Dipeptidyl peptidase-4 inhibition attenuates arrhythmias via a protein kinase A-dependent pathway in infarcted hearts.
The effect of dipeptidyl peptidase-4 (DPP-4) inhibitors on arrhythmias remains unknown. The aim of this study was to investigate whether sitagliptin attenuates arrhythmias through inhibiting nerve growth factor (NGF) expression, focusing on cyclic adenosine monophosphate (cAMP) downstream signaling such as protein kinase A (PKA) and exchange protein directly activated by cAMP (Epac). Male Wistar rats were randomized to either vehicle or sitagliptin for 4 weeks starting 24 h after ligating the coronary artery. Post-infarction was associated with increased oxidative stress. Measurement of myocardial norepinephrine levels revealed a significant elevation in vehicle-treated rats compared with sham. Compared with the vehicle, infarcted rats treated with sitagliptin had significantly increased cAMP levels, decreased DPP-4 activity, oxidative stress, NGF levels and immunofluorescence-stained sympathetic hyperinnervation. Arrhythmic scores were significantly lower in the sitagliptin-treated infarcted rats than in vehicle. Ex vivo studies showed that sitagliptin increased the phosphorylated cAMP response element-binding protein (CREB), which can be reversed by H-89 (a PKA inhibitor), not brefeldin A (an Epac inhibitor).Heme oxygenase-1(HO-1) expression was increased by a PKA agonist but not by an Epac agonist.HO-1expression was attenuated in KG-501 (a CREB inhibitor)-treated infarcted rats in the presence of a PKA agonist. Sitagliptin protects ventricular arrhythmias by attenuating NGF-induced sympathetic innervation via upregulation ofHO-1expression in a cAMP/PKA/CREB-dependent antioxidant pathway in non-diabetic infarcted rats.


Implementing new routines in adult mental health care to identify and support children of mentally ill parents.
Mental health problems are often transmitted from one generation to the next. This knowledge has led to changes in Norwegian legislation, making it mandatory to assess whether or not patients have children, and to provide necessary support for the children of mentally ill patients. The main purpose of this study was to evaluate the process of implementing new routines in adult mental health services to identify and support children of mentally ill parents. The design was a pre-test post-test study. The sample (N = 219 at pre-test and N = 185 at post-test) included mental health professionals in the largest hospital in the region, who responded to a web-based survey on the routines of the services, attitudes within the workforce capacity, worker's knowledge on the impact of parental mental illness on children, knowledge on legislation concerning children of patients, and demographic variables. The results of this study indicated that some changes are taking place in clinical practice in terms of increased identification of children. Adult mental health services providing support for the children was however not fully implemented as a new practice. The main finding in this study is that the identification frequency had increased significantly according to self-reported data since the Family Assessment Form was implemented. The increase in self-reported identification behavior is however taking place very slowly. Three years after the legislation was changed to making it mandatory to assess whether or not patients have children, it was still not fully incorporated in the routines of the entire workforce. In terms of support for the families affected by parental mental illness, the changes are not yet significant.


Monocytes and macrophages in malignant melanoma. II. Lysis of antibody-coated human erythrocytes as an assay of monocyte function.
Peripheral blood mononuclear cells will lyse antibody-treated human erythrocytes. Using Group A red cells and a hyperimmune anti-A1 serum, we have devised a microassay for the cytolytic capacity of mononuclear cell suspensions. The effector cells responsible for red-cell lysis are mononuclear, adherent and phagocytic, and their activity is blocked by aggregated IgG. Their presence correlates well with non-specific esterase-containing cells and we conclude that they are monocytes. Dose-response curves of red-cell lysis plotted against numbers of monocytes were used to derive a simple parameter expressing the number of monocytes needed to lyse 15% of the 51Cr-labelled red cells. The assay was applied to a group of 27 normal controls and 36 patients with a histologically proven diagnosis of malignant melanoma. The results indicate that monocytes from patients show significantly greater lytic activity than those from the controls. These data suggest that monocytes from cancer patients are in some way activated, and that other defects in monocyte function which have been detected in cancer patients (defective chemotaxis and maturation) may be associated with monocyte "activation".


Effect of temporal domain on self-reported walking behaviors in the California Health Interview Survey.
Question design can influence the validity and reliability of physical activity (PA) self-report instruments. This study assesses the effect of temporal domain ("days" walked versus "times" walked) on survey questions about walking behavior. A 2005 California Health Interview Survey (CHIS) subsample (n = 6332) reported the number of days or times they walked for leisure or transportation in the past 7 days and the usual time spent per day or per time. Question order was randomized by temporal domain. Minutes walked per week (mean ± SE) and adherence to PA guidelines (≥150 min/wk) were assessed. Estimates of leisure walking remained stable across temporal domain (days = 71.4 ± 2.5 min; times = 73.4 ± 2.4 min), but transportation walking differed depending on domain (days = 70.4 ± 3.2 min; times = 52.5 ± 2.6 min). Adherence to PA guidelines based on leisure walking was stable across temporal domain (days = 14.9 ± 0.6%; times = 14.9 ± 0.6%), but again differed by domain for transportation walking (days = 10.4 ± 0.6%; times = 7.8 ± 0.5%). A large order effect (number-of-days versus number-of-times asked first) was observed for reports of days walking for transportation (days first = 87.8 ± 2.9 min; times first = 52.3 ± 2.5 min). Temporal domain influences estimates of self-reported transportation walking behavior. Current efforts to capture PA from both transportation and leisure activities in health research appear to present distinct methodological challenges.


Membrane microviscosity is increased in the erythrocytes of patients with adrenoleukodystrophy and adrenomyeloneuropathy.
Adrenoleukodystrophy (ALD) and adrenomyeloneuropathy (AMN) are related X-linked disorders characterized by adrenal, gonadal, and nervous system dysfunction. While the pathologic finding common to these tissues appears to be the accumulation of excessive amounts of very long chain fatty acids, the mechanism leading to functional impairment in these tissues is unclear. Measurements of fluorescence polarization (P), using the lipid probe diphenylhexatriene, demonstrate a highly significant increase in the microviscosity of erythrocyte membranes in affected patients (P = 0.286 +/- 0.012) vs. normals (P = 0.239 +/- 0.020). Analyses of these membranes by gas-liquid chromatography revealed 1.9-, 1.6-, and 1.3-fold increases above normal values in the C25:0, C26:0, and C27:0 fatty acids, respectively. These observations are compatible with previously obtained data in animals that correlate membrane microviscosity with the number of hormone receptors in target tissues. The present data support the thesis that a decrease in responsiveness to trophic hormones in ALD and AMN is secondary to changes in the membrane microviscosity of the target tissues and suggest a mechanism by which adrenal and gonadal failure occur in such patients.


Photoperiod regulates growth, puberty and hypothalamic neuropeptide and receptor gene expression in female Siberian hamsters.
In seasonal mammals, both the growth and reproductive axes are regulated by photoperiod. Female Siberian hamsters were kept, for up to 12 weeks, in long-day (LD) or short-day (SD) photoperiod, from weaning at 3 weeks of age (Exp 1). LD hamsters had characteristically faster growth and higher asymptotic body weight, adiposity, and leptin gene expression in adipose tissue. Only LD females attained puberty. Gene expression in the hypothalamic arcuate nucleus for leptin receptor (OB-Rb), POMC, and melanocortin 3-receptor (MC3-R) was higher in LD but did not change from weaning levels in SD. In contrast, gene expression in the arcuate nucleus for cocaine and amphetamine-regulated transcript (CART) was higher in SD than LD, a difference that was apparent at 2 weeks post weaning. Transfer of SD females to LD at 15 weeks post weaning (Exp 2) increased body weight, leptin signal, and gene expression for POMC but failed to induce normal puberty onset or to increase gene expression for OB-Rb and MC3-R. Therefore, photoperiodic regulation of puberty may be modulated by age, by photoperiodic history, and by changes in leptin signaling and the activity of the leptin-sensitive hypothalamic melanocortin system (POMC, MC3-R). A role for CART in photoperiodic regulation of growth is suggested, because the changes in CART gene expression preceded significant divergence of growth trajectories in the opposite photoperiods.


Risk Factors for Hemorrhoids on Screening Colonoscopy.
Constipation, a low fiber diet, sedentary lifestyle and gravidity are commonly assumed to increase the risk of hemorrhoids. However, evidence regarding these factors is limited. We examined the association between commonly cited risk factors and the prevalence of hemorrhoids. We performed a cross sectional study of participants who underwent a colonoscopy in a colorectal adenoma prevention trial and who had a detailed assessment of bowel habits, diet and activity. The presence of hemorrhoids was extracted from the subjects' colonoscopy reports. We used logistic regression to estimate odds ratios and 95% confidence intervals while adjusting for age and sex. The study included 2,813 participants. Of these, 1,074 had hemorrhoids recorded. Constipation was associated with an increased prevalence of hemorrhoids (OR 1.43, 95% CI 1.11, 1.86). Of the fiber subtypes, high grain fiber intake was associated with a reduced risk (OR for quartile 4 versus quartile 1 = 0.78, 95% CI 0.62, 0.98). We found no association when comparing gravid and nulligravida women (OR 0.93, 95% CI 0.62-1.40). Sedentary behavior was associated with a reduced risk (OR 0.80, 95% CI 0.65-0.98), but not physical activity (OR 0.83, 95% CI 0.66-1.03). Neither being overweight nor obese was associated with the presence of hemorrhoids (OR 0.89, 95% CI 0.72-1.09 and OR 0.86, 95% CI 0.70-1.06). Constipation is associated with an increased risk of hemorrhoids. Gravidity and physical activity do not appear to be associated. High grain fiber intake and sedentary behavior are associated with a decreased risk of hemorrhoids.


