quantities like sixty-three and (exactly) one. How do we derive exact interpretations? By some views, these words are lexically exact, and are therefore unlike other grammatical forms in language. Other theories, however, argue that numbers are not special and that their exact interpretation arises from pragmatic enrichment, rather than lexically. For example, the word one may gain its exact interpretation because the presence of the immediate successor two licenses the pragmatic inference that one implies "one, and not two". To investigate the possible role of pragmatic enrichment in the development of exact representations, we looked outside the test case of number to grammatical morphological markers of quantity. In particular, we asked whether children can derive an exact interpretation of singular noun phrases (e.g., "a button") when their language features an immediate "successor" that encodes sets of two. To do this, we used a series of tasks to compare English-speaking children who have only singular and plural morphology to Slovenian-speaking children who have singular and plural forms, but also dual morphology, that is used when describing sets of two. Replicating previous work, we found that English-speaking preschoolers failed to enrich their interpretation of the singular and did not treat it as exact. New to the present study, we found that 4- and 5-year-old Slovenian-speakers who comprehended the dual treated the singular form as exact, while younger Slovenian children who were still learning the dual did not, providing evidence that young children may derive exact meanings pragmatically.


Problem based review: The patient with hypercalcaemia.
Hypercalcaemia is a common problem which may present to the Acute Medical Unit. Primary hyperparathyroidism (PHPT) and malignancy are the commonest causes of hypercalcaemia, accounting for over 90% of cases. Assessment of parathyroid hormone (PTH) levels is key to determining whether hypercalcaemia is parathyroid-mediated. Initial systematic assessment and adequate rehydration are important to help make the underlying diagnosis and determine longer-term management. The medical management of primary hyperparathyroidism not requiring surgery, with Cinacalcet is highlighted.


Photocopies yield lower digit ratios (2D:4D) than direct finger measurements.
The ratio between 2nd and 4th digit length (2D:4D) may be a negative correlate of prenatal testosterone. This possibility has led to a number of studies of 2D:4D and its relationship with sexual orientation and other sex-dependent traits. At first, 2D:4D ratio was calculated from measurements made directly on the fingers but recently a number of studies have used measurements from photocopies of the hands. Here, we compared finger lengths (2D, 3D, 4D, and 5D) and ratios obtained from these two measurement techniques. Our sample consisted of 30 homosexual men and 50 men and 70 women who were not selected for their sexual orientation. We found evidence that (1)2D:4D from photocopies tended to be lower than that from direct measurements, (2) there were differences in finger lengths such that 2D from photocopies tended to be shorter or equal in length to direct measurements, while 4D from photocopies tended to be longer or equal in length to direct measurements, (3) the sex differences in 2D:4D tended to be stronger for photocopy measurements, and (4) the pattern for length differences across 2D to 5D appeared to be different for homosexual men compared to men and women recruited without regard to sexual orientation. We conclude that there are differences in digit ratios obtained from photocopies and direct measurements, and these differences arise from length differences recorded from the different protocols. Therefore, 2D:4D ratios obtained from photocopies and direct measurements should not be combined within one study nor should they be used together in comparative studies. We suggest that finger length differences between the two techniques could result from the shapes of fat-pads at the tips of the fingers and these may be dependent on sex and sexual orientation.


Efficacy of Myofunctional Therapy Associated with Voice Therapy in the Rehabilitation of Neurogenic Oropharyngeal Dysphagia: a pilot study.
Introduction Dysphagia causes changes in the laryngeal and stomatognathic structures; however, the use of vocal exercises is poorly described. Objective To verify whether the therapy consisting of myofunctional exercises associated with vocal exercises is more effective in rehabilitating deglutition in stroke patients. Methods This is a pilot study made up of two distinct groups: a control group, which performed only myofunctional exercises, and an experimental group, which performed myofunctional and vocal exercises. The assessment used for oral intake was the functional oral intake scale (FOIS). Results The FOIS levels reveal that the pre-therapy median of the experimental group was 4, and increased to 7 after therapy, while in the control group the values were 5 and 6 respectively. Thus, the experimental group had a statistically significant difference between the pre- and post-therapy assessments ( p = 0.039), which indicates that the combination of myofunctional and vocal exercises was more effective in improving the oral intake levels than the myofunctional exercises alone ( p = 0.059). On the other hand, the control group also improved, albeit at a lower rate compared with the experimental group; hence, there was no statistically significant difference between the groups post-therapy ( p = 0.126). Conclusion This pilot study showed indications that using vocal exercises in swallowing rehabilitation in stroke patients was able to yield a greater increase in the oral intake levels. Nevertheless, further controlled blind clinical trials with larger samples are required to confirm such evidence, as this study points to the feasibility of conducting this type of research.


A texture-processing model of the 'visual sense of number'.
It has been suggested that numerosity is an elementary quality of perception, similar to colour. If so (and despite considerable investigation), its mechanism remains unknown. Here, we show that observers require on average a massive difference of approximately 40% to detect a change in the number of objects that vary irrelevantly in blur, contrast and spatial separation, and that some naive observers require even more than this. We suggest that relative numerosity is a type of texture discrimination and that a simple model computing the contrast energy at fine spatial scales in the image can perform at least as well as human observers. Like some human observers, this mechanism finds it harder to discriminate relative numerosity in two patterns with different degrees of blur, but it still outpaces the human. We propose energy discrimination as a benchmark model against which more complex models and new data can be tested.


