PDK1 controls upstream PI3K expression and PIP3 generation.
The PI3K/PDK1/Akt signaling axis is centrally involved in cellular homeostasis and controls cell growth and proliferation. Due to its key function as regulator of cell survival and metabolism, the dysregulation of this pathway is manifested in several human pathologies including cancers and immunological diseases. Thus, current therapeutic strategies target the components of this signaling cascade. In recent years, numerous feedback loops have been identified that attenuate PI3K/PDK1/Akt-dependent signaling. Here, we report the identification of an additional level of feedback regulation that depends on the negative transcriptional control of phosphatidylinositol 3-kinase (PI3K) class IA subunits. Genetic deletion of 3-phosphoinositide-dependent protein kinase 1 (PDK1) or the pharmacological inhibition of its downstream effectors, that is, Akt and mammalian target of rapamycin (mTOR), relieves this suppression and leads to the upregulation of PI3K subunits, resulting in enhanced generation of phosphatidylinositol-3,4,5-trisphosphate (PIP3). Apparently, this transcriptional induction is mediated by the concerted action of different transcription factor families, including the transcription factors cAMP-responsive element-binding protein and forkhead box O. Collectively, we propose that PDK1 functions as a cellular sensor that balances basal PIP3 generation at levels sufficient for survival but below a threshold being harmful to the cell. Our study suggests that the efficiency of therapies targeting the aberrantly activated PI3K/PDK1/Akt pathway might be increased by the parallel blockade of feedback circuits.


Study of sexuality-related characteristics in young adults with schizophrenia treated with novel neuroleptics and in a comparison group of young adults.
This study compared characteristics related to sexual history, sexual activities, sexual functioning, and psychological tendencies associated with sexuality in 45 young adults with schizophrenia treated with novel neuroleptics and in 61 young adults from a comparison group. A smaller proportion of young adults with schizophrenia currently had a sexual partner or had ever engaged in sexual relations. They also had sexual relations and sexual desires less often. Whether affected by schizophrenia or not, a smaller proportion of women had ever masturbated, and a smaller proportion of men currently had a sexual partner. Women masturbated less often, felt less sexual desire, and desired sexual relations less often, compared with men. Proportionally more men with schizophrenia treated with risperidone or olanzapine than men in the comparison group had at least one sexual dysfunction, lacked sexual desire, and reported problems with sexual arousal and ejaculation. Women with schizophrenia were more likely to report problems with sexual arousal and galactorrhea, compared with women in the comparison group. Finally, young adults with schizophrenia were more likely to develop negative psychological tendencies associated with sexuality than were young adults in the comparison group. Sexual problems are highly prevalent among young adults with schizophrenia. Sexuality should occupy the space it deserves within psychosocial rehabilitation programs and the treatment of schizophrenia.


Influence of age, season, body condition and geographical area on concentrations of chlorinated and brominated contaminants in wild mink (Neovison vison) in Sweden.
The wild mink has gained acceptance as a sentinel species in environmental monitoring. However, only limited data are available in the literature on factors driving variability in concentrations of organic pollutants in this species. This study characterizes the differences in contaminant concentrations in subcutaneous fat of male mink from four different areas in Sweden and demonstrates how age, season and body condition influence concentrations of polychlorinated biphenyl (PCB) congeners, polybrominated diphenyl ether (PBDE) congeners (including methoxylated forms, MeO-PBDEs), as well as the pesticides dichlorodiphenyldichloroethylene (DDE), chlordane and hexachlorobenzene (HCB). The data were statistically treated using multiple regression and principal component analysis. The ∑PCB concentration and concentrations of PCB congeners 138, 156, 157, 180, 170/190, 189, 194, 206, 209 as well as PBDE 153/154 varied with age. Season had an influence on ∑PCB, PBDE 47 and PBDE 153/154 concentrations, as well as concentrations of most PCB congeners, with the exception of PCB 101, 110, 141 and 182/187. Lean mink had higher concentrations of most PCBs and PBDEs than mink with larger fat depots. The analyzed pesticides (DDE, oxychlordane, HCB) showed no systematic variation with season, age or body condition. The concentrations of MeO-PBDEs were generally low and 6MeO-PBDE 47 was the most commonly detected MeO-PBDE in mink from marine, brackish and freshwater areas. The results indicate that age, season and body condition are factors that may influence the concentrations of PCBs and PBDEs, and it is thus recommended to take these factors into account when analyzing mink exposure data.


Abhorring the vacuum: use of Alzheimer's disease medications in frontotemporal dementia.
There is no dedicated therapy for frontotemporal dementia (FTD). In order to treat the often devastating behavioral disturbances that interfere with both normal social functioning and the ability of caregivers to provide needed support, off-label medication usage is frequent. In addition to antidepressant and antipsychotic medications, which afford some benefits, US FDA-approved treatments for Alzheimer's disease are often used, including both cholinesterase inhibitors and memantine. Here, we review the various clinical manifestations of FTD, a general approach to treatment and the goals of any potential therapies. We review all of the existing literature on the use of cholinesterase inhibitors and memantine in FTD. While cholinesterase inhibitors do not currently have a place in FTD treatment, memantine may be helpful, although the results of two placebo-controlled trials with this agent are not yet available. Finally, we discuss our view that such approaches will probably become supplanted by rational, molecularly-based therapies currently in development.


Military genitourinary injuries: past, present, and future.
Genitourinary (GU) injuries among military service members are as old as war itself. The frequency and clinical picture of GU injuries sustained in conflicts over the ages have evolved along with the constantly changing nature of combat. In this review, we discuss changing trends in the diagnosis and management of GU injuries over the past century and introduce areas of innovation which could impact the care of casualties who sustain GU trauma in the future.


Host migration impacts on the phylogeography of Lyme Borreliosis spirochaete species in Europe.
The geographic patterns of transmission opportunities of vector-borne zoonoses are determined by a complex interplay between the migration patterns of the host and the vector. Here we examine the impact of host migration on the spread of a tick-borne zoonotic disease, using Lyme Borreliosis (LB) spirochaetal species in Europe. We demonstrate that the migration of the LB species is dependent on and limited by the migration of their respective hosts. We note that populations of Borrelia spp. associated with birds (Borrelia garinii and B. valaisiana) show limited geographic structuring between countries compared with those associated with small mammals (Borrelia afzelii), and we argue that this can be explained by higher rates of migration in avian hosts. We also show the presence of B. afzelii strains in England and, through the use of the multi-locus sequence analysis scheme, reveal that the strains are highly structured. This pattern in English sites is very different from that observed at the continental sites, and we propose that these may be recent introductions.


Pronounced effects of the densities of threaded rings on the strain-dependent Poisson's ratio of polyrotaxane gels with movable cross-links.
The density of threaded ring molecules (fCD) in polyrotaxane (PR) chains has pronounced effects on the strain-induced swelling of PR gels where the cross-linked ring molecules are slidable along the network strands. The equilibrium Poisson's ratio (μ∞), which is a measure of the strain-induced volume change, for the PR gel increases with an increase in elongation (λ) at moderate λ but becomes a constant value () at sufficiently large λ. When the modulus exceeds a threshold value (Ec), the λ dependence of μ∞ disappears due to the loss of the slidability of the cross-links. The fraction fCD significantly influences the values of and Ec. When fCD is sufficiently small (<14%), (≈0.25) agrees with the values of μ∞ for the classical gels in good solvents. When fCD is high (>25%), varies over a wide range (0.22 < < 0.33) depending on fCD and the cross-link concentration in a complicated way. The modulus Ec at fCD = 25% is more than twice as high as that at fCD = 5% due to the finite contribution of the larger amount of uncross-linked ring molecules via combinatorial entropy in the axial polymers. The origin of the markedly small values of μ∞ (less than 0.1) at small λ is also considered on the basis of the magnitude of the accompanying force reduction caused by the slidable function of the cross-links.