Exploiting cancer's phenotypic guise against itself: targeting ectopically expressed peptide G-protein coupled receptors for lung cancer therapy.
Lung cancer, claiming millions of lives annually, has the highest mortality rate worldwide. This advocates the development of novel cancer therapies that are highly toxic for cancer cells but negligibly toxic for healthy cells. One of the effective treatments is targeting overexpressed surface receptors of cancer cells with receptor-specific drugs. The receptors-in-focus in the current review are the G-protein coupled receptors (GPCRs), which are often overexpressed in various types of tumors. The peptide subfamily of GPCRs is the pivot of the current article owing to the high affinity and specificity to and of their cognate peptide ligands, and the proven efficacy of peptide-based therapeutics. The article summarizes various ectopically expressed peptide GPCRs in lung cancer, namely, Cholecystokinin-B/Gastrin receptor, the Bombesin receptor family, Bradykinin B1 and B2 receptors, Arginine vasopressin receptors 1a, 1b and 2, and the Somatostatin receptor type 2. The autocrine growth and pro-proliferative pathways they mediate, and the distinct tumor-inhibitory effects of somatostatin receptors are then discussed. The next section covers how these pathways may be influenced or 'corrected' through therapeutics (involving agonists and antagonists) targeting the overexpressed peptide GPCRs. The review proceeds on to Nano-scaled delivery platforms, which enclose chemotherapeutic agents and are decorated with peptide ligands on their external surface, as an effective means of targeting cancer cells. We conclude that targeting these overexpressed peptide GPCRs is potentially evolving as a highly promising form of lung cancer therapy.


Initial treatment combined with Prunella vulgaris reduced prednisolone consumption for patients with subacute thyroiditis.
Subacute thyroiditis (SAT) is a self-limited disease commonly treated with prednisolone (PSL). The present study aimed to assess the effectiveness and safety of the new treatment protocol which consisted of PSL and Prunella vulgaris (PV) to reduce the dosage and incidence of side effects from PSL. Data regarding the patients with SAT treated at the First Affiliated Hospital, School of Medicine, Zhejiang University between September 2013 and May 2016 were retrospectively analyzed. Patients treated with PSL only or a combination of PSL and PV were divided into two groups. In total, 87 patients were included. Patients treated with PSL and PV showed a similar remission rate to the patients who received only PSL. The recurrence rate (4.4% vs. 9.5%) and incidence of transient hypothyroidism (2.2% vs. 4.8%) were similar between the two groups (P=0.350 and P=0.517, respectively). Only two cases of a mild skin rash were recorded, and these were related to the use of PV. The combination of low-dose PSL as a treatment choice for SAT was both effective and safe.


Prognostic and predictive value of TOPK stratified by KRAS and BRAF gene alterations in sporadic, hereditary and metastatic colorectal cancer patients.
Our aim was to investigate the prognostic and predictive value of the oncogenic MAPKK-like protein T-cell-originated protein kinase (TOPK) stratified by KRAS and BRAF mutations in patients with sporadic, hereditary and metastatic colorectal cancer (CRC) treated with anti-EGFR therapy. Immunohistochemistry (IHC) for TOPK was performed on four study groups. Group 1 included two subgroups of 543 and 501 sporadic CRC patients used to test the reliability of TOPK expression by IHC. In Group 2, representing an additional 222 sporadic CRCs, the prognostic effect of TOPK stratified by KRAS and BRAF was assessed. The prognostic effect of TOPK was further analysed in Group 3, representing 71 hereditary Lynch syndrome-associated CRC patients. In Group 4, the predictive and prognostic value of TOPK was analysed on 45 metastatic patients treated with cetuximab or panitumumab stratified by KRAS and BRAF gene status. In both sporadic CRC subgroups (Group 1), associations of diffuse TOPK expression with clinicopathological features were reproducible. Molecular analysis of sporadic CRCs in Group 2 showed that diffuse TOPK expression was associated with KRAS and BRAF mutations (p<0.001) and with poor outcome in patients with either mutation in univariate and multivariate analysis (P=0.017). In hereditary patients (Group 3), diffuse TOPK was linked to advanced pT stage. In metastatic patients treated with anti-EGFR therapy (Group 4), diffuse TOPK expression was linked to dismal outcome despite objective response to treatment (P=0.01). TOPK expression is an unfavourable prognostic indicator in sporadic patients with KRAS or BRAF mutations and also in patients with metastatic disease experiencing a response to anti-EGFR therapies. The inhibition of TOPK, which could benefit 30-40% of CRC patients, may represent a new avenue of investigation for targeted therapy.


Diffusion-weighted MRI in the differential diagnosis of uterine endometrial cavity tumors.
This study aimed to investigate the efficacy of quantitative apparent diffusion coefficient (ADC) measurement in the differential diagnosis of the uterine endometrial cavity tumors (UECT). This study included consecutive 36 female patients with UECT. The groups were formed as follows: group 1, patients with endometrial carcinoma; group 2, patients with endometrial polyp; group 3, patients with submucosal leiomyoma; and additionally group A, patients with malignant lesion; group B patients with benign lesion. Tumoral and outer myometrial ADC values were measured and the tumor-myometrium ADC ratios were calculated in all patients. Kolmogorov-Smirnov tests were used to test the normality of the data distributions. The data were not normally distributed, and therefore, nonparametric tests were performed. The cut-off values, sensitivity, and specificity were determined by the receiver operating characteristic analysis. The mean ADC value and ratio of group 1 were lower than that of group 2 and 3, and the mean ADC value and ratio of group 3 were lower than that of group 2. The sensitivity and specificity for group 1, 2, and 3 were as follows: 90, 100, and 66.7 %; and 81.8, 88, and 58.8 %, respectively, in terms of the ADC values; 90, 100 and 67 %; and 77.3, 96, and 64.7 % in terms of the ADC ratios. Statistically significant differences were demonstrated between group A and B in terms of mean tumoral ADC values and ratios. Sensitivity and specificity were found to be 90 and 81.8 %, respectively, in terms of the ADC values. The sensitivity and specificity were found to be 90 and 77.3 %, respectively, in terms of the ADC ratios. ADC values and ratios represent a promising parameter in the determination of the tumoral lesions in patients with UECT.


[Mineralization of the basal ganglia as the supposed cause of poor tolerance of zuclopenthixol in a patient with long-term untreated paranoid schizophrenia].
Formations described as intracranial calcifications can appear in the course of diseases of the central nervous system, other systems and organs (e.g. endocrine), but also as a disorder of idiopathic character. They are frequently located in subcortical nuclei and usually constitute an incidental finding. This report presents the case of a patient suffering from paranoid schizophrenia for approximately 40 years, who did not agree to any treatment and was hospitalized against her will because she was the threat to the lives of others. She was treated with zuklopentixol resulting in positive symptoms reduction and considerable improvement in social functioning. Unfortunately neurological symptoms appeared: bradykinesis, rigidity--of the type of the lead pipe, balance, posture and gait abnormalities, disturbances in precise hands movements, double-sided Rossolimo's sign, plantar reflex without the participation of the big toe on the left. Neuroimaging studies have demonstrated changes in the form of lenticular nuclei calcification and reduction of signal intensity in posterior parts of both putamens. Neurological symptoms decreased significantly after switching to atypical neuroleptic (olanzapine), and the patient did not require any additional treatment. Mineralization of the basal ganglia can often be associated with psychiatric disorders and it shouldn't be neglected because it can require modification of pharmacotherapy or additional neurological treatment.


Single cycle of arsenic trioxide-based consolidation chemotherapy spares anthracycline exposure in the primary management of acute promyelocytic leukemia.
PURPOSE Event-free survival following all-trans-retinoic acid (ATRA) -based therapy for acute promyelocytic leukemia (APL) averages 70% at 5 years. While arsenic trioxide (ATO) can induce remissions in 95% of relapsed patients, few studies have addressed the integration of ATO into the primary management of APL. This study examines the efficacy of a single cycle of ATO-based consolidation therapy in a treatment regimen designed to decrease exposure to other cytotoxic agents. PATIENTS AND METHODS After induction with ATRA and daunorubicin (DRN), untreated patients with APL received 3 days of cytarabine and DRN followed by 30 doses of ATO beginning on day 8. Molecular remitters received 2 years of risk-based maintenance therapy. Results Forty-one of 45 patients receiving induction therapy achieved remission; four patients died (one before treatment was initiated). Thirty-seven patients received consolidation and maintenance; of these one patient relapsed (CNS) and one died in remission during maintenance therapy (hepatic sickle cell crisis). With a median follow-up of 2.7 years, estimated disease-free survival was 90%; overall survival for all patients was 88%. Despite a total anthracycline dose of only 360 mg/m(2), cardiac ejection fraction decreased by > or = 20% in 20% of patients. CONCLUSION These data, combined with other recent studies using ATO in the primary management of APL, demonstrate the important role that ATO can play in the primary management of this curable disease. Future studies should continue to focus on reducing the toxicity of treatment without increasing the relapse rate.


Bacopa monniera extract reduces amyloid levels in PSAPP mice.
PSAPP mice expressing the "Swedish" amyloid precursor protein and M146L presenilin-1 mutations are a well-characterized model for spontaneous amyloid plaque formation. Bacopa monniera has a long history of use in India as an anti-aging and memory-enhancing ethnobotanical therapy. To evaluate the effect of Bacopa monniera extract (BME) on amyloid (Abeta) pathology in PSAPP mice, two doses of BME (40 or 160 mg/kg/day) were administered starting at 2 months of age for either 2 or 8 months. Our present data suggests that BME lowers Abeta 1-40 and 1-42 levels in cortex by as much as 60%, and reverses Y-maze performance and open field hyperlocomotion behavioral changes present in PSAPP mice. The areas encompassed by Congo Red-positive fibrillar amyloid deposits, however, were not altered by BME treatment. The data suggest that BME has potential application in Alzheimer's disease therapeutics.


Bioavailability and effects of microplastics on marine zooplankton: A review.
Microplastics are abundant and widespread in the marine environment. They are a contaminant of global environmental and economic concern. Due to their small size a wide range of marine species, including zooplankton can ingest them. Research has shown that microplastics are readily ingested by several zooplankton taxa, with associated negative impacts on biological processes. Zooplankton is a crucial food source for many secondary consumers, consequently this represents a route whereby microplastic could enter the food web and transfer up the trophic levels. In this review we aim to: 1) evaluate the current knowledge base regarding microplastic ingestion by zooplankton in both the laboratory and the field; and 2) summarise the factors which contribute to the bioavailability of microplastics to zooplankton. Current literature shows that microplastic ingestion has been recorded in 39 zooplankton species from 28 taxonomic orders including holo- and meroplanktonic species. The majority of studies occurred under laboratory conditions and negative effects were reported in ten studies (45%) demonstrating effects on feeding behaviour, growth, development, reproduction and lifespan. In contrast, three studies (14%) reported no negative effects from microplastic ingestion. Several physical and biological factors can influence the bioavailability of microplastics to zooplankton, such as size, shape, age and abundance. We identified that microplastics used in experiments are often different to those quantified in the marine environment, particularly in terms of concentration, shape, type and age. We therefore suggest that future research should include microplastics that are more representative of those found in the marine environment at relevant concentrations. Additionally, investigating the effects of microplastic ingestion on a broader range of zooplankton species and life stages, will help to answer key knowledge gaps regarding the effect of microplastic on recruitment, species populations and ultimately broader economic consequences such as impacts on shell- and finfish stocks.