Structural studies of the streptavidin binding loop.
The streptavidin-biotin complex provides the basis for many important biotechnological applications and is an interesting model system for studying high-affinity protein-ligand interactions. We report here crystallographic studies elucidating the conformation of the flexible binding loop of streptavidin (residues 45 to 52) in the unbound and bound forms. The crystal structures of unbound streptavidin have been determined in two monoclinic crystal forms. The binding loop generally adopts an open conformation in the unbound species. In one subunit of one crystal form, the flexible loop adopts the closed conformation and an analysis of packing interactions suggests that protein-protein contacts stabilize the closed loop conformation. In the other crystal form all loops adopt an open conformation. Co-crystallization of streptavidin and biotin resulted in two additional, different crystal forms, with ligand bound in all four binding sites of the first crystal form and biotin bound in only two subunits in a second. The major change associated with binding of biotin is the closure of the surface loop incorporating residues 45 to 52. Residues 49 to 52 display a 3(10) helical conformation in unbound subunits of our structures as opposed to the disordered loops observed in other structure determinations of streptavidin. In addition, the open conformation is stabilized by a beta-sheet hydrogen bond between residues 45 and 52, which cannot occur in the closed conformation. The 3(10) helix is observed in nearly all unbound subunits of both the co-crystallized and ligand-free structures. An analysis of the temperature factors of the binding loop regions suggests that the mobility of the closed loops in the complexed structures is lower than in the open loops of the ligand-free structures. The two biotin bound subunits in the tetramer found in the MONO-b1 crystal form are those that contribute Trp 120 across their respective binding pockets, suggesting a structural link between these binding sites in the tetramer. However, there are no obvious signatures of binding site communication observed upon ligand binding, such as quaternary structure changes or shifts in the region of Trp 120. These studies demonstrate that while crystallographic packing interactions can stabilize both the open and closed forms of the flexible loop, in their absence the loop is open in the unbound state and closed in the presence of biotin. If present in solution, the helical structure in the open loop conformation could moderate the entropic penalty associated with biotin binding by contributing an order-to-disorder component to the loop closure.


Experiences of Older Adults With Mobile Phone Text Messaging as Reminders of Home Exercises After Specialized Manual Therapy for Recurrent Low Back Pain: A Qualitative Study.
Clinical experience of manual therapy for musculoskeletal pain is that patients often suffer from recurrent pain and disorders, but that they do not continue to perform their physical home exercises when they are free from symptoms. The chance of positive long-term effects of manual therapy would probably increase if patients were reminded that they are to continue to perform their exercises. Mobile phone text messaging (short messaging service, SMS) is increasingly used as an innovative intervention to remind patient to exercise. However, there are only a few studies on such interventions in the field of low back pain (LBP). Qualitative studies of patients' experiences of receiving text messages as reminders of home exercises after manual treatment for recurrent LBP have to the best of our knowledge never been published. The aim of this study was to explore older persons' common experiences of receiving reminders of home exercises through mobile phone text messaging after specialized manual therapy for recurrent LBP. A total of 7 men and 8 women (67-86 years), who had sought specialized manual therapy (Naprapathic manual therapy) for recurrent LBP were included in the study. Individual one-way text messages as reminders of home exercises (to be performed on a daily basis) were sent to each patient every third day for 3 weeks, then once a week for another 2 weeks. Semistructured interviews with 2 broad, open-ended questions were held and data were analyzed with systematic text condensation, based on Giorgi's principles of psychological phenomenological analysis. The participants appreciated the messages, which were perceived as timely and usable, and also stimulated memorizing. The messages made the participants reflect on the aim of the exercise, value of being reminded, and on their improvement in pain. During the interviews, the participants created their own routines for continued adherence to the exercises. It seems plausible that mobile phone text messaging may serve as a useful tool for patient empowerment with regard to recurrent LBP in older persons. Further studies are needed to explore whether future compliance with the exercises will be as large if the participants are not being interviewed.


Effect of lisinopril on renal tissue damage in unilateral ureteral obstruction in rats.
In this study, it was aimed to investigate apoptosis in renal injury and the effect of lisinopril in rat model, which constitute unilateral ureteral obstruction. The retroperitoneal ureter was ligated with a 4.0 silk for the experimental model of ureteral obstruction in Wistar albino rats. Untreated group (n = 20) received no treatment. For the lisinopril-treated group (n = 20), 20 mg/kg/day of drug was given orally. Ultrastructural differences were analyzed using electron microscopic technique; apoptotic distribution was analyzed using the TUNEL method. After electron microscopic evaluation, on the 4th and 14th day in the untreated group, edema in the glomeruli, loss of microvillus and apoptotic cells in proximal tubule cells and sclerosis in the glomeruli were detected. On the 4th day in the lisinopril-treated group, the kidney was ultrastructurally normal and a less number of apoptotic cells were only observed on the 14th day. On light microscopic examination on the 4th and 14th day in the untreated group, while the glomeruli were normal in structure, the boundary of the proximal tubule was disrupted and some picnotic cells in both the proximal and collecting tubules were observed. In both 4th and 14th day of the lisinopril-treated group, kidney showed normal structure, although in some places picnotic cells in the collecting tubules were observed. In conclusion, lisinopril was effective and it may prevent early renal damage in the direct obstruction model.