Factors affecting survival of Shigatoxin-producing Escherichia coli on abiotic surfaces.
Shigatoxin-producing Escherichia coli (STEC) causes severe infections, and has been the cause of a number of foodborne outbreaks. Knowledge on the survival of STEC is crucial in order to limit the risk of cross contamination and transfer of STEC to food during processing. In this study survival of STEC and non-STEC on surfaces under various humidities, temperatures and in the presence of different types of soil was investigated. A model system with controlled relative humidity and temperature was established by using saturated salt solutions. All the 12 STEC strains had a reduction in viable count during incubation at 70% RH at 12 degrees C. The reduction was 2-3.5 log and 4.5-5.5 log after 1 and 7 days of incubation, respectively. Surviving cells were observed after 19 days of incubation. The STEC strains were more resistant to desiccation than non-STEC strains. STEC survived better at 12 degrees C, compared to 20 degrees C. The survival of STEC was much lower than the survival of a Staphylococcus simulans strain tested, which showed less than 1 log reduction until day 7 at 70% RH at 12 degrees C, while several STEC strains had comparable survival to a Salmonella Agona strain. The survival of two STEC strains tested was highest at 98% RH. The lowest survival was observed at 85% RH, with better survival at drier conditions. Presence of proteins and glucose protected the cells at dry conditions. Two commercial disinfectants tested at in-use concentration had limited effect (0.8-2.5 log reduction) against STEC on stainless steel, especially for cells incubated at high relative humidity (98% RH). STEC surviving on surfaces in the food industry may impose a risk for cross contamination. Cleaning and use of suitable disinfectants will reduce the survival of STEC, but surfaces should be allowed to dry completely since humid conditions will promote the survival and growth of STEC.


Vaccine-Induced Protection Against Furunculosis Involves Pre-emptive Priming of Humoral Immunity in Arctic Charr.
With respect to salmonid aquaculture, one of the most important bacterial pathogens due to high mortality and antibiotic usage is the causative agent of typical furunculosis, Aeromonas salmonicida spp. salmonicida (Asal). In Atlantic salmon, Salmo salar, the host response during infections with Asal is well-documented, with furunculosis outbreaks resulting in significant mortality in commercial settings. However, less is known about the host-pathogen interactions in the emerging aquaculture species, Arctic charr Salvelinus alpinus. Furthermore, there is no data on the efficacy or response of this species after vaccination with commonly administered vaccines against furunculosis. To this end, we examined the immunological response of S. alpinus during infection with Asal, with or without administration of vaccines (Forte Micro®, Forte Micro® + Renogen®, Elanco Animal Health). Artic charr (vaccinated or unvaccinated) were i.p.-injected with a virulent strain of Asal (106 CFUs/mL) and tissues were collected pre-infection/post-vaccination, 8, and 29 days post-infection. Unvaccinated Arctic charr were susceptible to Asal with 72% mortalities observed after 31 days. However, there was 72-82% protection in fish vaccinated with either the single or dual-vaccine, respectively. Protection in vaccinated fish was concordant with significantly higher serum IgM concentrations, and following RNA sequencing and transcriptome assembly, differential expression analysis revealed several patterns and pathways associated with the improved survival of vaccinated fish. Most striking was the dramatically higher basal expression of complement/coagulation factors, acute phase-proteins, and iron hemostasis proteins in pre-challenged, vaccinated fish. Remarkably, following Asal infection, this response was abrogated and instead the transcriptome was characterized by a lack of immune-stimulation compared to that of unvaccinated fish. Furthermore, where pathways of actin assembly and FcγR-mediated phagocytosis were significantly differentially regulated in unvaccinated fish, vaccinated fish showed either the opposite regulation (ForteMicro®), or no impact at all (ForteMicro®Renogen®). The present data indicates that vaccine-induced protection against Asal relies on the pre-activation and immediate control of humoral immune parameters that is coincident with reduced activation of apoptotic (e.g., NF-κB) and actin-associated pathways.


Connecting Air Quality with Emotional Well-Being and Neighborhood Infrastructure in a US City.
Cities in the United States have announced initiatives to become more sustainable, healthy, resilient, livable, and environmentally friendly. However, indicators for measuring all outcomes related to these targets and the synergies between them have not been well defined or studied. One such relationship is the linkage between air quality with emotional well-being (EWB) and neighborhood infrastructure. Here, regulatory monitoring, low-cost sensors (LCSs), and air quality modeling were combined to assess exposures to PM2.5 and traffic-related NOx in 6 Minneapolis, MN, neighborhoods of varying infrastructure parameters (median household income, urban vs suburban, and access to light rail). Residents of the study neighborhoods concurrently took real-time EWB assessments using a smart phone application, Daynamica, to gauge happiness, tiredness, stress, sadness, and pain. Both LCS PM2.5 observations and mobile-source-simulated NOx were calibrated using regulatory observations in Minneapolis. No statistically significant (α = 0.05) PM2.5 differences were found between urban poor and urban middle-income neighborhoods, but average mobile-source NOx was statistically significantly (α = 0.05) higher in the 4 urban neighborhoods than in the 2 suburban neighborhoods. Close proximity to light rail had no observable impact on average observed PM2.5 or simulated mobile-source NOx. Home-based exposure assessments found that PM2.5 was negatively correlated with positive emotions such as happiness and to net affect (the sum of positive and negative emotion scores) and positively correlated (ie, a higher PM2.5 concentration led to higher scores) for negative emotions such as tiredness, stress, sadness, and pain. Simulated mobile-source NOx, assessed from both home-based exposures and in situ exposures, had a near-zero relationship with all EWB indicators. This was attributed to low NOx levels throughout the study neighborhoods and at locations were the EWB-assessed activities took place, both owing to low on-road mobile-source NOx impacts. Although none of the air quality and EWB responses were determined to be statistically significant (α = 0.05), due in part to the relatively small sample size, the results are suggestive of linkages between air quality and a variety of EWB outcomes.