Association of long-term proton pump inhibitor therapy with bone fractures and effects on absorption of calcium, vitamin B12, iron, and magnesium.
Proton pump inhibitors (PPI) are one of the most widely used classes of drugs. PPIs have a very favorable safety profile, and it is unusual for a patient to stop them because of side effects. However, with increasing numbers of patients chronically taking PPIs for gastroesophageal reflux disease and other common, persistent conditions, the long-term potential adverse effects are receiving increasing attention. An insufficiently studied area receiving much attention is the long-term effect of chronic acid suppression on the absorption of vitamins and nutrients. This increased attention results from the reported potential adverse effect of chronic PPI treatment leading to an increased occurrence of bone fractures. Interest in this area has led to examination of the effects of PPIs on calcium absorption/metabolism and numerous cohort, case-control, and prospective studies of their ability to affect bone density and cause bone fractures. In this article, these studies are systematically examined, as are studies of the effects of chronic PPI use on absorption of VB(12), iron, and magnesium. Studies in each area have led to differing conclusions, but when examined systematically, consistent results of several studies support the conclusion that long-term adverse effects on these processes can have important clinical implications.


Reorientation to more health promotion in health services - a study of barriers and possibilities from the perspective of health professionals.
The objective of this study is to analyze the commitment to a more health-promoting health service and to illuminate important barriers for having a health-promoting role in daily practice, among Swedish health care professionals. Out of a total of 3751 health professionals who are working daytime in clinical practice in the province of Västerbotten, 1810 were invited to participate in a survey. The health professionals represented eight different occupational groups: counselors, dieticians, midwives, nurses, occupational therapists, physical therapists, psychologists, and physicians. A questionnaire that operationalized perceptions found in a previous qualitative study was mailed to residential addresses of the participants. The majority believed that health services play a major role in long-term health development in the population and saw a need for health orientation as a strategy to provide more effective health care. Willingness to work more in health promotion and disease prevention was reported significantly more often by women than men, and by primary health care personnel compared to hospital personnel. Among the professional groups, psychologists, occupational therapists, and physiotherapists most frequently reported willingness. The most common barriers to health promotion roles in daily practice were reported to be heavy workload, lack of guidelines, and unclear objectives. This study found strong support for reorientation of health services in the incorporation of a greater health promotion. A number of professions that are not usually associated with health promotion practices are knowledgeable and wish to focus more on health promotion and disease prevention. Management has a major role in creating opportunities for these professionals to participate in health promotion practices. Men and physicians reported less positive attitudes to a more health-promoting health service and often possess high positions of power. Therefore, they may play an important role in the process of change toward more health promotion in health services.


Categorization of multiple sclerosis relapse subtypes by B cell profiling in the blood.
B cells are attracting increasing attention in the pathogenesis of multiple sclerosis (MS). B cell-targeted therapies with monoclonal antibodies or plasmapheresis have been shown to be successful in a subset of patients. Here, patients with either relapsing-remitting (n = 24) or secondary progressive (n = 6) MS presenting with an acute clinical relapse were screened for their B cell reactivity to brain antigens and were re-tested three to nine months later. Enzyme-linked immunospot technique (ELISPOT) was used to identify brain-reactive B cells in peripheral blood mononuclear cells (PBMC) directly ex vivo and after 96 h of polyclonal stimulation. Clinical severity of symptoms was determined using the Expanded Disability Status Scale (EDSS). Nine patients displayed B cells in the blood producing brain-specific antibodies directly ex vivo. Six patients were classified as B cell positive donors only after polyclonal B cell stimulation. In 15 patients a B cell response to brain antigens was absent. Based on the autoreactive B cell response we categorized MS relapses into three different patterns. Patients who displayed brain-reactive B cell responses both directly ex vivo and after polyclonal stimulation (pattern I) were significantly younger than patients in whom only memory B cell responses were detectable or entirely absent (patterns II and III; p = 0.003). In one patient a conversion to a positive B cell response as measured directly ex vivo and subsequently also after polyclonal stimulation was associated with the development of a clinical relapse. The evaluation of the predictive value of a brain antigen-specific B cell response showed that seven of eight patients (87.5%) with a pattern I response encountered a clinical relapse during the observation period of 10 months, compared to two of five patients (40%) with a pattern II and three of 14 patients (21.4%) with a pattern III response (p = 0.0005; hazard ratio 6.08 (95% confidence interval 1.87-19.77). Our data indicate actively ongoing B cell-mediated immunity against brain antigens in a subset of MS patients that may be causative of clinical relapses and provide new diagnostic and therapeutic options for a subset of patients.


Lower eyelid involutional ectropion repair with lateral tarsal strip and internal retractor reattachment with full-thickness eyelid sutures.
To report a novel surgical technique for lower eyelid involutional ectropion repair using a lateral tarsal strip and internal retractor reattachment procedure involving full-thickness eyelid sutures. A retrospective review was performed of patients who underwent repair of involutional ectropion via lateral tarsal strip and internal retractor reattachment with full-thickness eyelid sutures by 1 surgeon. Patients having concomitant or previous eyelid surgical procedures were excluded. Collected data included patient demographics, surgical outcomes, and length of follow up. Forty-one lower eyelids of 31 patients with involutional ectropion underwent surgical repair. There were 17 men and 14 women in the age range of 69 to 92 years (mean age 82.2±5.9 years). Surgical sites included 22 right and 19 left lower eyelids. Follow up ranged from 1 to 48 months with an average of 5.9 months. Surgical success with anatomical correction of involutional ectropion was achieved in 39 of 41 eyelids (95.1%). There were no perioperative or postoperative complications. Two of 41 (4.9%) eyelids had recurrence of ectropion 7 and 18 months after the procedure. This procedure combining lateral tarsal strip with internal retractor reattachment involving full-thickness eyelid sutures effectively addresses horizontal eyelid laxity and tarsal instability, providing an effective technique to correct involutional ectropion of the lower eyelid.


Insertional tagging, cloning, and expression of the Toxoplasma gondii hypoxanthine-xanthine-guanine phosphoribosyltransferase gene. Use as a selectable marker for stable transformation.
A nonhomologous integration vector was used to identify the Toxoplasma gondii hypoxanthine-xanthine-guanine phosphoribosyl transferase (HXGPRT) gene by insertional mutagenesis. Parasite mutants resistant to 6-thioxanthine arose at a frequency of approximately3 x 10(-7). Genomic DNA flanking the insertion sites was retrieved by marker rescue and used to identify molecular clones exhibiting unambiguous homology to H(X)GPRT genes from other species. Sequence analysis of vector/genome junction sites reveals that integration of the linearized vector occurred with minimal rearrangement of either vector or target sequences, although the addition of filler DNA and small duplications or deletions of genomic sequences at the transgene termini was observed. Two differentially spliced classes of cDNA clones were identified, both of which complement hpt and gpt mutations in Escherichia coli. Kinetic analysis of purified recombinant enzyme revealed no significant differences between the two isoforms. Internally deleted clones spanning the genomic locus were used to create "knock-out" parasites, which lack all detectable HXGPRT activity. Complete activity could be restored to these knock-out mutants by transient transformation with either genomic DNA or cDNA-derived minigenes encoding both enzyme isoforms. Stable HXGPRT+ transformants were isolated under selection with mycophenolic acid, demonstrating the feasibility of HXGPRT as both a positive and negative selectable marker for stable transformation of T. gondii.


Breast MRI in the Diagnostic and Preoperative Workup Among Medicare Beneficiaries With Breast Cancer.
We compared the frequency and sequence of breast imaging and biopsy use for the diagnostic and preoperative workup of breast cancer according to breast magnetic resonance imaging (MRI) use among older women. Using SEER-Medicare data from 2004 to 2010, we identified women with and without breast MRI as part of their diagnostic and preoperative breast cancer workup and measured the number and sequence of breast imaging and biopsy events per woman. A total of 10,766 (20%) women had an MRI in the diagnostic/preoperative period, 32,178 (60%) had mammogram and ultrasound, and 10,669 (20%) had mammography alone. MRI use increased across study years, tripling from 2005 to 2009 (9%-29%). Women with MRI had higher rates of breast imaging and biopsy compared with those with mammogram and ultrasound or those with mammography alone (5.8 vs. 4.1 vs. 2.8, respectively). There were 4254 unique sequences of breast events; the dominant patterns for women with MRI were an MRI occurring at the end of the care pathway. Among women receiving an MRI postdiagnosis, 26% had a subsequent biopsy compared with 51% receiving a subsequent biopsy in the subgroup without MRI. Older women who receive breast MRI undergo additional breast imaging and biopsy events. There is much variability in the diagnostic/preoperative work-up in older women, demonstrating the opportunity to increase standardization to optimize care for all women.