Distribution of corticotropin releasing hormone receptor immunoreactivity in the rat hypothalamus: coexpression in neuropeptide Y and dopamine neurons in the arcuate nucleus.
An abundance of physiological data suggests an interaction between neuropeptide Y (NPY) and corticotropin-releasing hormone (CRH) in the regulation of endocrine and autonomic functions. Previously, studies in our laboratory have indicated that NPY neurons in the arcuate nucleus of the hypothalamus (ARH) project to and come in close contact with CRH neurons in the paraventricular nucleus of the hypothalamus (PVH). Conversely, it has been demonstrated that the ventromedial portion of the ARH, an area containing NPY neurons, displays CRH receptor binding and CRH receptor mRNA. These data suggest a possible reciprocal feedback regulation between NPY and CRH neurons. The ARH also contains several other populations of neurons that may be targets of the CRH system and express CRH receptors; most notable are tuberoinfundibular dopaminergic neurons (TIDA). The PVH is an important component in the regulation of prolactin secretion and may play a role in the suppression of TIDA activity, which is a critical step in the prolactin stress response. The purpose of the present study was to characterize the distribution and cellular localization of CRH R(1) receptor-like immunoreactivity (CRH R(1)-ir) in the rat hypothalamus and to determine the phenotype of neurons in the ARH that contain CRH R(1)-ir. CRH R(1)-ir was present throughout the rat brain. Hypothalamic regions with the highest levels of immunostaining were the supraoptic nucleus, magnocellular PVH, ARH, and suprachiasmatic nucleus. Double label immunofluorescence was used to demonstrate that CRH R(1)-ir in the ARH was localized to NPY cell bodies. Furthermore, TIDA neurons in the ARH also displayed CRH R(1)-ir. However, despite an abundance of CRH R(1)-ir cells in the ARH, CRH-ir fiber innervation to the ARH was extremely sparse. Therefore, although this study provides neuroanatomical evidence for direct CRH R(1) regulation of ARH NPY and TIDA neurons in the rat, it is not consistent with the idea of a reciprocal feedback loop and suggests the involvement of other CRH-like ligands, such as urocortin.


The relationship between advertising, price, and nursing home quality.
Theoretically, nursing homes should engage in advertising for the following two reasons: (a) to improve awareness of the services offered in a particular market and (b) to signal high-quality services. In this study, we build upon results from prior studies of nursing home advertising activity, market competition, and quality. The purpose of this study was to examine the association between advertising expenses, price, and quality. We focused on answering the question: Do nursing homes use advertising and price to signal superior quality? The Texas Nursing Facilities Medicaid Cost Report, the Texas Quality Reporting System, and the Area Resource File were merged for the year 2003. We used three alternative measures of quality to improve the robustness of this exploratory analysis. Quality measures were examined using Bonferroni correlation coefficient analysis. Associations between advertising expenses and quality were evaluated using three regression models predicting quality. We also examined the association of the price of a private bed per day with quality. Advertising expenses were not associated with better nursing home quality as measured by three quality scales. The average price customers pay for one private bed per day was associated with better quality only in one of the three quality regression models. The price of nursing home care might be a better indicator of quality and necessary to increase as quality of care is improved in the nursing homes sector. Because more advertising expenditures are not necessarily associated with better quality, consumers could be mislead by advertisements and choose poor quality nursing homes. Nursing home administrators should focus on customer relationship management tools instead of expensive advertising. Relationship management tools are proven marketing techniques for the health services sector, usually less expensive than advertising, and help with staff retention and quality outcomes.


RNA processing generates the mature 3' end of yeast CYC1 messenger RNA in vitro.
In whole cell extracts of Saccharomyces cerevisiae, incubation of precursor mRNA transcripts encoding the sequences essential in vivo for forming the 3' end of the iso-1-cytochrome c mRNA (CYC1) revealed an endonuclease activity with the characteristics required for producing the mature mRNA 3' end. The observed cleavage in vitro is (i) accurate, occurring at or near the polyadenylation site of CYC1 RNA, (ii) 30 to 50 percent efficient, (iii) adenosine triphosphate dependent, (iv) specific for the 3' ends of at least two yeast pre-mRNA's, and (v) absent with related pre-mRNA's carrying mutations that abolish correct 3' end formation in vivo. In addition, a second activity in the extract polyadenylates the product under appropriate conditions. Thus, the mature 3' ends of yeast mRNA's may be generated by endonucleolytic cleavage and polyadenylation rather than by transcription termination.