Kidney Functional Magnetic Resonance Imaging and Change in eGFR in Individuals with CKD.
Kidney functional magnetic resonance imaging (MRI) requires further investigation to enhance the noninvasive identification of patients at high risk of CKD progression. In this exploratory study, we obtained baseline diffusion-weighted and blood oxygen level-dependent MRI in 122 participants of the CKD Optimal Management with Binders and Nicotinamide trial, which was a multicenter, randomized, double-blinded, 12-month, four-group parallel trial of nicotinamide and lanthanum carbonate versus placebo conducted in individuals with eGFR 20-45 ml/min per 1.73 m2. Lower values of apparent diffusion coefficient (ADC) on diffusion-weighted MRI may indicate increased fibrosis, and higher values of relaxation rate (R2*) on blood oxygen level-dependent MRI may represent decreased oxygenation. Because there was no effect of active treatment on eGFR over 12 months, we tested whether baseline kidney functional MRI biomarkers were associated with eGFR decline in all 122 participants. In a subset of 87 participants with 12-month follow-up MRI data, we evaluated whether kidney functional MRI biomarkers change over time. Mean baseline eGFR was 32±9 ml/min per 1.73 m2, and mean annual eGFR slope was -2.3 (95% confidence interval [95% CI], -3.4 to -1.1) ml/min per 1.73 m2 per year. After adjustment for baseline covariates, baseline ADC was associated with change in eGFR over time (difference in annual eGFR slope per 1 SD increase in ADC: 1.3 [95% CI, 0.1 to 2.5] ml/min per 1.73 m2 per year, ADC×time interaction P=0.04). This association was no longer significant after further adjustment for albuminuria (difference in annual eGFR slope per 1 SD increase in ADC: 1.0 (95% CI, -0.1 to 2.2) ml/min per 1.73 m2 per year, ADC×time interaction P=0.08). There was no significant association between baseline R2* and change in eGFR over time. In 87 participants with follow-up functional MRI, ADC and R2* values remained stable over 12 months (intraclass correlation: 0.71 and 0.68, respectively). Baseline cortical ADC was associated with change in eGFR over time, but this association was not independent of albuminuria. Kidney functional MRI biomarkers remained stable over 1 year. CKD Optimal Management with Binders and Nicotinamide (COMBINE), NCT02258074.


Adverse events and in-hospital mortality: an analysis of all deaths in a Norwegian health trust during 2011.
The estimated number of in-hospitals deaths due to adverse events is often different when using data from deceased patients compared with that of a population experiencing adverse events. The study was conducted at three hospitals in the Bergen Hospital Trust, including a 950-bed university hospital. The objective was to study the reported deaths and investigate the probable number of deaths caused by adverse events. Information about all patients who died in the hospitals during 2011 was retrieved from the electronic patient data management system and the medical records. All deaths were classified into two groups according to Norwegian law based on whether or not the death was sudden and/or unexpected. The cause of death in the latter group was further classified as being due to either natural or unnatural causes according to national requirements. An expert review panel screened the patient records for information regarding adverse events and possible (≥ 50%) preventability. Age, length of hospital stay, and Charlson Comorbidity Index were also registered. There were 59,605 unique patients admitted in 2011 and 1185 registered deaths (1.98%). The mean and median ages of the deceased were 73,8 and 78 years, respectively, and the median length of stay was 5.6 days (range). Of these deaths, 290 (24.5%) were considered sudden and/or unexpected and 218 were considered to be due to natural causes. Of the 72 unnatural deaths, 16 (1.4%) were classified as preventable or probably preventable. For 18 deaths (%) it was impossible to confirm or rule out preventability. Using this method, we identified a small proportion of hospital deaths that could be classified as unnatural. Furthermore, there was a ≥ 50% chance or more that 34 deaths (2.9%) were due to causes that could have been prevented.


Site-specific characterization of (D)-amino acid containing peptide epimers by ion mobility spectrometry.
Traditionally, the d-amino acid containing peptide (DAACP) candidate can be discovered by observing the differences of biological activity and chromatographic retention time between the synthetic peptides and naturally occurring peptides. However, it is difficult to determine the exact position of d-amino acid in the DAACP candidates. Herein, we developed a novel site-specific strategy to rapidly and precisely localize d-amino acids in peptides by ion mobility spectrometry (IMS) analysis of mass spectrometry (MS)-generated epimeric fragment ions. Briefly, the d/l-peptide epimers were separated by online reversed-phase liquid chromatography and fragmented by collision-induced dissociation (CID), followed by IMS analysis. The epimeric fragment ions resulting from d/l-peptide epimers exhibit conformational differences, thus showing different mobilities in IMS. The arrival time shift between the epimeric fragment ions was used as criteria to localize the d-amino acid substitution. The utility of this strategy was demonstrated by analysis of peptide epimers with different molecular sizes, [d-Trp]-melanocyte-stimulating hormone, [d-Ala]-deltorphin, [d-Phe]-achatin-I, and their counterparts that contain all-l amino acids. Furthermore, the crustacean hyperglycemia hormones (CHHs, 8.5 kDa) were isolated from the American lobster Homarus americanus and identified by integration of MS-based bottom-up and top-down sequencing approaches. The IMS data acquired using our novel site-specific strategy localized the site of isomerization of l- to d-Phe at the third residue of the CHHs from the N-terminus. Collectively, this study demonstrates a new method for discovery of DAACPs using IMS technique with the ability to localize d-amino acid residues.


Integrating psychiatry and primary care improves acceptability to mental health services among Chinese Americans.
The objective of this study was to investigate whether integrating psychiatry and primary healthcare improves referral to and treatment acceptability of mental health services among Chinese Americans. The "Bridge Project," a program to enhance collaboration between primary care and mental health services for low-income Chinese immigrants was implemented at South Cove Community Health Center in Boston. The project consisted of conducting training seminars to primary care physicians to enhance recognition of common mental disorders, using a primary care nurse as the "bridge" to facilitate referrals to the Behavioral Health Department of the same facility, and co-locating a psychiatrist in the primary care clinic to provide onsite evaluation and treatment. The rate of mental health service referrals and successful treatment engagement before and during the project were compared. During the 12-month period of the Bridge Project, primary care physicians referred 64 (1.05% of all clinic patients) patients to mental health services, a 60% increase (chi(2)=4.97, P<.05) in the percentage of clinic patients referred in the previous 12 months. Eighty-eight percent of patients referred during the project showed up for psychiatric evaluation, compared to 53% (chi(2)=15.3, P<.001) in the previous 12 months. Integrating psychiatry and primary care is effective in improving access to mental health services and in increasing treatment engagement among low-income immigrant Chinese Americans.


Decompositional Representation of Morphological Complexity: Multivariate fMRI Evidence from Italian.
Derivational morphology is a cross-linguistically dominant mechanism for word formation, combining existing words with derivational affixes to create new word forms. However, the neurocognitive mechanisms underlying the representation and processing of such forms remain unclear. Recent cross-linguistic neuroimaging research suggests that derived words are stored and accessed as whole forms, without engaging the left-hemisphere perisylvian network associated with combinatorial processing of syntactically and inflectionally complex forms. Using fMRI with a "simple listening" no-task procedure, we reexamine these suggestions in the context of the root-based combinatorially rich Italian lexicon to clarify the role of semantic transparency (between the derived form and its stem) and affix productivity in determining whether derived forms are decompositionally represented and which neural systems are involved. Combined univariate and multivariate analyses reveal a key role for semantic transparency, modulated by affix productivity. Opaque forms show strong cohort competition effects, especially for words with nonproductive suffixes (ventura, "destiny"). The bilateral frontotemporal activity associated with these effects indicates that opaque derived words are processed as whole forms in the bihemispheric language system. Semantically transparent words with productive affixes (libreria, "bookshop") showed no effects of lexical competition, suggesting morphologically structured co-representation of these derived forms and their stems, whereas transparent forms with nonproductive affixes (pineta, pine forest) show intermediate effects. Further multivariate analyses of the transparent derived forms revealed affix productivity effects selectively involving left inferior frontal regions, suggesting that the combinatorial and decompositional processes triggered by such forms can vary significantly across languages.