Factors modifying the risk of IDDM in offspring of an IDDM parent.
Offspring of mothers with insulin-dependent diabetes mellitus (IDDM) have a much lower risk of IDDM than do offspring of diabetic fathers, and this risk is particularly low for offspring born to diabetic mothers over the age of 25 years. To determine whether increasing maternal age also protects the offspring of IDDM fathers from IDDM, we surveyed 367 IDDM fathers (IDDM onset before age 35) who first came to the Joslin Clinic (Boston, MA) between 1945 and 1969. Of the 840 offspring of these men, IDDM developed in 28 before the age of 20, giving a cumulative risk of 5.1 +/- 1.0% (means +/- SE). Because this is similar to the result of our earlier study of IDDM fathers, the two groups were combined to give 1,084 offspring, 39 having IDDM (cumulative risk of IDDM 5.4 +/- 0.9% by age 20), for comparison with our cohort of 1,391 offspring of 739 IDDM mothers. In that cohort, IDDM developed in 20 offspring before the age of 20 years, giving a cumulative risk of 2.1 +/- 0.5%. The risk of diabetes in offspring was higher if the parent's IDDM was diagnosed before age 11 than if it was diagnosed later: 9.3 compared with 4.0% (P = 0.006) for the offspring of IDDM fathers and 2.7 compared with 1.8% for the offspring of IDDM mothers (P = 0.06). In the families in which the father's IDDM was diagnosed after age 11, a protective effect of maternal age > or = 25, similar to that in families of IDDM mothers, seems to be present.(ABSTRACT TRUNCATED AT 250 WORDS)


Cosegregation of elastin-associated microfibrillar abnormalities with the Marfan phenotype in families.
The Marfan syndrome is a serious heritable connective-tissue disorder characterized primarily by ocular, cardiovascular, and musculoskeletal abnormalities but also involving multiple other tissues and organs of the body. Inherited as an autosomal dominant disorder, the etiology and pathogenesis of the Marfan syndrome are presently unknown. We have documented consistent apparent deficient content of elastin-associated microfibrillar fibers by indirect immunofluorescent (IF) studies of Marfan skin, as well as deficient accumulation of related fibrous materials in cultures of Marfan fibroblasts as compared with normal controls and patients with other heritable disorders of connective tissue. These data have suggested that abnormalities in the microfibrillar component of elastic-fiber systems may have a role in the etiology and pathogenesis of the Marfan syndrome. In the present study, we have analyzed the IF staining patterns of skin and fibroblast cultures from Marfan syndrome patients and normal first-degree relatives in nine Marfan kindreds. Three of these families had at least one affected individual in each of 2 generations, permitting intergenerational comparison of IF patterns. Six kindreds had one or more affected individuals in a single generation, making comparisons between siblings and/or parent-child possible. In all cases, IF abnormalities cosegregated with the Marfan phenotype and all nonaffected family members were normal. Within family groups containing more than one affected individual, the IF staining patterns were similar between affected patients. These data provide further confirmation of consistent and relatively specific deficiency of microfibrillar fibers in Marfan syndrome.


The utility of Escherichia coli as a contamination indicator for rural drinking water: Evidence from whole genome sequencing.
Across the water sector, Escherichia coli is the preferred microbial water quality indicator and current guidance upholds that it indicates recent faecal contamination. This has been challenged, however, by research demonstrating growth of E. coli in the environment. In this study, we used whole genome sequencing to investigate the links between E. coli and recent faecal contamination in drinking water. We sequenced 103 E. coli isolates sampled from 9 water supplies in rural Kitui County, Kenya, including points of collection (n = 14) and use (n = 30). Biomarkers for definitive source tracking remain elusive, so we analysed the phylogenetic grouping, multi-locus sequence types (MLSTs), allelic diversity, and virulence and antimicrobial resistance (AMR) genes of the isolates for insight into their likely source. Phylogroup B1, which is generally better adapted to water environments, is dominant in our samples (n = 69) and allelic diversity differences (z = 2.12, p = 0.03) suggest that naturalised populations may be particularly relevant at collection points with lower E. coli concentrations (<50 / 100mL). The strains that are more likely to have originated from human and/or recent faecal contamination (n = 50), were found at poorly protected collection points (4 sites) or at points of use (12 sites). We discuss the difficulty of interpreting health risk from E. coli grab samples, especially at household level, and our findings support the use of E. coli risk categories and encourage monitoring that accounts for sanitary conditions and temporal variability.


Demise of the LCP: villain or scapegoat?
The winding down and withdrawal of the Liverpool Care Pathway (LCP) following the Neuberger Report has been met with mixed reviews. It appears that responsibility for failures of clinical care has been laid at the feet of a care pathway rather than the practitioners who used it, a rather curious outcome given that the LCP was primarily a system of documentation, a tool with no intrinsic therapeutic properties. The Neuberger inquiry was the result of persistent and repeated reports of poor-quality end-of-life care associated with the use of the LCP. There were indeed problems with the LCP regarding the process of diagnosing dying and its approach to supportive care, particularly artificial nutrition and hydration. Some of the problems were the product of personal or professional ideology influencing goals of care rather than patient-centred considerations. These problems were not insurmountable, however, and were being addressed by the organisation responsible for the LCP. With the removal of the LCP, we are left with no bench mark for end-of-life care, only aspirational goals for individualised care plans. It seems unlikely that practitioners who could not provide appropriate care with the LCP will do so without it.


Enhancing the laser power by stacking multiple dye-doped chiral polymer films.
We demonstrate a method for enhancing the laser efficiency by stacking multiple dye-doped chiral polymer films. No laser emission was observed from a single 8 mum film. By stacking two films together, the laser efficiency is dramatically enhanced. Further increasing the number of stacked films, the output laser power is further increased. It is also observed that the output laser power in the forward direction is almost the same as that in the backward for the two- and three-layered films. However, in the six-layered film the output laser power is much stronger in the backward direction than the forward one. This is due to the absorption of the laser dyes and the distributed feedback in the chiral polymer films.


Breadth of T Cell Responses After Immunization with Adenovirus Vectors Encoding Ancestral Antigens or Polyvalent Papillomavirus Antigens.
Oncogenic human papillomaviruses (HPVs) are in most cases eliminated by intervention of T cells. As many other pathogens, these oncogenic HPVs belong to an ancient and diverse virus family. Therefore, we found it relevant to investigate the potential and limitations of inducing a broad response-either by inducing cross-reactive T cells or by administering a polyvalent vaccine. To test these strategies, we designed three ancestral and two circulating sequences based on the two domains of the E1 and E2 proteins of papillomaviruses (PVs) that exhibit the highest degree of conservation in comparison with the other PV proteins. The PV sequences were fused to a T cell adjuvant, the murine invariant chain and encoded in a recombinant adenoviral vector which was administered to naïve outbred mice. By measuring T cell responses induced by these different vaccines and towards peptide pools representing three circulating strains and a putative ancestor of oncogenic HPVs, we showed that the ancestral vaccine antigen has to be approximately 90% identical to the circulating PVs before a marked drop of ~90% mean CD8+ T cell responses ensues. Interestingly, the combination of two or three type-specific PV vaccines did not induce a significant decrease in the CD8+ T cell response to the individual-targeted PV types. Polyvalent HPV vaccine based on the E1 and E2 proteins seem to be capable of triggering responses towards more than one type of PV while the cross-reactivity of ancestral vaccine seems insufficient in consideration of the sequence diversity between HPV types.


Multivalent bifunctional chelator scaffolds for gallium-68 based positron emission tomography imaging probe design: signal amplification via multivalency.
The role of the multivalent effect has been well recognized in the design of molecular imaging probes toward the desired imaging signal amplification. Recently, we reported a bifunctional chelator (BFC) scaffold design, which provides a simple and versatile approach to impart multivalency to radiometal based nuclear imaging probes. In this work, we report a series of BFC scaffolds ((t)Bu(3)-1-COOH, (t)Bu(3)-2-(COOH)(2), and (t)Bu(3)-3-(COOH)(3)) constructed on the framework of 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA) for (68)Ga-based PET probe design and signal amplification via the multivalent effect. For proof of principle, a known integrin α(v)β(3) specific ligand (c(RGDyK)) was used to build the corresponding NOTA conjugates (H(3)1, H(3)2, and H(3)3), which present 1-3 copies of c(RGDyK) peptide, respectively, in a systematic manner. Using the integrin α(v)β(3) binding affinities (IC(50) values), enhanced specific binding was observed for multivalent conjugates (H(3)2: 43.9 ± 16.1 nM; H(3)3: 14.7 ± 5.0 nM) as compared to their monovalent counterpart (H(3)1: 171 ± 60 nM) and the intact c(RGDyK) peptide (204 ± 76 nM). The obtained conjugates were efficiently labeled with (68)Ga(3+) within 30 min at room temperature in high radiochemical yields (>95%). The in vivo evaluation of the labeled conjugates, (68)Ga-1, (68)Ga-2, and (68)Ga-3, was performed using male severe combined immunodeficiency (SCID) mice bearing integrin α(v)β(3) positive PC-3 tumor xenografts (n = 3). All (68)Ga-labeled conjugates showed high in vivo stability with no detectable metabolites found by radio-HPLC within 2 h postinjection (p.i.). The PET signal amplification in PC-3 tumor by the multivalent effect was clearly displayed by the tumor uptake of the (68)Ga-labeled conjugates ((68)Ga-3: 2.55 ± 0.50%ID/g; (68)Ga-2: 1.90 ± 0.10%ID/g; (68)Ga-1: 1.66 ± 0.15%ID/g) at 2 h p.i. In summary, we have designed and synthesized a series of NOTA-based BFC scaffolds with signal amplification properties, which may find potential applications as diagnostic gallium radiopharmaceuticals.


Multilevel genetic analyses of two European supercolonies of the Argentine ant, Linepithema humile.
Some ants have an extraordinary unicolonial social organization, whereby individuals mix freely among physically separated nests. Recently, it was shown that the European population of Linepithema humile consisted of two enormous unicolonial supercolonies. Workers of the same supercolony are never aggressive to each other. In contrast, aggressiveness is invariably high between workers from different supercolonies. Here we investigated whether gene flow occurs between two supercolonies. We identified a contact zone in which we sampled 46 nests. For each nest, aggression tests were conducted against workers from reference nests from both supercolonies. Workers were always very aggressive towards workers of one of the supercolonies but not to workers of the other. Thus, all nests could be clearly assigned to one of the two supercolonies. For 22 of the 46 nests, we genotyped 15-16 workers at five microsatellite loci. A four-level hierarchical analysis of variance revealed very strong genetic differentiation between the two supercolonies (F(SUPERCOLONY-TOTAL) = 0.541) and low differentiation between sectors (i.e. group of nests connected together with trails) within supercolonies (F(SECTOR-SUPERCOLONY) = 0.064). The very high differentiation between the two supercolonies indicates a lack of ongoing gene flow, a conclusion further bolstered by the finding that the two supercolonies share no common alleles at two of the five microsatellite loci. A Bayesian clustering method also revealed the occurrence of two distinct clusters. These clusters exactly match the grouping obtained by aggression tests. None of the 332 genotyped individuals were admixed despite the fact that some nests of the two supercolonies were separated by less than 30 m. These results demonstrate that the two supercolonies have completely separate gene pools.


Would mobile health be a solution to rehospitalization?
It has been well-established that social environmental factors can increase the risk of rehospitalization for people receiving home healthcare services. For caregivers who might be challenged to keep up with sometimes unfamiliar health monitoring tasks or to know when to seek help, mobile health technology offers the potential to enhance the skills of informal caregivers and to improve the communication between home and clinical care. This paper described our recent work to determine the usability, functionality, and style of interaction that would be needed to provide an effective and well-accepted tool. Caregivers would likely adopt new mobile health tools, as long as care is taken to eliminate potential barriers, for example, by providing adequate training, and to include design aspects that enhance one's motivation to use a tool, such as by supporting autonomy and engagement.