Group B Streptococcus (Streptococcus agalactiae) peritonitis associated with continuous ambulatory peritoneal dialysis (CAPD).
Streptococcus agalactiae typically induces serious infections in pregnant women and newborns. Nonpregnant adult patients can also be infected and mortality rate exceeds 40%. CAPD peritonitis is very rarely induced by S. agalactiae. Seven cases have been described previously and all had a very severe course, which included bacteremia, septic shock and death. A 27-year-old male with end-stage renal disease due to membranoprolipherative glomerulonephritis type I, who was on CAPD for 17 months, was admitted with the clinical and laboratory picture of CAPD peritonitis. Severe abdominal pain, shaking chills and fever 38.5 microC were also observed at presentation. Streptococcus agalactiae was isolated from the peritoneal fluid and blood culture was sterile. Under treatment with ceftazidime and tobramycin (i.p.) and vancomycin (i.v.) cultures became negative after 48 hours, abdominal symptoms resolved after 12 days and WBC count in the dialysate normalized after 14 days. As a possible source of infection the patient's partner was shown to be a vaginal carrier of a clone of S. agalactiae identical to that isolated in the peritoneal fluid. S. agalactiae is a rare cause of CAPD peritonitis with potentially very serious consequences. Anal or genital tract colonization is, in general, the source of contamination with S. agalactiae. The microbiological findings in the case presented here suggest that colonization of the patient or of his close environment may be important in the pathogenesis of S. agalactiae-induced CAPD peritonitis.


A physiologically based pharmacokinetic model for ethylene oxide in mouse, rat, and human.
Ethylene oxide (EO) is widely used as a gaseous sterilant and industrial intermediate and is a direct-acting mutagen and carcinogen. The objective of these studies was to develop physiologically based pharmacokinetic (PB-PK) models for EO to describe the exposure-tissue dose relationship in rodents and humans. We previously reported results describing in vitro and in vivo kinetics of EO metabolism in male and female F344 rats and B6C3F1 mice. These studies were extended by determining the kinetics of EO metabolism in human liver cytosol and microsomes. The results indicate enzymatically catalyzed GSH conjugation via cytosolic glutathione S-transferase (cGST) and hydrolysis via microsomal epoxide hydrolase (mEH) occur in both rodents and humans. The in vitro kinetic constants were scaled to account for cytosolic (cGST) and microsomal (mEH) protein content and incorporated into PB-PK descriptions for mouse, rat, and human. Flow-limited models adequately predicted blood and tissue EO levels, disposition, and elimination kinetics determined experimentally in rats and mice, with the exception of testis concentrations, which were overestimated. Incorporation of a diffusion-limited description for testis improved the ability of the model to describe testis concentrations. The model accounted for nonlinear increases in blood and tissue concentrations that occur in mice on exposure to EO concentrations greater than 200 ppm. Species differences are predicted in the metabolism and exposure-dose relationship, with a nonlinear relationship observed in the mouse as a result of GSH depletion. These models represent an essential step in developing a mechanistically based EO exposure-dose-response description for estimating human risk from exposure to EO.


Examining rainfall and cholera dynamics in Haiti using statistical and dynamic modeling approaches.
Haiti has been in the midst of a cholera epidemic since October 2010. Rainfall is thought to be associated with cholera here, but this relationship has only begun to be quantitatively examined. In this paper, we quantitatively examine the link between rainfall and cholera in Haiti for several different settings (including urban, rural, and displaced person camps) and spatial scales, using a combination of statistical and dynamic models. Statistical analysis of the lagged relationship between rainfall and cholera incidence was conducted using case crossover analysis and distributed lag nonlinear models. Dynamic models consisted of compartmental differential equation models including direct (fast) and indirect (delayed) disease transmission, where indirect transmission was forced by empirical rainfall data. Data sources include cholera case and hospitalization time series from the Haitian Ministry of Public Health, the United Nations Water, Sanitation and Health Cluster, International Organization for Migration, and Hôpital Albert Schweitzer. Rainfall data was obtained from rain gauges from the U.S. Geological Survey and Haiti Regeneration Initiative, and remote sensing rainfall data from the National Aeronautics and Space Administration Tropical Rainfall Measuring Mission. A strong relationship between rainfall and cholera was found for all spatial scales and locations examined. Increased rainfall was significantly correlated with increased cholera incidence 4-7 days later. Forcing the dynamic models with rainfall data resulted in good fits to the cholera case data, and rainfall-based predictions from the dynamic models closely matched observed cholera cases. These models provide a tool for planning and managing the epidemic as it continues.


Temperature-dependent intensity anomalies in amino acid esters: weak hydrogen bonds in protected glycine, alanine and valine.
Esters of glycine, alanine and valine are investigated by FTIR and Raman spectroscopy in supersonic jets as gas phase model systems for the neutral peptide N-terminus. The NH-stretching vibrations exhibit very large temperature- and substitution-dependent intensity anomalies which are related to weak, bifurcated intramolecular hydrogen bonds to the carbonyl group. Comparison to theory is only satisfactory at low temperature. Spectral NH aggregation shifts are small or even negligible and the associated IR intensity is remarkably low. In the case of valine, chirality recognition effects are nevertheless detected and rationalized. Comparison to quantum-chemical calculations for dimers shows that dispersion interactions are essential. It also rules out cooperative hydrogen bond topologies and points at deficiencies in standard harmonic treatments with the linear dipole approximation.