Prevalence of Adolescent Problem Gambling: A Systematic Review of Recent Research.
Previous research has shown that gambling is a popular activity among adolescents. Following a rapid expansion of legalized gambling opportunities and the emergence of new forms of gambling, many researchers have carried out studies on adolescent gambling and problem gambling. The present paper reviews studies that have been conducted worldwide since 2000, and then presents a more detailed picture of adolescent gambling research in Europe, by providing a country-by country analysis. After an extensive search on academic databases and following an exclusion process, 44 studies were identified. The findings showed that 0.2-12.3 % of youth meet criteria for problem gambling, notwithstanding differences among assessment instruments, cut-offs, and timeframes. However, despite this variability, several demographic characteristics were associated with adolescent gambling involvement and problem gambling. It is concluded that a small but significant minority of adolescents have gambling-related problems. Such findings will hopefully encourage more research into youth gambling to further understand the determinants of this phenomenon.


NTP Toxicology and Carcinogenesis Studies of Malonaldehyde, Sodium Salt (3-Hydroxy-2-propenal, Sodium Salt) (CAS No. 24382-04-5) in F344/N Rats and B6C3F1 Mice (Gavage Studies).
Malonaldehyde occurs as a natural metabolic byproduct of prostaglandin biosynthesis and as an end product of polyunsaturated lipid peroxidation. Toxicology and carcinogenesis studies of malonaldehyde were conducted by administering the chemical as malonaldehyde, sodium salt, a stabilized form of malonaldehyde, in distilled water by gavage to groups of F344/N rats and B6C3F1 mice of each sex for 14 days, 13 weeks, and two years. The study material was 63%-79% malonaldehyde, sodium salt, 22%-38% water, and 1% or less other impurities. The water content was taken into account when the dose mixtures were prepared. Fourteen-Day and Thirteen-Week Studies: In the 14-day studies, groups of five rats and five mice of each sex were dosed with 250, 500, 750, 1,000, or 1,500 mg/kg malonaldehyde, sodium salt. Controls were untreated. Rats and mice that received 1,500 mg/kg malonaldehyde, sodium salt, did not survive to the end of the 14-day studies. No compound-related gross lesions were seen in the dosed animals. In the 13-week studies, groups of 10 males and 10 females of each species were administered 0, 30, 60, 125, 250, or 500 mg/kg malonaldehyde, sodium salt. Nine of 10 male rats, 10/10 female rats, 3/10 male mice, and 1/10 female mice that received 500 mg/kg malonaldehyde, sodium salt, died before the end of the studies. Body weights were reduced by more than 15% in rats receiving 250 or 500 mg/kg and in mice receiving 500 mg/kg. Compound-related nonneoplastic lesions were present in the stomach, testis, and kidney of rats and in the pancreas, stomach, and testis of mice. Focal and multifocal erosive lesions were observed in the gastric mucosa of the glandular stomach in the 500 mg/kg groups of male and female rats. Dilatation of the gastric glands of the stomach mucosa occurred in the 500 mg/kg male mice. Lesions of the kidney included membranous glomerular nephropathy in the 250 and 500 mg/kg male rats and the 125, 250, and 500 mg/kg female rats and mineralization in the 250 and 500 mg/kg male rats and the 60, 125, 250, and 500 mg/kg female rats. Degeneration of the testicular germinal epithelium was observed in male rats and male mice receiving 250 and 500 mg/kg. Atrophy of the exocrine pancreas was seen in the 125, 250, and 500 mg/kg male and the 250 and 500 mg/kg female mice. Based on these results, 2-year studies of malonaldehyde, sodium salt, were conducted by exposing groups of 50F344/N rats of each sex at doses of 0, 50, or 100 mg/kg, administered 5 days per week for 103 weeks. Doses of 0, 60, or 120 mg/kg were administered in the same schedule to groups of 50 male and 50 female B6C3F1 mice. Body Weight and Survival in the Two-Year Studies: Final mean body weights at the end of the study were reduced by 26% and 36% for high dose male and female rats compared with those for the vehicle controls. The final mean body weight of high dose male mice was 92% that of the vehicle controls. The final mean body weights of low dose male mice, low dose rats, and all groups of female mice were comparable to those of the vehicle controls. The survival of high dose male and female rats was significantly lower than that of the vehicle controls, with survival declining rapidly after week 76 for high dose males and after week 59 for high dose females (survival-- male: vehicle control, 37/50; low dose, 33/50; high dose, 15/50; female: 37/50; 37/50; 14/50). Survival of all groups of male mice was low (male: 24/50; 20/50; 14/50; female: 41/50; 38/50; 30/50). Survival of the high dose groups of male mice was significantly lower than that of the vehicle controls; no other significant differences in survival were observed between any groups of mice. Nonneoplastic and Neoplastic Effects in the Two-Year Studies: The incidences of a variety of nonneoplastic lesions were increased in dosed rats of each sex, primarily in the high dose male and female rat groups. These lesions were ulceration and inflammation of the glandular stomach; epithelial hyperplasia of the forestomach; inflammation of the cornea, retinal atrophy, and cataracts of the crysttion of the cornea, retinal atrophy, and cataracts of the crystalline lens; focal lipoid degeneration of the adrenal cortex; and diffuse pancreatic atrophy. Cytoplasmic vacuolization and cystic degeneration in the liver occurred at increased incidences in the high dose rat groups; in addition, the incidences of bile duct hyperplasia and bile duct fibrosis were increased in the high dose female and male rat groups, respectively. Bone marrow hematopoietic hyperplasia, hematopoiesis of the spleen, and ultimobranchial cysts of thyroid gland occurred with increased incidences in high dose female rats. The incidences of thyroid gland follicular cell adenomas or carcinomas (combined) were significantly increased in high dose male (vehicle control, 4/50; low dose, 8/49; high dose, 13/50) and female (2/50; 1/50; 7/50) rats. Follicular cell hyperplasia of the thyroid gland also occurred at an increased incidence in high dose female rats (10/50; 10/50;26/50) but not in male rats (9/50; 7/49; 7/50). The incidence of pancreatic islet cell adenomas was increased in low dose male rats (0/49; 9/50; 1/49). Adenomas and adenomas or carcinomas (combined) of the anterior pituitary gland occurred at significantly lower incidences in high dose rats than those in vehicle controls (combined incidence--male: 20/47; 14/49; 8/49; female: 18/49; 10/49; 2/48). Nonneoplastic lesions that occurred at increased incidences in dosed mice included atrophy of the pancreatic acinus and dilatation of the uterus. Depigmentation of hair shafts and change of coat color from agouti to gray were observed in high dose mice. No compound-related neoplasms were observed in dosed mice. Genetic Toxicology: Malonaldehyde, sodium salt, was not mutagenic in the Salmonella typhimurium/microsome assay when tested at doses of up to 10,000 ug/plate in a preincubational protocol using the excision-repair deficient strains TA98, TA100, TA1535, and TA1537 with or without S9 metabolic activation. The chemical induced forward mutations in mouse L5178Y lymphoma cells in the absence of S9; it was not tested with S9. Malonaldehyde, sodium salt was not mutagenic in the Drosophila melanogaster sex-linked recessive lethal mutagenicity test in which adult male flies were exposed either by feeding or by abdominal injection. In cytogenetic assays with cultured Chinese hamster ovary (CHO) cells, malonaldehyde, sodium salt, produced a dose-related increase in the frequency of sister-chromatid exchanges both in the presence and absence of rat liver S9; no increase in the number of chromosomal aberrations was observed in CHO cells in the absence or presence of S9. Audit: The data, documents, and pathology materials from the 2-year studies of malonaldehyde, sodium salt, have been audited. The audit found no special circumstances or significant deficiencies in the conduct or documentation of the studies which needed to be taken into consideration for reporting purposes. Conclusions: Under the conditions of these 2-year gavage studies, there was clear evidence of carcinogenic activity for male and female F344/N rats administered malonaldehyde, sodium salt, as shown by the increased incidences of follicular cell adenomas or carcinomas (combined) of the thyroid gland. Pancreatic islet cell adenomas were also observed at an increased incidence in low dose male rats. There was no evidence of carcinogenic activity for B6C3F1 mice administered 60 or 120 mg/kg malonaldehyde, sodium salt, in distilled water by gavage 5 days per week for 2 years. Chemically related increased incidences of nonneoplastic lesions included ulcers and inflammation of the glandular stomach and epithelial hyperplasia of the forestomach; corneal inflammation, retinal atrophy, and cataracts of the crystalline lens; and cystic degeneration of the liver, bile duct fibrosis, and bile duct hyperplasia in rats. Most of these nonneoplastic lesions as well as the thyroid gland follicular cell neoplasms occurred primarily in the high dose rat groups, in which survival and final body weights were reduced in high dose male and female rats. Increased incidences of atrophy of the pancreatic acinus and pigmentation loss in hair shafts were seen in high dose mice. Synonyms: malonaldehyde, enol, sodium salt; propanedial, sodium; 3-hydroxy-2-propenal, sodium salt; sodium b-oxyacrolein