Radiographic examination of mesiodens and their associated complications.
To examine mesiodens with regard to their status, their influence on adjacent teeth and their alteration during the follow-up period. From retrospective reviews of all patients who visited our institution from 1990-2001, we identified 200 patients (256 mesiodentes) who were shown to have mesiodentes on the basis of a periapical radiograph, a panoramic radiograph or an axial radiograph. The number of supernumerary teeth was one in 146 cases (73%), two in 52 cases (26%) and three in 2 cases (1%). Of 256 mesiodentes, the direction of the crown of the mesiodens was inverted in 172 (67%), in a normal direction in 69 (27%) and in a horizontal direction with regard to the tooth axis in 15 (6%). Of the 147 mesiodentes for which axial radiography was performed, 131 (89%) were located at a palatal site against the dental arch, 16 (11%) overlapped the dental arch and none were at a labial site. Of our 200 cases, a delay of eruption of the permanent central incisor was seen in 12 (6%), malposition or rotation of the central incisor in 5 (2.5%) and dentigerous cyst formation arising from mesiodens in 22 (11%). Marked movement of the mesiodens was seen in 10 cases during the follow-up period of 5-7 years. Some complication arising from mesiodens was seen in 19.5% of all cases in our research. Although mesiodentes are not caused by malocclusion, they may cause it. A long period of impaction of mesiodentes may bring about dentigerous cyst formation or movement of the mesiodentes.


Effects of contractile activity on muscle damage in the dystrophin-deficient mdx mouse.
1. Isolated extensor digitorum longus muscles from control C57BL/10 and mutant dystrophin-deficient C57BL/10 mdx mice have been studied in vitro to determine whether dystrophin deficiency influences the susceptibility of muscle to contractile activity-induced damage. 2. mdx muscles were found to release reduced amounts of intracellular creatine kinase compared with control tissue in response to excessive contractile activity with or without simultaneous stretching of the muscle to 130% of its resting length. 3. In contrast, prostaglandin E2 release from mdx muscle was elevated compared with control tissue in response to either form of contractile activity or to treatment with the calcium ionophore A23187. 4. These results do not support the hypothesis that dystrophin-deficient muscle is more susceptible to damage induced by contractile activity, but suggest that dystrophin deficiency influences the activity of muscle membrane phospholipase enzymes.


Heat-assisted detection and ranging.
Machine perception uses advanced sensors to collect information about the surrounding scene for situational awareness1-7. State-of-the-art machine perception8 using active sonar, radar and LiDAR to enhance camera vision9 faces difficulties when the number of intelligent agents scales up10,11. Exploiting omnipresent heat signal could be a new frontier for scalable perception. However, objects and their environment constantly emit and scatter thermal radiation, leading to textureless images famously known as the 'ghosting effect'12. Thermal vision thus has no specificity limited by information loss, whereas thermal ranging-crucial for navigation-has been elusive even when combined with artificial intelligence (AI)13. Here we propose and experimentally demonstrate heat-assisted detection and ranging (HADAR) overcoming this open challenge of ghosting and benchmark it against AI-enhanced thermal sensing. HADAR not only sees texture and depth through the darkness as if it were day but also perceives decluttered physical attributes beyond RGB or thermal vision, paving the way to fully passive and physics-aware machine perception. We develop HADAR estimation theory and address its photonic shot-noise limits depicting information-theoretic bounds to HADAR-based AI performance. HADAR ranging at night beats thermal ranging and shows an accuracy comparable with RGB stereovision in daylight. Our automated HADAR thermography reaches the Cramér-Rao bound on temperature accuracy, beating existing thermography techniques. Our work leads to a disruptive technology that can accelerate the Fourth Industrial Revolution (Industry 4.0)14 with HADAR-based autonomous navigation and human-robot social interactions.


Mannitol-guided delivery of Ciprofloxacin in artificial cystic fibrosis mucus model.
Abnormal airway mucus presents a significant challenge for inhalational drug delivery. Recognizing the thick and tenacious airway mucus seen in the cystic fibrosis (CF) patients as a critical barrier to effective drug delivery, both into the mucus layer itself as well as across that layer to the underlying airway epithelium, we hypothesize that mannitol or NaCl can form inhalable drug carriers, improve drug penetration into the mucus, and ultimately enhance the drug's therapeutic effect. The objective of this study is to test whether mannitol and NaCl particles, as inhalable drug carriers, improve drug delivery into and enhance a drug's activity within a mucus-like material. Microparticles containing Ciprofloxacin (Cipro), an active ingredient, and either mannitol or NaCl were produced by spray-drying. Cipro encapsulated in mannitol particles (Cipro-mannitol) was significantly more effective at killing Pseudomonas aeruginosa (P. aeruginosa) grown in artificial mucus (AM) than Cipro encapsulated in either NaCl particles (Cipro-NaCl) or in hydrophobic particles consisting of dipalmitoylphosphatidylcholine (DPPC), albumin, and lactose (Cipro-DAL). The relatively high antibacterial effectiveness of Cipro-mannitol was not due to the effect of mannitol on bacteria or on Cipro. Rather, the unique performance of the mannitol-based particles in AM is attributable to its ability to increase local water content in the AM and enhance drug penetration into it. Mannitol is a promising excipient for inhalable microparticles that facilitate the drug delivery into the CF mucus.


Stretchable, porous, and conductive energy textiles.
Recently there is strong interest in lightweight, flexible, and wearable electronics to meet the technological demands of modern society. Integrated energy storage devices of this type are a key area that is still significantly underdeveloped. Here, we describe wearable power devices using everyday textiles as the platform. With an extremely simple "dipping and drying" process using single-walled carbon nanotube (SWNT) ink, we produced highly conductive textiles with conductivity of 125 S cm(-1) and sheet resistance less than 1 Omega/sq. Such conductive textiles show outstanding flexibility and stretchability and demonstrate strong adhesion between the SWNTs and the textiles of interest. Supercapacitors made from these conductive textiles show high areal capacitance, up to 0.48F/cm(2), and high specific energy. We demonstrate the loading of pseudocapacitor materials into these conductive textiles that leads to a 24-fold increase of the areal capacitance of the device. These highly conductive textiles can provide new design opportunities for wearable electronics and energy storage applications.


A multicentered study on efficiency of noninvasive ventilation procedures (SAFE-NIV)
To characterize the clinical course of noninvasive positive pressure ventilation (NIPPV) and high flow humidified nasal cannula ventilation (HFNC) procedures; perform risk analysis for ventilation failure. This prospective, multi-centered, observational study was conducted in 352 PICU admissions (1 month-18 years) between 2016 and 2017. SPSS-22 was used to assess clinical data, define thresholds for ventilation parameters and perform risk analysis. Patient age, onset of disease, previous intubation and hypoxia influenced the choice of therapy mode: NIPPV was preferred in older children (p = 0.002) with longer intubation (p < 0.001), ARDS (p = 0.001), lower respiratory tract infections (p < 0.001), chronic respiratory disease, (p = 0.005), malignancy (p = 0.048) and immune deficiency (p = 0.026). The failure rate was 13.4%. sepsis, ARDS, prolonged intubation, and use of nasal masks were associated with NIV failure (p = 0.001, p < 0.001, p < 0.001, p = 0.025). The call of intubation or re-intubation was given due to respiratory failure in twenty-seven (57.5%), hemodynamic instability in eight (17%), bulbar dysfunction or aspiration in 5 (10.6%), neurological deterioration in 4 (8.5%) and developing ARDS in 3 (6.4%) children. A reduction of less than 10% in the respiration within an hour increased the odds of failure by 9.841 times (OR: 9.841, 95% CI: 2.0021–48.3742). FiO2 > 55% at 6th hours and PRISM-3 >8 were other failure predictors. Of the 9.9% complication rate, the most common complication was pressure ulcerations (4.8%) and mainly observed when using full-face masks (p = 0.047). Fifteen (4.3%) patients died of miscellaneous causes. Tracheostomy cannulation was performed on 16 children due to prolonged mechanical ventilation (8% in NIPPV, 2.6% in HFNC) Absence of reduction in the respiration rate within an hour, FiO2 requirement >55% at 6th hours and PRISM-3 score >8 predict NIV failure.


Cloning of the gene for the 73 kD subunit of the DNA polymerase alpha primase of Drosophila melanogaster.
We have isolated both cDNA and genomic clones for the 73 kDa subunit of the DNA polymerase alpha primase of Drosophila melanogaster. Analysis of these clones has identified an open reading frame of 1959 bases coding for a protein of 72.5 kDa. Northern analysis has shown the mRNA for the gene to be approximately 2.5 kb, and comparison of the cDNA and the genomic clones shows that the coding region of the gene lacks introns. The 5' end of the transcript has been mapped by primer extension, and the position of the gene in the genome mapped using in situ analysis. Computer analysis has been carried out on both coding and non coding regions of the gene. The protein sequence shows some homology to the analogous subunit in the S. cerevisiae DNA polymerase alpha, however a search of the data banks failed to reveal other homologies, or provide any clues as to the function of the protein. Analysis of the non-coding regions indicates some potential control regions for the gene. The 73 kDa protein has been overproduced, but a preliminary analysis failed to reveal any enzymatic activities.


Peril in the market-classification and dosage of species used as anti-diabetics in Lima, Peru.
Peru is what Peruvian anthropologist Lupe Camino calls the "health axis" of the old Central Andean culture area stretching from Ecuador to Bolivia. In particular in the North of the country the traditional use of medicinal dates back as far as the first millennium B.C. Both healers, and the wider population, often buy their medicinal plants in local markets, but there is very little comparative information available about which plants are sold under which vernacular name at any given time, for which indication, and which dosage information and information about side effects is given by vendors. For this study we used two traditionally used species groups "Hercampuri" Gentianella spec. (Gentianaceae) and "Pasuchaca" Geranium spec. (Geraniaceae.), found in the Mercado Aviación in Lima, as small, clearly circumscribed plant group frequently used to treat symptoms of diabetes as a test case to study the taxonomy, indications, dosage, indicated side effects, and additional species used as admixtures and hypothesized that: 1. A wide variety of different species is sold under the same common name, and often several common names exist for one species. 2. There is no consistency in the dosage, or a relationship between dosage and species marketed under one name. 3. However, there is consistency in the knowledge about usage and side effects. Surveys focusing on medicinal plants sold and their properties were conducted at the Mercado Aviaciónin Lima in December 2012. Vouchers of all specimens were deposited at the National Herbarium of Peru. Our surveys in Mercado Aviación in Lima yielded four species of Gentianella, two of Geranium, and three additional species from three genera used as common additives that were sold as anti-diabetic. These results indicate that even in case of only a few plant species, used for a very clearly circumscribed application, patients run a considerable risk when purchasing their remedies in the market. The possible side effects in this case are the more serious because diabetes has to be treated long term, and as such the patients are ingesting possible toxic remedies over a long period of time. Much more control, and a much more stringent identification of the material sold in public markets, and entering the global supply chain via internet sales, would be needed.