c-fos expression in bladder-specific spinal neurons after spinal cord injury using pseudorabies virus.
c-fos expression in spinal neurons that are activated by lower urinary tract stimulation are not organ specific. In this experiment, we demonstrated changes of c-fos expression in bladder-specific preganglionic neurons (PGNs) and interneurons using pseudorabies virus (PRV). Forty Sprague-Dawley rats were used. We identified the neuronal pathway associated with the bladder by injecting PRV into the detrusor. An immunohistochemical method was used to stain Fos-protein encoded by the c-fos gene. Immunofluorescent staining for PRV was performed to evaluate changes in bladder-specific spinal neurons. Immunofluorescent staining with choline acetyltransferase (ChAT) revealed that the sacral parasympathetic nucleus (SPN) regions contained 9.8 PGNs/section. In rats with chronic spinal cord injury by intravesical saline instillation, 82.4+/-10.3% of PGNs in SPN exhibited Fos-immunoreactive (IR). Two and a half days after PRV infection, PRV-IR PGNs were observed at 5.4 PGNs/section, and 2.7+/-1.6% of them exhibited Fos-IR. Unlike ChAT-IR PGNs, PRV-IR PGNs are bladder-specific neurons and PRV-IR and Fos-IR cells found in the back of PRV-IR PGNs are bladder-specific interneurons. Three days after PRV infection, we observed many PRV-IR and Fos-IR cells in the dorsal commissure. These neurons are interneurons distributed in the bladder. We confirmed that in chronic spinal cord injury, the patterns of c-fos expression in bladder-specific spinal neurons were similar to those in voiding-reflex related spinal neurons, which had already been demonstrated earlier. We believe that our methodology can be applied to study interactions between voiding and other organs as well, such as the urethra and prostate.


The TOR signal transduction cascade controls cellular differentiation in response to nutrients.
Rapamycin binds and inhibits the Tor protein kinases, which function in a nutrient-sensing signal transduction pathway that has been conserved from the yeast Saccharomyces cerevisiae to humans. In yeast cells, the Tor pathway has been implicated in regulating cellular responses to nutrients, including proliferation, translation, transcription, autophagy, and ribosome biogenesis. We report here that rapamycin inhibits pseudohyphal filamentous differentiation of S. cerevisiae in response to nitrogen limitation. Overexpression of Tap42, a protein phosphatase regulatory subunit, restored pseudohyphal growth in cells exposed to rapamycin. The tap42-11 mutation compromised pseudohyphal differentiation and rendered it resistant to rapamycin. Cells lacking the Tap42-regulated protein phosphatase Sit4 exhibited a pseudohyphal growth defect and were markedly hypersensitive to rapamycin. Mutations in other Tap42-regulated phosphatases had no effect on pseudohyphal differentiation. Our findings support a model in which pseudohyphal differentiation is controlled by a nutrient-sensing pathway involving the Tor protein kinases and the Tap42-Sit4 protein phosphatase. Activation of the MAP kinase or cAMP pathways, or mutation of the Sok2 repressor, restored filamentation in rapamycin treated cells, supporting models in which the Tor pathway acts in parallel with these known pathways. Filamentous differentiation of diverse fungi was also blocked by rapamycin, demonstrating that the Tor signaling cascade plays a conserved role in regulating filamentous differentiation in response to nutrients.


Unbiased and efficient estimation of the volume of the fibroid uterus using the Cavalieri method and magnetic resonance imaging.
The aim of our study was to develop a reliable technique for measuring volume of the fibroid uterus using Magnetic Resonance Imaging. We applied the Cavalieri method and standard calliper technique to measure the volume of the uterus and largest fibroid in 26 patients, and results were compared with "gold-standard" planimetry measurements. We found Cavalieri measurements to be unbiased, while calliper measurements systematically underestimated uterine volume (- 13.2%, P < 10(-5)) and had greater variance. Repeatability was similar for the 2 techniques (standard deviation [SD] = 4.0%-6.9%). Reproducibility of Cavalieri measurements was higher for measurement of uterine (SD = 9.0%) than fibroid volume (SD = 19.1%), whereas the reproducibility of calliper measurements was higher for fibroid (SD = 9.1%) than uterine volume (SD = 15.9%). The additional measurement time for the Cavalieri method was approximately 1 to 2 minutes. In conclusion, the Cavalieri method permits more accurate measurement of uterine and fibroid volumes and is suitable for application in both clinical practice and scientific research.