A Systematic Review of Systematic Reviews on Blended Learning: Trends, Gaps and Future Directions.
Blended Learning (BL) is one of the most used methods in education to promote active learning and enhance students' learning outcomes. Although BL has existed for over a decade, there are still several challenges associated with it. For instance, the teachers' and students' individual differences, such as their behaviors and attitudes, might impact their adoption of BL. These challenges are further exacerbated by the COVID-19 pandemic, as schools and universities had to combine both online and offline courses to keep up with health regulations. This study conducts a systematic review of systematic reviews on BL, based on PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines, to identify BL trends, gaps and future directions. The obtained findings highlight that BL was mostly investigated in higher education and targeted students in the first place. Additionally, most of the BL research is coming from developed countries, calling for cross-collaborations to facilitate BL adoption in developing countries in particular. Furthermore, a lack of ICT skills and infrastructure are the most encountered challenges by teachers, students and institutions. The findings of this study can create a roadmap to facilitate the adoption of BL. The findings of this study could facilitate the design and adoption of BL which is one of the possible solutions to face major health challenges, such as the COVID-19 pandemic.


Prognostic factors for pain chronicity in low back pain: a systematic review.
Low back pain is the leading cause for years lived in disability. Most people with acute low back pain improve rapidly, but 4% to 25% of patients become chronic. Since the previous systematic reviews on the subject, a large number of new studies have been conducted. The objective of this article was to review the evidence of the prognostic factors behind nonspecific chronic low back pain. A systematic literature search was performed without date limitation from the MEDLINE, Cochrane library, and Medic databases. Specific inclusion criteria were used, and risk factors before the onset of chronic symptoms were searched. Study quality was assessed by 2 independent reviewers. One hundred eleven full articles were read for potential inclusion, and 25 articles met all the inclusion criteria. One study was rated as good quality, 19 studies were rated as fair quality, and 5 articles were rated as poor quality. Higher pain intensity, higher body weight, carrying heavy loads at work, difficult working positions, and depression were the most frequently observed risk factors for chronic low back pain. Maladaptive behavior strategies, general anxiety, functional limitation during the episode, smoking, and particularly physical work were also explicitly predictive of chronicity. According to this systematic review, several prognostic factors from the biomechanical, psychological and psychosocial point of view are significant for chronicity in low back pain.


Auditory verbal hallucinations in persons with and without a need for care.
Auditory verbal hallucinations (AVH) are complex experiences that occur in the context of various clinical disorders. AVH also occur in individuals from the general population who have no identifiable psychiatric or neurological diagnoses. This article reviews research on AVH in nonclinical individuals and provides a cross-disciplinary view of the clinical relevance of these experiences in defining the risk of mental illness and need for care. Prevalence rates of AVH vary according to measurement tool and indicate a continuum of experience in the general population. Cross-sectional comparisons of individuals with AVH with and without need for care reveal similarities in phenomenology and some underlying mechanisms but also highlight key differences in emotional valence of AVH, appraisals, and behavioral response. Longitudinal studies suggest that AVH are an antecedent of clinical disorders when combined with negative emotional states, specific cognitive difficulties and poor coping, plus family history of psychosis, and environmental exposures such as childhood adversity. However, their predictive value for specific psychiatric disorders is not entirely clear. The theoretical and clinical implications of the reviewed findings are discussed, together with directions for future research.


Physical activity attenuates the influence of FTO variants on obesity risk: a meta-analysis of 218,166 adults and 19,268 children.
The FTO gene harbors the strongest known susceptibility locus for obesity. While many individual studies have suggested that physical activity (PA) may attenuate the effect of FTO on obesity risk, other studies have not been able to confirm this interaction. To confirm or refute unambiguously whether PA attenuates the association of FTO with obesity risk, we meta-analyzed data from 45 studies of adults (n = 218,166) and nine studies of children and adolescents (n = 19,268). All studies identified to have data on the FTO rs9939609 variant (or any proxy [r(2)>0.8]) and PA were invited to participate, regardless of ethnicity or age of the participants. PA was standardized by categorizing it into a dichotomous variable (physically inactive versus active) in each study. Overall, 25% of adults and 13% of children were categorized as inactive. Interaction analyses were performed within each study by including the FTO×PA interaction term in an additive model, adjusting for age and sex. Subsequently, random effects meta-analysis was used to pool the interaction terms. In adults, the minor (A-) allele of rs9939609 increased the odds of obesity by 1.23-fold/allele (95% CI 1.20-1.26), but PA attenuated this effect (p(interaction) = 0.001). More specifically, the minor allele of rs9939609 increased the odds of obesity less in the physically active group (odds ratio = 1.22/allele, 95% CI 1.19-1.25) than in the inactive group (odds ratio = 1.30/allele, 95% CI 1.24-1.36). No such interaction was found in children and adolescents. The association of the FTO risk allele with the odds of obesity is attenuated by 27% in physically active adults, highlighting the importance of PA in particular in those genetically predisposed to obesity.