The role of diffusion MRI in neuroscience.
Diffusion-weighted imaging has pushed the boundaries of neuroscience by allowing us to examine the white matter microstructure of the living human brain. By doing so, it has provided answers to fundamental neuroscientific questions, launching a new field of research that had been largely inaccessible. We briefly summarize key questions that have historically been raised in neuroscience concerning the brain's white matter. We then expand on the benefits of diffusion-weighted imaging and its contribution to the fields of brain anatomy, functional models and plasticity. In doing so, this review highlights the invaluable contribution of diffusion-weighted imaging in neuroscience, presents its limitations and proposes new challenges for future generations who may wish to exploit this powerful technology to gain novel insights.


Perturbed cholesterol and vesicular trafficking associated with dengue blocking in Wolbachia-infected Aedes aegypti cells.
Wolbachia are intracellular maternally inherited bacteria that can spread through insect populations and block virus transmission by mosquitoes, providing an important approach to dengue control. To better understand the mechanisms of virus inhibition, we here perform proteomic quantification of the effects of Wolbachia in Aedes aegypti mosquito cells and midgut. Perturbations are observed in vesicular trafficking, lipid metabolism and in the endoplasmic reticulum that could impact viral entry and replication. Wolbachia-infected cells display a differential cholesterol profile, including elevated levels of esterified cholesterol, that is consistent with perturbed intracellular cholesterol trafficking. Cyclodextrins have been shown to reverse lipid accumulation defects in cells with disrupted cholesterol homeostasis. Treatment of Wolbachia-infected Ae. aegypti cells with 2-hydroxypropyl-β-cyclodextrin restores dengue replication in Wolbachia-carrying cells, suggesting dengue is inhibited in Wolbachia-infected cells by localised cholesterol accumulation. These results demonstrate parallels between the cellular Wolbachia viral inhibition phenotype and lipid storage genetic disorders. Wolbachia infection of mosquitoes can block dengue virus infection and is tested in field trials, but the mechanism of action is unclear. Using proteomics, Geoghegan et al. here identify effects of Wolbachia on cholesterol homeostasis and dengue virus replication in Aedes aegypti.


Mouse inbred strain differences in ethanol drinking to intoxication.
Recently, we described a simple procedure, Drinking in the Dark (DID), in which C57BL/6J mice self-administer ethanol to a blood ethanol concentration (BEC) above 1 mg/ml. The test consists of replacing the water with 20% ethanol in the home cage for 4 h early during the dark phase of the light/dark cycle. Three experiments were conducted to explore this high ethanol drinking model further. In experiment 1, a microanalysis of C57BL/6J behavior showed that the pattern of ethanol drinking was different from routine water intake. In experiment 2, drinking impaired performance of C57BL/6J on the accelerating rotarod and balance beam. In experiment 3, 12 inbred strains were screened to estimate genetic influences on DID and correlations with other traits. Large, reliable differences in intake and BEC were detected among the strains, with C57BL/6J showing the highest values. Strain means were positively correlated with intake and BEC in the standard (24 h) and a limited (4 h) two-bottle ethanol vs. water test, but BECs reached higher levels for DID. Strain mean correlations with other traits in the Mouse Phenome Project database supported previously reported genetic relationships of high ethanol drinking with low chronic ethanol withdrawal severity and low ethanol-conditioned taste aversion. We extend these findings by showing that the correlation estimates remain relatively unchanged even after correcting for phylogenetic relatedness among the strains, thus relaxing the assumption that the strain means are statistically independent. We discuss applications of the model for finding genes that predispose pharmacologically significant drinking in mice.


Unsupervised Deep Hashing with Similarity-Adaptive and Discrete Optimization.
Recent vision and learning studies show that learning compact hash codes can facilitate massive data processing with significantly reduced storage and computation. Particularly, learning deep hash functions has greatly improved the retrieval performance, typically under the semantic supervision. In contrast, current unsupervised deep hashing algorithms can hardly achieve satisfactory performance due to either the relaxed optimization or absence of similarity-sensitive objective. In this work, we propose a simple yet effective unsupervised hashing framework, named Similarity-Adaptive Deep Hashing (SADH), which alternatingly proceeds over three training modules: deep hash model training, similarity graph updating and binary code optimization. The key difference from the widely-used two-step hashing method is that the output representations of the learned deep model help update the similarity graph matrix, which is then used to improve the subsequent code optimization. In addition, for producing high-quality binary codes, we devise an effective discrete optimization algorithm which can directly handle the binary constraints with a general hashing loss. Extensive experiments validate the efficacy of SADH, which consistently outperforms the state-of-the-arts by large gaps.


CX3CR1 deficiency accelerates the development of retinopathy in a rodent model of type 1 diabetes.
In this study, the role of CX3CR1 in the progression of diabetic retinopathy (DR) was investigated. The retinas of wild-type (WT), CX3CR1 null (CX3CR1gfp/gfp, KO), and heterozygous (CX3CR1+/gfp, Het) mice were compared in the presence and absence of streptozotocin (STZ)-induced diabetes. CX3CR1 deficiency in STZ-KO increased vascular pathology at 4 months of diabetes, as a significant increase in acellular capillaries was observed only in the STZ-KO group. CX3CR1 deficiency and diabetes had similar effects on retinal neurodegeneration measured by an increase in DNA fragmentation. Retinal vascular pathology in STZ-KO mice was associated with increased numbers of monocyte-derived macrophages in the retina. Furthermore, compared to STZ-WT, STZ-KO mice exhibited increased numbers of inflammatory monocytes in the bone marrow and impaired homing of monocytes to the spleen. The induction of retinal IL-10 expression by diabetes was significantly less in KO mice, and when bone marrow-derived macrophages from KO mice were maintained in high glucose, they expressed significantly less IL-10 and more TNF-α in response to LPS stimulation. These findings support that CX3CR1 deficiency accelerates the development of vascular pathology in DR through increased recruitment of proinflammatory myeloid cells that demonstrate reduced expression of anti-inflammatory IL-10. • CX3CR1 deletion in STZ-diabetic mice accelerated the onset of diabetic retinopathy (DR). • The early onset of DR was associated with increased retinal cell apoptosis. • The early onset of DR was associated with increased recruitment of bone marrow-derived macrophages to the retina. • Bone marrow-derived macrophages from CX3CR1 KO diabetic mice expressed more TNF-α and less IL-10. • The role of IL-10 in protection from progression of DR is highlighted.


Classification of herpes simplex virus keratitis.
We propose a nomenclature for classification of herpes simplex virus (HSV) keratitis. We hope that a more consistent classification system will lead to a better understanding of the disease processes, thus resulting in improved diagnosis, treatment, and patient outcomes. A review of the literature was performed to evaluate current HSV classification systems. These systems were evaluated in the context of both current clinical and basic science studies and our own clinical observations. The proposed classification system is based on the anatomy and pathophysiology of the specific presentations of HSV keratitis. Anatomically, the primary level of corneal involvement, whether epithelium, stroma, or endothelium, must be elucidated. Pathophysiologically, the cause of the inflammation. whether immunologic, infectious, or neurotrophic, must be determined. There are four major categories of HSV keratitis. (1) Infectious epithelial keratitis, which is made up of cornea vesicles, dendritic ulcer, geographic ulcer, and marginal ulcer. (2) Neurotrophic keratopathy, which includes punctate epithelial erosions and neurotrophic ulcer. (3) Stromal keratitis, which is subdivided into necrotizing stromal keratitis and immune stromal keratitis. (4) Endotheliitis, which has three clinical presentations: disciform, diffuse, and linear. We believe that by categorizing cases of HSV keratitis by their primary anatomic and pathophysiologic etiologic characteristics, clinicians can better understand and therefore treat all types of HSV keratitis. The four main categories of HSV keratitis are infectious epithelial keratitis, neurotrophic keratopathy, stromal keratitis, and endotheliitis. Each of these is subdivided to more specific clinical presentations.


VarFish: comprehensive DNA variant analysis for diagnostics and research.
VarFish is a user-friendly web application for the quality control, filtering, prioritization, analysis, and user-based annotation of DNA variant data with a focus on rare disease genetics. It is capable of processing variant call files with single or multiple samples. The variants are automatically annotated with population frequencies, molecular impact, and presence in databases such as ClinVar. Further, it provides support for pathogenicity scores including CADD, MutationTaster, and phenotypic similarity scores. Users can filter variants based on these annotations and presumed inheritance pattern and sort the results by these scores. Variants passing the filter are listed with their annotations and many useful link-outs to genome browsers, other gene/variant data portals, and external tools for variant assessment. VarFish allows users to create their own annotations including support for variant assessment following ACMG-AMP guidelines. In close collaboration with medical practitioners, VarFish was designed for variant analysis and prioritization in diagnostic and research settings as described in the software's extensive manual. The user interface has been optimized for supporting these protocols. Users can install VarFish on their own in-house servers where it provides additional lab notebook features for collaborative analysis and allows re-analysis of cases, e.g. after update of genotype or phenotype databases.


Cascaded uncoupled dual-ring modulator.
We demonstrate, by coherent driving two uncoupled rings in same direction, that the effective photon circulating time in the dual-ring modulator is reduced, with increased modulation quality. The inter-ring detuning-dependent photon dynamics, Q factor, extinction ratio, and optical modulation amplitude of two cascaded silicon ring resonators are studied and compared with that of a single-ring modulator. Experimentally measured eye diagrams, together with coupled mode theory simulations, demonstrate the enhancement of the dual-ring configuration at 20 Gbps with a Q∼20,000.