Prevalence and burden of headache disorders in Lithuania and their public-health and policy implications: a population-based study within the Eurolight Project.
The Eurolight project assessed the impact of headache disorders in ten EU countries, using the same structured questionnaire but varying sampling methods. In Lithuania, sample selection employed methods in line with consensus recommendations for population-based burden-of-headache studies. The survey was cross-sectional. We identified, from the Residents' Register Service, a sample of inhabitants of Kaunas city and surrounding Kaunas region reflecting age (in the range 18-65 years), gender and rural/urban distributions of Lithuania. Medical students called unannounced at their homes and conducted face-to-face interviews employing a structured questionnaire. Of 1137 people in the pre-identified sample, 573 (male 237 [41.4%], female 336 [58.6%]; mean age 40.9 ± 13.8 years) completed interviews (participation proportion: 50.4%). Gender-adjusted 1-year prevalences were: any headache 74.7%; migraine 18.8%; tension-type headache (TTH) 42.2%; all headache on ≥15 days/month 8.6%; probable medication-overuse headache (pMOH) 3.2%. Migraine (OR: 3.6) and pMOH (OR: 2.9) were associated with female gender. All headache types except TTH were associated with significantly diminished quality of life. Migraine caused a mean 4.5% loss in paid worktime per affected male and 3.5% per affected female. Lost per-person times due to TTH were much less, but to pMOH and other headache on ≥15 days/month much higher. Among the entire workforce, lost productivity to migraine was estimated at 0.7%, to TTH 0.3% and to pMOH or other headache on ≥15 days/month 0.5%. The total of 1.5% may translate directly into lost GDP. Alternative calculations based on headache yesterday (with little recall error) produced, for all headache, a corroborating 1.7%. Similar losses from household work would also drain the nation's economy. Our findings were comparable to those from earlier studies using similar methods in Russia and Georgia. The multiple burdens from headache in Lithuania indicate substantial ill-health and unmet need for health care. The heavy burdens on individuals are matched by heavy economic burden. Of particular concern is the high prevalence of headache on ≥15 days/month, seen also in Russia and Georgia. Health policy in Lithuania must heed WHO's advice that effective treatment of headache, clearly desirable for its health benefits, is also expected to be cost-saving.


Inflammation, focal atrophic lesions, and prostatic intraepithelial neoplasia with respect to risk of lethal prostate cancer.
A challenge in prostate cancer (PCa) management is identifying potentially lethal disease at diagnosis. Inflammation, focal prostatic atrophy, and prostatic intraepithelial neoplasia (PIN) are common in prostate tumor specimens, but it is not clear whether these lesions have prognostic significance. We conducted a case-control study nested in a cohort of men diagnosed with stage T1a-b PCa through transurethral resection of the prostate in Sweden. Cases are men who died of PCa (n = 228). Controls are men who survived more than 10 years after PCa diagnosis without metastases (n = 387). Slides were assessed for Gleason grade, inflammation, PIN, and four subtypes of focal prostatic atrophy: simple atrophy (SA), postatrophic hyperplasia (PAH), simple atrophy with cyst formation, and partial atrophy. We estimated OR and 95% CI for odds of lethal PCa with multivariable logistic regression. Chronic inflammation and PIN were more frequently observed in tumors with PAH, but not SA. No specific type of atrophy or inflammation was significantly associated with lethal PCa overall, but there was a suggestion of a positive association for chronic inflammation. Independent of age, Gleason score, year of diagnosis, inflammation, and atrophy type, men with PIN were 89% more likely to die of PCa (95% CI: 1.04-3.42). Our data show that PIN, and perhaps presence of moderate or severe chronic inflammation, may have prognostic significance for PCa. Lesions in tumor adjacent tissue, and not just the tumor itself, may aid in identification of clinically relevant disease.


A 6-year longitudinal study of predictors for suicide attempts in major depressive disorder.
Major depressive disorder (MDD), represent a major source of risk for suicidality. However, knowledge about risk factors for future suicide attempts (SAs) within MDD is limited. The present longitudinal study examined a wide range of putative non-clinical risk factors (demographic, social, lifestyle, personality) and clinical risk factors (depressive and suicidal indicators) for future SAs among persons with MDD. Furthermore, we examined the relationship between a number of significant predictors and the incidence of a future SA. Data are from 1713 persons (18-65 years) with a lifetime MDD at the baseline measurement of the Netherlands Study of Depression and Anxiety who were subsequently followed up 2, 4 and 6 years. SAs were assessed in the face-to-face measurements. Cox proportional hazard regression analyses were used to examine a wide range of possible non-clinical and clinical predictors for subsequent SAs during 6-year follow-up. Over a period of 6 years, 3.4% of the respondents attempted suicide. Younger age, lower education, unemployment, insomnia, antidepressant use, a previous SA and current suicidal thoughts independently predicted a future SA. The number of significant risk factors (ranging from 0 to 7) linearly predicted the incidence of future SAs: in those with 0 predictors the SA incidence was 0%, which increased to 32% incidence in those with 6+ predictors. Of the non-clinical factors, particularly socio-economic factors predicted a SA independently. Furthermore, preexisting suicidal ideation and insomnia appear to be important clinical risk factors for subsequent SA that are open to preventative intervention.