Development of an in vitro assay and demonstration of Plasmodium berghei liver-stage inhibition by TRAP-specific CD8+ T cells.
The development of an efficacious vaccine against the Plasmodium parasite remains a top priority. Previous research has demonstrated the ability of a prime-boost virally vectored sub-unit vaccination regimen, delivering the liver-stage expressed malaria antigen TRAP, to produce high levels of antigen-specific T cells. The liver-stage of malaria is the main target of T cell-mediated immunity, yet a major challenge in assessing new T cell inducing vaccines has been the lack of a suitable pre-clinical assay. We have developed a flow-cytometry based in vitro T cell killing assay using a mouse hepatoma cell line, Hepa1-6, and Plasmodium berghei GFP expressing sporozoites. Using this assay, P. berghei TRAP-specific CD8+ T cell enriched splenocytes were shown to inhibit liver-stage parasites in an effector-to-target ratio dependent manner. Further development of this assay using human hepatocytes and P. falciparum would provide a new method to pre-clinically screen vaccine candidates and to elucidate mechanisms of protection in vitro.


A new family of nitrate/nitrite transporters involved in denitrification.
Denitrifying bacteria carry out nitrate and nitrite respiration inside and outside the cell, respectively. In Thermus thermophilus, nitrate and nitrite transport processes are carried out by major facilitator superfamily (MFS) transporters. The sequence of the nar operon of nitrate-only respiring strains of T. thermophilus includes two tandemly organized MFS transporter genes (narK and narT) of the NarK1 and NarK2 families. Both can function as nitrate/nitrite antiporters, but NarK has been proposed as more specific for nitrate whereas NarT more specific for nitrite. In some nitrate- and nitrite-respiring strains of the same species, a single MFS transporter (NarO) belonging to a different MFS subfamily appears. To analyze the role of this single MFS in the same genetic context, we transferred the two types of nar operon to the aerobic strain HB27, and further included in both of them the ability to respire nitrite. The new denitrifying strains HB27dn, with two MFS, and HB27dp, with a single one, were used to isolate mutants devoid of transporters. Through in trans complementation experiments, we demonstrate that the NarO single MFS works efficiently in the transport of both nitrate and nitrite.


Calcium homeostasis, signalling and protein phosphorylation during calcium-induced conidiation in Penicillium notatum.
Cytosolic free calcium concentration [Ca2+]c of protoplasts from Penicillium notatum was measured using the permeant acetoxy ester (quin-2-AM) of the calcium-chelating fluorescent dye quin-2. Low uptake of the ester occurred at pH 5.8-7.0 and its subsequent hydrolysis was low. Uptake was promoted by an external pH of 5.0 and significant hydrolysis to quin-2 achieved by adjustment of the internal pH to 7.2, which was near the optimum of the carboxylic esterases responsible for the hydrolysis. Uptake of Ca2+ was biphasic with the average cell calcium concentration of protoplasts increasing from an initial value of 2 mumol to 50 mumol (kg cell water)-1, during attainment of the steady state after 30 min, at which time [Ca2+]c was unchanged at 20 nM but increased to 182 nM at 2-6 h exposure to 2.5 mM-Ca2+. Broadly similar changes in [Ca2+]c were found in protoplasts derived from mycelium samples exposed to Ca2+ over the same period of time. The location of Ca2+ was determined in subfractionated organelles and characterized using enzyme markers and electron microscopy. In 32 h mycelium preloaded with Ca2+ for 6 h, Ca2+ was located principally in the mitochondria with lower concentrations associated with the endoplasmic reticulum, Golgi, vacuoles and plasma membrane components. Calcium was not released by inositol 1,4,5-trisphosphate or the calcium ionophore A23187 from any subcellular fractions obtained from mycelium on Percoll gradients, nor from preparations of vacuoles or plasmalemma vesicles, except in the case of mitochondria where rapid release of the ion was achieved by the addition of 2-5 microM-A23187. The anti-calmodulin agent calmidazolium (R24571) greatly reduced sporulation when addition preceded that of Ca2+. Calcium-induced cultures showed massive novel protein phosphorylation 2 h after addition of the ion which was virtually eliminated by R24571, whilst 1 h and 4-6 h protein phosphorylations, which were also present to some degree in vegetative controls, were substantially reduced. Two-dimensional SDS-PAGE analysis of phosphoproteins confirmed that Ca(2+)-induced mycelium had enhanced capacity for calmodulin-mediated phosphorylation relative to corresponding vegetative cells and that complex differential changes in such phosphorylations occurred during Ca(2+)-induction of the sporulation process.


Synchrotron X-ray tomographic microscopy of fossil embryos.
Fossilized embryos from the late Neoproterozoic and earliest Phanerozoic have caused much excitement because they preserve the earliest stages of embryology of animals that represent the initial diversification of metazoans. However, the potential of this material has not been fully realized because of reliance on traditional, non-destructive methods that allow analysis of exposed surfaces only, and destructive methods that preserve only a single two-dimensional view of the interior of the specimen. Here, we have applied synchrotron-radiation X-ray tomographic microscopy (SRXTM), obtaining complete three-dimensional recordings at submicrometre resolution. The embryos are preserved by early diagenetic impregnation and encrustation with calcium phosphate, and differences in X-ray attenuation provide information about the distribution of these two diagenetic phases. Three-dimensional visualization of blastomere arrangement and diagenetic cement in cleavage embryos resolves outstanding questions about their nature, including the identity of the columnar blastomeres. The anterior and posterior anatomy of embryos of the bilaterian worm-like Markuelia confirms its position as a scalidophoran, providing new insights into body-plan assembly among constituent phyla. The structure of the developing germ band in another bilaterian, Pseudooides, indicates a unique mode of germ-band development. SRXTM provides a method of non-invasive analysis that rivals the resolution achieved even by destructive methods, probing the very limits of fossilization and providing insight into embryology during the emergence of metazoan phyla.


The effect of body mass index on survival in advanced epithelial ovarian cancer.
Controversy remains regarding the effect of obesity on the survival of patients with ovarian cancer in Asia. This study examined the impact of obesity on the survival outcomes in advanced epithelial ovarian cancer (EOC) using Asian body mass index (BMI) criteria. The medical records of patients undergoing surgery for advanced (stage III and IV) EOC were reviewed. Statistical analyses included ANOVA, chi-square test, Kaplan-Meier survival and Cox regression analysis. Among all 236 patients, there were no differences in overall survival according to BMI except in underweight patients. In a multivariate Cox analysis, surgical optimality and underweight status were independent and significant prognostic factors for survival (HR, 2.302; 95% CI, 1.326-3.995; P=0.003 and HR, 8.622; 95% CI, 1.871-39.737; P = 0.006, respectively). In the subgroup of serous histology and optimal surgery, overweight and obese I patients showed better survival than normal weight patients (P = 0.012). We found that underweight BMI and surgical optimality are independent risk factors for the survival of patients with advanced ovarian cancer. High BMI groups (overweight, obese I and II) are not associated with the survival of advanced EOC patient. However, in the subgroup of EOC patients with serous histology and after optimal operation, overweight and obese I group patients show better survival than the normal weight group patients.