Effect of sperm washing and swim-up on antibodies bound to sperm membrane: use of immunobead/sperm cervical mucus contact tests.
The direct immunobead test (IBT) and the sperm cervical mucus contact (SCMC) test were used to evaluate the effect of sperm washes and swim-up on antibodies bound to the sperm membrane in 11 patients with autosperm antibodies (30-100% IgA and 30-100% IgG) but otherwise normal semen measurements. The tests were performed on semen samples before and after a wash/swim-up procedure in Ham F10 + 10% human blood serum. Sperm-bound antibodies in washed spermatozoa that were able to swim into a layer of medium did not differ from those in unwashed samples. The IBT and the SCMC test on unwashed and washed spermatozoa were also not significantly different. However, all other washed semen parameters were improved. Correct washing of semen samples is important when performing the IBT to prevent false negative results. Eight of the 11 partners (73%) of the patients tested became pregnant after treatment with washed sperm. The ongoing pregnancy rate was 64%.


Vitamin D and female fertility.
Apart from the well known effects of vitamin D on maintaining calcium homeostasis and promoting bone mineralization, there is some evidence suggesting that vitamin D also modulates human reproductive processes. We will review the most interesting and relevant studies on vitamin D and female fertility published over the past year. In the past year, several observational studies reported a better in-vitro fertilization outcome in women with sufficient vitamin D levels (≥30 ng/ml), which was mainly attributed to vitamin D effects on the endometrium. One randomized controlled trial found an increased endometrial thickness in women with polycystic ovary syndrome (PCOS) receiving vitamin D during intrauterine insemination cycles. Further, vitamin D supplementation had a beneficial effect on serum lipids in PCOS women. Vitamin D treatment improved endometriosis in a rat model and increased vitamin D intake was related to a decreased risk of incident endometriosis. Vitamin D was also favorably associated with primary dysmenorrhea, uterine leiomyoma, and ovarian reserve in late reproductive aged women. In women undergoing in-vitro fertilization, a sufficient vitamin D level (≥30 ng/ml) should be obtained. Vitamin D supplementation might improve metabolic parameters in women with PCOS. A high vitamin D intake might be protective against endometriosis.


Estimates of Tibial Shock Magnitude in Men and Women at the Start and End of a Military Drill Training Program.
Foot drill is a key component of military training and is characterized by frequent heel stamping, likely resulting in high tibial shock magnitudes. Higher tibial shock during running has previously been associated with risk of lower limb stress fractures, which are prevalent among military populations. Quantification of tibial shock during drill training is, therefore, warranted. This study aimed to provide estimates of tibial shock during military drill in British Army Basic training. The study also aimed to compare values between men and women, and to identify any differences between the first and final sessions of training. Tibial accelerometers were secured on the right medial, distal shank of 10 British Army recruits (n = 5 men; n = 5 women) throughout a scheduled drill training session in week 1 and week 12 of basic military training. Peak positive accelerations, the average magnitude above given thresholds, and the rate at which each threshold was exceeded were quantified. Mean (SD) peak positive acceleration was 20.8 (2.2) g across all sessions, which is considerably higher than values typically observed during high impact physical activity. Magnitudes of tibial shock were higher in men than women, and higher in week 12 compared with week 1 of training. This study provides the first estimates of tibial shock magnitude during military drill training in the field. The high values suggest that military drill is a demanding activity and this should be considered when developing and evaluating military training programs. Further exploration is required to understand the response of the lower limb to military drill training and the etiology of these responses in the development of lower limb stress fractures.


Synthesis and photophysics of extended π-conjugated systems of substituted 10-aryl-pyrenoimidazoles.
The synthesis of π-extended 10-aryl-pyrenoimidazoles having different substituents was realised via Ru(ii)-catalyzed oxidative annulation of 10-aryl-pyrenoimidazole with diphenylacetylene. The single crystal X-ray structure of trifluoromethyl and carboxylate substituted annulated-10-aryl-pyrenoimidazoles confirms the near coplanarity of the pyrene and imidazole moieties and the presence of twisted conformation resulting in intermolecular C-Hπ interactions. The lowest energy absorption maximum becomes red-shifted characteristic to the nature of the substituent owing to the extended π-conjugation, and specifically the nitro substituent shows intense absorption in the visible region with the maximum at 440 nm. All the molecules were found to show intense fluorescence both in solution and solid states. Strikingly, 170 nm red-shifted fluorescence with a large Stokes shift ca. 7000 cm-1 for the nitro derivative, a value nearly two-fold higher than the parent compound despite its rigid polyaromatic skeleton was observed. The combination of electron rich π-conjugated aromatic systems with electron deficient substituents induces the intramolecular charge transfer interactions, which has been corroborated with the theoretical calculations.


Metabolite-related dietary patterns and the development of islet autoimmunity.
The role of diet in type 1 diabetes development is poorly understood. Metabolites, which reflect dietary response, may help elucidate this role. We explored metabolomics and lipidomics differences between 352 cases of islet autoimmunity (IA) and controls in the TEDDY (The Environmental Determinants of Diabetes in the Young) study. We created dietary patterns reflecting pre-IA metabolite differences between groups and examined their association with IA. Secondary outcomes included IA cases positive for multiple autoantibodies (mAb+). The association of 853 plasma metabolites with outcomes was tested at seroconversion to IA, just prior to seroconversion, and during infancy. Key compounds in enriched metabolite sets were used to create dietary patterns reflecting metabolite composition, which were then tested for association with outcomes in the nested case-control subset and the full TEDDY cohort. Unsaturated phosphatidylcholines, sphingomyelins, phosphatidylethanolamines, glucosylceramides, and phospholipid ethers in infancy were inversely associated with mAb+ risk, while dicarboxylic acids were associated with an increased risk. An infancy dietary pattern representing higher levels of unsaturated phosphatidylcholines and phospholipid ethers, and lower sphingomyelins was protective for mAb+ in the nested case-control study only. Characterization of this high-risk infant metabolomics profile may help shape the future of early diagnosis or prevention efforts.


Studying ritual and individual orientations to alcohol use: Drinking motives and their connection to intoxication in Finland in the 2000s.
Finland was an agricultural country until the 1960s. Thereafter, Finland modernized rapidly. Studies have postulated that as Finland becomes modernized, intoxication-oriented drinking would gradually decrease. Current studies, however, show that heavy episodic drinking has lately become more common among men and women. Simultaneously, drinking is seldom motivated by the purpose of getting drunk. The article tackles this conundrum by approaching drinking motives from a ritual and an individual perspective. We study what kinds of drinking motives currently exist in Finland, their prevalence among different population groups, how they vary by social background, and their association with intoxication. The data were collected as part of the nationally representative Drinking Habit Survey in 2008. It consists of verbal descriptions on the most recent drinking occasion (N=521), estimations of its blood alcohol content, and responses to pre-defined standardized motive questions related to the latest drinking occasions (N=8732). Besides the motive 'to get drunk', also the motives of drinking as a 'time-out' ritual, 'to get into the mood' and 'I drunk to brighten up' predict a "wet" drinking occasion. Overall, Finns highlight drinking motives of sociability, relaxation, meal drinking and situational factors. The more educated orientate to their drinking more with motives that express mastery of cultural capital and individuality. The less educated and the young, again, orientate to their drinking more with motives that imply intoxication and external expectations. Whereas the ritual perspective discloses what kinds of situations predict intoxication, the individual perspective reveals what kinds of individualistic orientations are associated with drunkenness. These perspectives partly speak past each other and are difficult to combine. The article proposes that situational perspective would serve as a bridge between them and enable the incorporation of results from different research traditions.


Vegetarian diet as a risk factor for tuberculosis in immigrant south London Asians.
In a previous retrospective study of tuberculosis in south London among Asian immigrants from the Indian subcontinent Hindu Asians were found to have a significantly increased risk for tuberculosis compared with Muslims. This finding has been further investigated by examining the role of socioeconomic and lifestyle variables, including diet, as risk factors for tuberculosis in Asian immigrants from the Indian subcontinent resident in south London. Using a case-control study technique Asian immigrants from the Indian subcontinent diagnosed with tuberculosis during the past 10 years and two Asian control groups (community and outpatient clinic controls) from the Indian subcontinent were investigated. Cases and community controls were approached by letter. A structured questionnaire concerning a range of demographic, migration, socioeconomic, dietary, and health topics was administered by a single trained interviewer to subjects (56 cases and 100 controls) who agreed to participate. The results confirmed earlier findings that Hindu Asians had an increased risk of tuberculosis compared with Muslims. However, further analysis revealed that religion had no independent influence after adjustment for vegetarianism (common among Hindu Asians). Unadjusted odds ratios for tuberculosis among vegetarians were 2.7 (95% CI 1.1 to 6.4) using community controls, and 4.3 (95% CI 1.8 to 10.4) using clinic controls. There was a trend of increasing risk of tuberculosis with decreasing frequency of meat or fish consumption. Lactovegetarians had an 8.5 fold risk (95% CI 1.6 to 45.4) compared with daily meat/fish eaters. Adjustment for a range of other socioeconomic, migration, and lifestyle variables made little difference to the relative risks derived using either community or clinic controls. These results indicate that a vegetarian diet is an independent risk factor for tuberculosis in immigrant Asians. The mechanism is unexplained. However, vitamin D deficiency, common among vegetarian Asians in south London, is known to affect immunological competence. Decreased immunocompetence associated with a vegetarian diet might result in increased mycobacterial reactivation among Asians from the Indian subcontinent.


Tip regeneration and positional information in the slug of Dictyostelium discoideum.
We show in this paper that in the case of the slug of the cellular slime mould Dictyostelium discoideum the time which it takes for a new tip to regenerate at a given level can be used as a measure of positional information at that level. Our basic experiment consists of amputating slugs at various distances from the existing tip and thereby inducing the regeneration of a fresh tip; the time needed for regeneration is estimated by two independent methods. An identical operation, when performed in the anterior portion of a previously cut slug, tells us how this position-dependent regeneration time adjusts to a sudden change in the size of the slug. The reasons which lead us to conclude that tip regeneration times are in one-to-one correspondence with positional information are as follows. (i) Depending on their positions, the cells in a slug take different times to regenerate a new tip following amputation; (ii) regeneration times are scaled in relation to the total length of the slug and increase monotonically with the length cut off; and (iii) as judged by the regeneration time, cells can assess and remember their positions relative to the length of the slug. Our results highlight the importance of two rate processes. One might think of the slower process as being related to the setting up of a system of positional information in the slug, and the faster process as being a reflection of the kinetics of the positional value changing locally till it reaches the level appropriate to a tip.