Smartphone apps for urolithiasis.
There are an increasing number of healthcare smartphone applications ('apps') available. Urolithiasis presents a major healthcare burden. Patients are increasingly keen to educate themselves regarding the diagnosis and management of their condition. There is no formal regulation of healthcare apps, including a large number of apps relating to urolithiasis. This review aims to examine the range of apps available, and the prevalence of healthcare professional input. Four international smartphone app stores were searched: Apple's App Store, Google Play (Android), BlackBerry App World and the Windows Phone App store. A total of 42 unique apps were downloaded and analysed. Recorded data included the cost (£/$), publisher information, number of ratings, average rating and any documentation of medical professional involvement. Twenty-one (50%) apps required payment for download. The mean cost was £3.58 ($6.04) with range £0.61-£34.90 ($1.03-$58.87). Thirty-three (79%) of the 42 apps were designed to be used by patients. Fifteen (36%) of the 42 apps had clear input from health professionals. Twenty-two apps offered patient information, including dietary advice on lowering calcium intake, which is contrary to current evidence-based practice. We conclude that urolithiasis apps have future potential to inform both patients and healthcare professionals on stone management. However, inaccuracies in the recommendations made by some apps can be misleading or even harmful due to a lack of specialist involvement. We recommend improving the usefulness of these apps by seeking a 'quality stamp' from recognised urological organisations and greater clinician involvement in future app development.


[Characteristics of suicides in Bogotá, 1985-2000].
To establish how suicide's typologies are related with a group of variables described as risk factors and to describe the stability of these typologies during a period of 15 years. Observational-analytic study based on autopsy registers of suicides in Bogotá in 1985, 1990, 1995 and 2000. In order to determine typologies, the method of multivarioate analysis of multiple correspondences was employed. 171 cases of suicide were detected in 1985, 222 cases in 1990, 273 in 1995 and 329 in 2000. Physical or mental co-morbidity, the use of psychoactive substances, access to lethal methods of injury, and the rare use of fire weapons by women, were constant factors during the years studied. At the same time, changes in some typologies were related to the presence of addictions in women and to HIV/AIDS. Although relatively constant suicide typologies exist during the 15-year period studied, changes in the epidemiological profiles and new life styles generate modifications of these typologies. This suggests that suicide risk factors are a dynamic element that is modified as time passes.


Geospatial characteristics of measles transmission in China during 2005-2014.
Measles is a highly contagious and severe disease. Despite mass vaccination, it remains a leading cause of death in children in developing regions, killing 114,900 globally in 2014. In 2006, China committed to eliminating measles by 2012; to this end, the country enhanced its mandatory vaccination programs and achieved vaccination rates reported above 95% by 2008. However, in spite of these efforts, during the last 3 years (2013-2015) China documented 27,695, 52,656, and 42,874 confirmed measles cases. How measles manages to spread in China-the world's largest population-in the mass vaccination era remains poorly understood. To address this conundrum and provide insights for future public health efforts, we analyze the geospatial pattern of measles transmission across China during 2005-2014. We map measles incidence and incidence rates for each of the 344 cities in mainland China, identify the key socioeconomic and demographic features associated with high disease burden, and identify transmission clusters based on the synchrony of outbreak cycles. Using hierarchical cluster analysis, we identify 21 epidemic clusters, of which 12 were cross-regional. The cross-regional clusters included more underdeveloped cities with large numbers of emigrants than would be expected by chance (p = 0.011; bootstrap sampling), indicating that cities in these clusters were likely linked by internal worker migration in response to uneven economic development. In contrast, cities in regional clusters were more likely to have high rates of minorities and high natural growth rates than would be expected by chance (p = 0.074; bootstrap sampling). Our findings suggest that multiple highly connected foci of measles transmission coexist in China and that migrant workers likely facilitate the transmission of measles across regions. This complex connection renders eradication of measles challenging in China despite its high overall vaccination coverage. Future immunization programs should therefore target these transmission foci simultaneously.


Predominant cytosolic localization of type II transforming growth factor beta receptors in human breast carcinoma cells.
It is proposed that loss of a growth-inhibitory response to transforming growth factor beta (TGFbeta) contributes to breast cancer progression. Because cellular TGFbeta responsiveness often correlates with TGFbeta type II receptor (TGFbeta-IIR) expression, we have examined the cellular distribution of TGFbeta-IIRs in tumor and nontumor mammary epithelial cells. By immunoblot analysis, TGFbeta-IIR was detected both in membrane and cytosolic fractions of MDA-231 tumor cells as well as in normal human breast epithelial cells. The cytosolic protein appeared to be more abundant and was detected as a clear perinuclear staining by immunocytochemistry. The glycosylation patterns of the cytosolic and membrane form were different, indicating distinct receptor pools. The cytosolic TGFbeta-IIR did not bind 125I-labeled TGFbeta1 but had a detectable in vitro and in vivo kinase activity. MCF-7 breast cancer cells express the TGFbeta-IIR mRNA but show undetectable cell surface TGFbeta-IIR protein by affinity cross-linking. However, low levels of TGFbeta-IIR were observed in MCF-7 cytosol. Sequencing of the coding region of TGFbeta-IIR from MCF-7 cells indicated a point mutation (A439V) in a nonconserved region of the kinase domain. When MCF-7 cells were treated with sublethal doses of Adriamycin that induce cell differentiation, the membrane localization of TGFbeta-IIR and TGFbeta response were restored. Our results indicate the presence of a prominent, kinase-active TGFbeta-IIR in the cytosol of several mammary cell lines. This cytosolic pool of receptors is the only detectable one in MCF-7 cells. Loss of wild-type membrane receptors due to defects in trafficking presents a potential new mechanism for escape from negative growth control.