Meta-analysis of 375,000 individuals identifies 38 susceptibility loci for migraine.
Migraine is a debilitating neurological disorder affecting around one in seven people worldwide, but its molecular mechanisms remain poorly understood. There is some debate about whether migraine is a disease of vascular dysfunction or a result of neuronal dysfunction with secondary vascular changes. Genome-wide association (GWA) studies have thus far identified 13 independent loci associated with migraine. To identify new susceptibility loci, we carried out a genetic study of migraine on 59,674 affected subjects and 316,078 controls from 22 GWA studies. We identified 44 independent single-nucleotide polymorphisms (SNPs) significantly associated with migraine risk (P < 5 × 10(-8)) that mapped to 38 distinct genomic loci, including 28 loci not previously reported and a locus that to our knowledge is the first to be identified on chromosome X. In subsequent computational analyses, the identified loci showed enrichment for genes expressed in vascular and smooth muscle tissues, consistent with a predominant theory of migraine that highlights vascular etiologies.


Access To Care And Affordability Have Improved Following Affordable Care Act Implementation; Problems Remain.
There is growing evidence that millions of adults have gained insurance coverage under the Affordable Care Act, but less is known about how access to and affordability of care may be changing. This study used data from the Health Reform Monitoring Survey to describe changes in access and affordability for nonelderly adults from September 2013, just prior to the first open enrollment period in the Marketplace, to March 2015, after the end of the second open enrollment period. Overall, we found strong improvements in access to care for all nonelderly adults and across income and state Medicaid expansion groups. We also found improvements in the affordability of care for all adults and for low- and moderate-income adults. Despite this progress, there were still large gaps in access and affordability in March 2015, particularly for low-income adults.


Review of deep learning algorithms for the automatic detection of intracranial hemorrhages on computed tomography head imaging.
Artificial intelligence is a rapidly evolving field, with modern technological advances and the growth of electronic health data opening new possibilities in diagnostic radiology. In recent years, the performance of deep learning (DL) algorithms on various medical image tasks have continually improved. DL algorithms have been proposed as a tool to detect various forms of intracranial hemorrhage on non-contrast computed tomography (NCCT) of the head. In subtle, acute cases, the capacity for DL algorithm image interpretation support might improve the diagnostic yield of CT for detection of this time-critical condition, potentially expediting treatment where appropriate and improving patient outcomes. However, there are multiple challenges to DL algorithm implementation, such as the relative scarcity of labeled datasets, the difficulties in developing algorithms capable of volumetric medical image analysis, and the complex practicalities of deployment into clinical practice. This review examines the literature and the approaches taken in the development of DL algorithms for the detection of intracranial hemorrhage on NCCT head studies. Considerations in crafting such algorithms will be discussed, as well as challenges which must be overcome to ensure effective, dependable implementations as automated tools in a clinical setting.


miRNAs are Essential for the Survival and Maturation of Cortical Interneurons.
Complex and precisely orchestrated genetic programs contribute to the generation, migration, and maturation of cortical GABAergic interneurons (cIN). Yet, little is known about the signals that mediate the rapid alterations in gene expression that are required for cINs to transit through a series of developmental steps leading to their mature properties in the cortex. Here, we investigated the function of post-transcriptional regulation of gene expression by microRNAs on the development of cIN precursors. We find that conditional removal of the RNAseIII enzyme Dicer reduces the number of cINs in the adult mouse. Dicer is further necessary for the morphological and molecular maturation of cINs. Loss of mature miRNAs affects cINs development by impairing migration and differentiation of this cell type, while leaving proliferation of progenitors unperturbed. These developmental defects closely matched the abnormal expression of molecules involved in apoptosis and neuronal specification. In addition, we identified several miRNAs that are selectively upregulated in the postmitotic cINs, consistent with a role of miRNAs in the post-transcriptional control of the differentiation and apoptotic programs essential for cIN maturation. Thus, our results indicate that cIN progenitors require Dicer-dependent mechanisms to fine-tune the migration and maturation of cINs.


Plague-Positive Mouse Fleas on Mice Before Plague Induced Die-Offs in Black-Tailed and White-Tailed Prairie Dogs.
Plague is a lethal zoonotic disease associated with rodents worldwide. In the western United States, plague outbreaks can decimate prairie dog (Cynomys spp.) colonies. However, it is unclear where the causative agent, Yersinia pestis, of this flea-borne disease is maintained between outbreaks, and what triggers plague-induced prairie dog die-offs. Less susceptible rodent hosts, such as mice, could serve to maintain the bacterium, transport infectious fleas across a colony, or introduce the pathogen to other colonies, possibly facilitating an outbreak. Here, we assess the potential role of two short-lived rodent species, North American deer mice (Peromyscus maniculatus) and Northern grasshopper mice (Onychomys leucogaster) in plague dynamics on prairie dog colonies. We live-trapped short-lived rodents and collected their fleas on black-tailed (Cynomys ludovicianus, Montana and South Dakota), white-tailed (Cynomys leucurus, Utah and Wyoming), and Utah prairie dog colonies (Cynomys parvidens, Utah) annually, from 2013 to 2016. Plague outbreaks occurred on colonies of all three species. In all study areas, deer mouse abundance was high the year before plague-induced prairie dog die-offs, but mouse abundance per colony was not predictive of plague die-offs in prairie dogs. We did not detect Y. pestis DNA in mouse fleas during prairie dog die-offs, but in three cases we found it beforehand. On one white-tailed prairie dog colony, we detected Y. pestis positive fleas on one grasshopper mouse and several prairie dogs live-trapped 10 days later, months before visible declines and plague-confirmed mortality of prairie dogs. On one black-tailed prairie dog colony, we detected Y. pestis positive fleas on two deer mice 3 months before evidence of plague was detected in prairie dogs or their fleas and also well before a plague-induced die-off. These observations of plague positive fleas on mice could represent early spillover events of Y. pestis from prairie dogs or an unknown reservoir, or possible movement of infectious fleas by mice.


Obligatory heterotetramerization of three previously uncharacterized Kv channel alpha-subunits identified in the human genome.
Voltage-gated K(+) channels control excitability in neuronal and various other tissues. We identified three unique alpha-subunits of voltage-gated K(+)-channels in the human genome. Analysis of the full-length sequences indicated that one represents a previously uncharacterized member of the Kv6 subfamily, Kv6.3, whereas the others are the first members of two unique subfamilies, Kv10.1 and Kv11.1. Although they have all of the hallmarks of voltage-gated K(+) channel subunits, they did not produce K(+) currents when expressed in mammalian cells. Confocal microscopy showed that Kv6.3, Kv10.1, and Kv11.1 alone did not reach the plasma membrane, but were retained in the endoplasmic reticulum. Yeast two-hybrid experiments failed to show homotetrameric interactions, but showed interactions with Kv2.1, Kv3.1, and Kv5.1. Co-expression of each of the previously uncharacterized subunits with Kv2.1 resulted in plasma membrane localization with currents that differed from typical Kv2.1 currents. This heteromerization was confirmed by co-immunoprecipitation. The Kv2 subfamily consists of only two members and uses interaction with "silent subunits" to diversify its function. Including the subunits described here, the "silent subunits" represent one-third of all Kv subunits, suggesting that obligatory heterotetramer formation is more widespread than previously thought.