Production of a monoclonal antibody specific to the El Amar strain of plum pox virus.
Plum pox virus (PPV) isolates are grouped into three clusters differentiated by biological, serological, molecular and epidemiological characteristics: Marcus (M), Dideron (D) and Cherry (C). The El Amar (EA) isolate that does not fit any of the above groups is also known. Monoclonal antibodies (MAbs) that specifically recognize M, D, and C strains of PPV are already available. To complete the set of PPV strain-specific serological reagents, MAbs against the EA isolate were raised by immunizing BALB/c mice and fusing their spleen cells with NS0/1 myeloma cells. After a preliminary characterization by double-antibody sandwich enzyme-linked immunosorbent assay (DAS-ELISA), 1 of 13 selected MAbs proved to be EA strain-specific. This MAb (EA24) reacted equally well with a homologous antigen and several PPV isolates from Egyptian apricot trees, supporting the hypothesis of an additional specific PPV group. MAb EA24 did not react either with about a hundred PPV isolates belonging to the D and M groups or with PPV-SwC and PPV-SoC isolates belonging to the C group. The strain specificity of MAb EA24 was confirmed by Western blot analysis and immunoelectron microscopy. We conclude that there is now available a set of MAbs which are highly specific to the four currently known groups of PPV strains.


Prevalence and correlates of burden among caregivers of patients with bipolar disorder enrolled in the Systematic Treatment Enhancement Program for Bipolar Disorder.
Caring for a relative with schizophrenia or dementia is associated with reports of high caregiver burden, symptoms of depression, poor physical health, negligence of the caregiver's own health needs, elevated health service use, low use of social supports, and financial strain. This study presents the design and preliminary data on the costs and consequences of caring for a relative or friend with bipolar disorder from the Family Experience Study, a longitudinal study of the primary caregivers to 500 patients enrolled in the Systematic Treatment Enhancement Program for Bipolar Disorder. Subjects were primary caregivers of 500 patients with bipolar disorder diagnosed by the Mini International Neuropsychiatric Interview and the Affective Disorder Evaluation. Caregivers were evaluated within 1 month after patients entered Systematic Treatment Enhancement Program using measures of burden, coping, health/mental health, and use of resources and costs. Eighty-nine percent, 52%, and 61% of caregivers, respectively, experienced moderate or higher burden in relation to patient problem behaviors, role dysfunction, or disruption of household routine. High burden caregivers reported more physical health problems, depressive symptoms, health risk behavior and health service use, and less social support than less burden caregivers. They also provided more financial support to their bipolar relative. Burdens experienced by family caregivers of people with bipolar disorder are associated with problems in health, mental health, and cost. Psychosocial interventions targeting the strains of caregiving for a patient with bipolar disorder are needed.


From the stand scale to the landscape scale: predicting the spatial patterns of forest regeneration after disturbance.
Shifting disturbance regimes can have cascading effects on many ecosystems processes. This is particularly true when the scale of the disturbance no longer matches the regeneration strategy of the dominant vegetation. In the yellow pine and mixed conifer forests of California, over a century of fire exclusion and the warming climate are increasing the incidence and extent of stand-replacing wildfire; such changes in severity patterns are altering regeneration dynamics by dramatically increasing the distance from live tree seed sources. This has raised concerns about limitations to natural reforestation and the potential for conversion to non-forested vegetation types, which in turn has implications for shifts in many ecological processes and ecosystem services. We used a California region-wide data set with 1,848 plots across 24 wildfires in yellow pine and mixed conifer forests to build a spatially explicit habitat suitability model for forecasting postfire forest regeneration. To model the effect of seed availability, the critical initial biological filter for regeneration, we used a novel approach to predicting spatial patterns of seed availability by estimating annual seed production from existing basal area and burn severity maps. The probability of observing any conifer seedling in a 60-m2 area (the field plot scale) was highly dependent on 30-yr average annual precipitation, burn severity, and seed availability. We then used this model to predict regeneration probabilities across the entire extent of a "new" fire (the 2014 King Fire), which highlights the spatial variability inherent in postfire regeneration patterns. Such forecasts of postfire regeneration patterns are of importance to land managers and conservationists interested in maintaining forest cover on the landscape. Our tool can also help anticipate shifts in ecosystem properties, supporting researchers interested in investigating questions surrounding alternative stable states, and the interaction of altered disturbance regimes and the changing climate.


Persistent elevation of carcinoembryonic antigen as first presentation of a medullary thyroid carcinoma.
Carcinoembryonic antigen (CEA) is still the most widely used tumour marker for gastrointestinal cancer. CEA was originally thought to be a specific marker for colorectal cancer, but it turned out to be a non-specific marker for further studies. CEA levels can be elevated in breast, lung and liver cancers, among others, including medullary thyroid cancer. The authors report a case of a 73-year-old woman who had a right hemicolectomy for an ascending colon adenocarcinoma and showed a persistent elevation in the CEA marker during follow-up. After several imaging tests, recurrence of the colon cancer was not found, but the presence of thyroid nodules had been detected. The diagnosis of a medullary thyroid carcinoma was made after the finding of a high value of calcitonin. The patient had a total thyroidectomy with resection of the central and lateral lymph nodes.


Third-Generation Hydroxyethyl Starch Causes Dose-Dependent Coagulopathy in Patients Undergoing Off-Pump Coronary Artery Bypass with Continuation of Preoperative Aspirin.
We aimed to evaluate the effect of third-generation hydroxyethyl starch (6% HES 130/0.4) on hemostasis and perioperative blood loss in patients undergoing off-pump coronary artery bypass (OPCAB) with continuation of preoperative aspirin. Forty-nine consecutive patients, who underwent OPCAB at a single institution between November 1, 2014 and March 31, 2016, were included. Coagulation tests, including thromboelastometry and clinical data of all patients, retrospectively were collected from anesthesia and medical records. The total amount of intraoperative crystalloid and HES was 2057.5 ± 771.6 mL (N = 32) and 1090.6 ± 645.0 mL (N = 32), respectively. In the coagulation pathway, the change ratio of fibrinogen concentration, prothrombin time, and fibrinogen thromboelastometry-maximum clot firmness (FIBTEM-MCF) significantly correlated with HES (P < 0.001, P = 0.00131, and P < 0.001, respectively), but not with crystalloid. In the coagulation pathway concerning interaction with platelets, the change ratio of platelet count, extrinsic thromboelastometry-clotting formation time (EXTEM-CFT), and EXTEM-MCF significantly were correlated with HES (P < 0.001, P < 0.001, and P < 0.001, respectively), but not with crystalloid. At chest closure, the hematocrit decreased in a dose-dependent manner with HES (P < 0.001), but not with crystalloid administration. There was an association between the change ratio of hematocrit and EXTEM-MCF (P = 0.00122). However, intra-postoperative blood loss was not correlated with HES 130/0.4 or crystalloid administration. We found that 6% HES 130/0.4 prolonged coagulation testing in a dose-dependent manner due to hemodilution but did not increase blood loss in patients undergoing OPCAB with continuation of preoperative aspirin.


Multicenter Evaluation of Colistin Broth Disk Elution and Colistin Agar Test: a Report from the Clinical and Laboratory Standards Institute.
Susceptibility testing of the polymyxins (colistin and polymyxin B) is challenging for clinical laboratories. The Clinical and Laboratory Standards Institute (CLSI) Antimicrobial Susceptibility Testing Subcommittee evaluated two methods to enable accurate testing of these agents. These methods were a colistin broth disk elution (CBDE) and a colistin agar test (CAT), the latter of which was evaluated using two inoculum volumes, 1 μl (CAT-1) and 10 μl (CAT-10). The methods were evaluated using a collection of 270 isolates of Enterobacterales, 122 Pseudomonas aeruginosa isolates, and 106 Acinetobacter spp. isolates. Overall, 94.4% of CBDE results were in essential agreement and 97.9% in categorical agreement (CA) with reference broth microdilution MICs. Nine very major errors (VME; 3.2%) and 3 major errors (ME; 0.9%) were observed. With the CBDE, 98.6% CA was observed for Enterobacterales (2.5% VME, 0% ME), 99.3% CA was observed for P. aeruginosa (0% VME, 0.7% ME), and 93.1% CA was observed for Acinetobacter spp. (5.6% VME, 3.3% ME). Overall, CA was 94.9% with 6.8% VME using CAT-1 and improved to 98.3% with 3.9% VME using CAT-10. No ME were observed using either CAT-1 or CAT-10. Using the CAT-1/CAT-10, the CA observed was 99.4%/99.7% for Enterobacterales (1%/0.5% VME), 98.7%/100% for P. aeruginosa (8.3%/0% VME), and 88.5%/92.3% for Acinetobacter spp. (21.4%/14.3% VME). Based on these data, the CLSI antimicrobial susceptibility testing (AST) subcommittee endorsed the CBDE and CAT-10 methods for colistin testing of Enterobacterales and P. aeruginosa.


Treatment of chronically infected open mastoid cavities with medical honey: a randomized controlled trial.
To investigate the efficacy of medical honey as topical treatment of chronically discharging open mastoid cavities in comparison with conventional eardrops. Single-center, prospective, randomized controlled, double-dose trial of 12 weeks. Twenty-eight patients diagnosed as having a chronically discharging open mastoid cavity underwent medical honey gel (intervention) or conventional eardrops (control) treatment. Treatment interventions were repeated after 4 weeks. Visual analogue scale of ear complaints, cavity inflammation, and bacterial infection. Most patients had a cavity with localized granulation. After treatment, inflammation score decreased in both groups (p < 0.05), with more pronounced inflammation-free cavities in the honey group. Honey treatment resulted in less discomfort (p < 0.001) and otorrhea (p < 0.001), even after correction for additional medication use (p < 0.05, p < 0.01). This decrease was not seen in the control group. Pain and itching did not change on treatment. Most cavities were infected with Pseudomonas species and Staphylococcus aureus. After treatment, a 23% increase of negative culture was seen with honey compared with 30% in the control group (nonsignificant). No serious adverse reactions were found. Medical honey gel is a safe alternative treatment option for patients with a chronically discharging open mastoid cavity and beneficial in reducing discomfort, otorrhea, and inflammation with a bactericidal effect.