A rare loss-of-function variant of ADAM17 is associated with late-onset familial Alzheimer disease.
Common variants of about 20 genes contributing to AD risk have so far been identified through genome-wide association studies (GWAS). However, there is still a large proportion of heritability that might be explained by rare but functionally important variants. One of the so far identified genes with rare AD causing variants is ADAM10. Using whole-genome sequencing we now identified a single rare nonsynonymous variant (SNV) rs142946965 [p.R215I] in ADAM17 co-segregating with an autosomal-dominant pattern of late-onset AD in one family. Subsequent genotyping and analysis of available whole-exome sequencing data of additional case/control samples from Germany, UK, and USA identified five variant carriers among AD patients only. The mutation inhibits pro-protein cleavage and the formation of the active enzyme, thus leading to loss-of-function of ADAM17 alpha-secretase. Further, we identified a strong negative correlation between ADAM17 and APP gene expression in human brain and present in vitro evidence that ADAM17 negatively controls the expression of APP. As a consequence, p.R215I mutation of ADAM17 leads to elevated Aß formation in vitro. Together our data supports a causative association of the identified ADAM17 variant in the pathogenesis of AD.


Pelvic lymphadenectomy improves survival in patients with cervical cancer with low-volume disease in the sentinel node: a retrospective multicenter cohort study.
In this study, we aimed to describe the value of pelvic lymph node dissection (LND) after sentinel lymph node (SN) biopsy in early-stage cervical cancer. We performed a retrospective multicenter cohort study in 8 gynecological oncology departments. In total, 645 women with International Federation of Gynecology and Obstetrics stage IA to IIB cervical cancer of squamous, adeno, or adenosquamous histologic type who underwent SN biopsy followed by pelvic LND were enrolled in this study. Radioisotope tracers and blue dye were used to localize the sentinel node, and pathologic ultrastaging was performed. Among the patients with low-volume disease (micrometastases and isolated tumor cells) in the sentinel node, the overall survival was significantly better (P = 0.046) if more than 16 non-SNs were removed. No such significant difference in survival was detected in patients with negative or macrometastatic sentinel nodes. Our findings indicate that in patients with negative or macrometastatic disease in the sentinel nodes, an additional LND did not alter survival. Conversely, our data suggest that the survival of patients with low-volume disease is improved when more than 16 additional lymph nodes are removed. If in a prospective trial our data are confirmed, we would suggest a 2-stage operation.


Clinical, Radiologic, and Pathologic Characteristics of Pulmonary Hamartomas With Uncommon Presentation.
To investigate the clinicopathologic and radiologic features of pulmonary hamartomas (PHs) with uncommon clinical presentation. A retrospective clinicopathologic and radiologic review was performed for patients diagnosed (1999-2019) with multiple hamartomas, lesions arising adjacent to a coexisting pulmonary malignancy, and tumors with predominantly extrapulmonary localization. Of 979 patients diagnosed with PHs, 6 (0.6%) had multiple hamartomas, 4 (0.4%) had hamartomas adjacent to lung adenocarcinoma, and 2 (0.2%) had large mediastinal masses. Patients with multiple lesions had a median age of 65 years and mean tumor size of 0.9 cm; 1 patient had 3 hamartomas, and 5 patients had 2. Lesions next to adenocarcinomas had a mean size of 1.4 cm, and affected patients had a median age of 69 years. Predominantly mediastinal PHs, diagnosed in a 63-year-old woman and a 68-year-old man, measured 4.1 to 6 cm and were connected to the lung. All lesions were solid on imaging with absence of definitive fat or calcification, concerning for granuloma or malignancy. All cases had typical histology of PH, although one of the mediastinal tumors had an unusual amount of epithelial hyperplasia. PHs can be clinically and radiologically challenging to diagnose. Histopathologic examination of biopsies and resection specimens is diagnostically crucial in this setting.


The relationship between extrapyramidal signs and cognitive performance in patients with Alzheimer's disease enrolled in the CERAD Study. Consortium to Establish a Registry for Alzheimer's Disease.
The objective of this study was to determine the relationship between the presence of extrapyramidal signs and the severity of cognitive and functional impairment in patients with Alzheimer's disease (AD). Eleven university medical centers in the United States and France participated in the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) study of extrapyramidal signs in AD. Forty-seven patients with probable AD who had extrapyramidal signs were matched by sex, race, education, and age with 132 probable AD patients without extrapyramidal signs. The main outcome measures were the Clinical Dementia Rating, Blessed Dementia Scale, and the CERAD Neuropsychology Battery (verbal fluency, naming, Mini-Mental State Examination, word list learning, word list recall, savings ratio, word list recognition, and constructional praxis). AD patients with extrapyramidal signs performed more poorly than AD patients without parkinsonism on various neuropsychological tests, even after controlling for the Clinical Dementia Rating and reported duration of cognitive impairment. The severity of the extrapyramidal manifestations was related to the degree of cognitive and functional impairment. Muscular rigidity and bradykinesia were the most frequent extrapyramidal signs associated with AD. Patients with AD associated with extrapyramidal signs have greater cognitive and functional impairment than AD patients without clinical evidence of parkinsonism.