Associations of heart failure with sleep quality: the Rotterdam Study.
The prevalence of sleep disturbances and heart failure increases with age. We aimed to evaluate the associations of incident heart failure and cardiac dysfunction with changes in sleep quality. This prospective population-based study was conducted in the Rotterdam Study. Of the 3445 eligible persons (mean age 72.0±7.1 years) available for cross-sectional analyses, 8.9% (n = 307) had prevalent clinical heart failure. In longitudinal analyses, 1989 eligible persons (mean age 70.0±5.8 years) were followed for an average of 6.5±0.4 years, of which 4.6% (n = 91) had prevalent or incident clinical heart failure. Heart failure was assessed according to European Society of Cardiology criteria. To estimate cardiac function, we measured left ventricular fractional shortening, left ventricular systolic function, and E/A ratio by echocardiography. Heart failure and cardiac dysfunction were studied with linear regression in relation to sleep quality, assessed by the Pittsburgh Sleep Quality Index. No associations between clinical heart failure and sleep quality were observed in cross-sectional analyses. Clinical heart failure predicted a reduction of sleep quality (B = 1.00 points on the Pittsburgh Sleep Quality Index; 95% CI 0.40, 1.60) in longitudinal assessment. This association was driven by the sleep onset latency and sleep quality components of the Pittsburgh Sleep Quality Index. Cardiac dysfunction was not related to sleep quality in cross-sectional or longitudinal analyses. Clinical heart failure, but not cardiac dysfunction measured by echocardiography, increases the risk of poor sleep quality in the general population over time. These findings suggest that clinical manifestations of heart failure negatively affect sleep.


Who plays what? Participation profiles in chance versus skill-based gambling.
To determine whether gambling participation falls into skill and chance-based categories and, if so, to determine the socio-demographic characteristics associated with these different categories. A cross-sectional analysis of all respondents to the 2005 Northern Territory Gambling Prevalence Survey who gambled in the 12 months prior to the survey. Factor analysis was employed to determine whether a chance versus skill-based dichotomy described the structure of gambling participation. Gambler preference groups were constructed using the median of rotated factor scores. Multinomial logit regression was then used to determine independent associations between explanatory variables and categories of gambler preferences. The skill and chance-based dichotomy did describe player preferences for the sample of adult gamblers in the Northern Territory, Australia. Gender, age, household income, household structure and the geographic location (access to gambling opportunities) of respondents were all associated with different degrees of participation in skill and chance based gambling activities. Notably, respondents 35 years and over were significantly over-represented in the low-skill/high-chance participation group, and under-represented in the high-skill/low-chance group. It is clear that the term gambling is a confounding rubric that hides differences both in the type of activity and the socio-demographic profiles of participants. An examination of the latter raises important questions about the role of chance in later life, as well as the role of self-determination in gambling for other groups, particularly younger men.


Off-label use and manipulations of antiepileptic drugs in children: Analysis of the outpatient prescriptions in a tertiary center.
Little is known about off-label use and manipulations to achieve the prescribed dose of antiepileptic drugs (AEDs) in outpatient prescriptions. This study aimed to evaluate this practice in a tertiary center for child epilepsy. We reviewed off-label use and manipulations of AEDs delivered to the outpatient's epilepsy clinic. Multivariate logistic regressions were used to determine the factors associated with off-label and manipulated uses. Five hundred eleven consultations generated 897 AED deliveries (1.75/consultation). Off-label use involved 182 (20.3%) of prescribed AEDs. Factors associated with off-label use were polytherapy and new AEDs while increase of age and nondevelopmental and structural-metabolic etiologies have a protective effect. Among the 1725 doses of AEDs prescribed per day, 33.5% generated manipulations (n=582): 40% inadequate (n=237) and 60% adequate (203 syrups, 112 scored tablets, 30 drops medicine). Polytherapy (p<10-4) and the absence of market authorization significantly favored manipulations whereas the increase in age restricted them. Off-label use and manipulations of AEDs remain an important problem in home care of children with epilepsy. This is mainly a concern for the most vulnerable groups, i.e., young patients, patients undergoing polytherapy, and patients with developmental and epileptic encephalopathy (DEE). International initiatives have been launched to improve the availability of labeled and adapted drugs in this population.


Selective inhibition of ASIC1a confers functional and morphological neuroprotection following traumatic spinal cord injury.
Tissue loss after spinal trauma is biphasic, with initial mechanical/haemorrhagic damage at the time of impact being followed by gradual secondary expansion into adjacent, previously unaffected tissue. Limiting the extent of this secondary expansion of tissue damage has the potential to preserve greater residual spinal cord function in patients. The acute tissue hypoxia resulting from spinal cord injury (SCI) activates acid-sensing ion channel 1a (ASIC1a). We surmised that antagonism of this channel should provide neuroprotection and functional preservation after SCI. We show that systemic administration of the spider-venom peptide PcTx1, a selective inhibitor of ASIC1a, improves locomotor function in adult Sprague Dawley rats after thoracic SCI. The degree of functional improvement correlated with the degree of tissue preservation in descending white matter tracts involved in hind limb locomotor function. Transcriptomic analysis suggests that PcTx1-induced preservation of spinal cord tissue does not result from a reduction in apoptosis, with no evidence of down-regulation of key genes involved in either the intrinsic or extrinsic apoptotic pathways. We also demonstrate that trauma-induced disruption of blood-spinal cord barrier function persists for at least 4 days post-injury for compounds up to 10 kDa in size, whereas barrier function is restored for larger molecules within a few hours. This temporary loss of barrier function provides a " treatment window" through which systemically administered drugs have unrestricted access to spinal tissue in and around the sites of trauma. Taken together, our data provide evidence to support the use of ASIC1a inhibitors as a therapeutic treatment for SCI. This study also emphasizes the importance of objectively grading the functional severity of initial injuries (even when using standardized impacts) and we describe a simple scoring system based on hind limb function that could be adopted in future studies.


Cytoprotective effects of ferritin on doxorubicin-induced breast cancer cell death.
Ferritin is a major iron storage protein and essential for iron homeostasis. It has a wide range of functions in the body including iron delivery, immunosuppression, angiogenesis, and cell proliferation. Ferritin is overexpressed in many cancer cells, but its precise role in cancer is unclear. In the present study, we examined the functional roles of ferritin in protecting the MCF-7 breast cancer cell line against treatment with the chemotherapeutic agent doxorubicin. The effects of ferritin (human liver ferritin) and doxorubicin on the human MCF-7 breast cancer cell line were evaluated using the cell viability assay. The impact of decreasing ferritin light chain (FTL) and ferritin heavy chain (FTH) expression on doxorubicin sensitivity was assessed using siRNA. Reactive oxygen species (ROS) was also measured using the fluorescence probe CM-H2DCFDA. The mechanism of modulated chemosensitivity was evaluated by western blot analysis. Ferritin treatment activated MCF-7 cell proliferation in a concentration- and time-dependent manner. While treatment with doxorubicin alone significantly increased intracelullar ROS production, the addition of ferritin decreased this ROS formation, thereby reducing doxorubicin‑induced MCF-7 cell death. The inhibition of FTL and FTH by siRNA sensitized cells to doxorubicin. Treatment with doxorubicin alone significantly induced the cell cycle‑dependent kinase inhibitor protein p21, whereas ferritin reduced p21 expression. Thus, ferritin plays a critical role in protecting MCF-7 cells against the chemotherapeutic drug doxorubicin. A targeted reduction of ferritin may be a useful strategy for overcoming chemoresistance in breast cancer.


Restoration of the organizer after radical ablation of Hensen's node and the anterior primitive streak in the chick embryo.
The region of the amniote embryo corresponding to Spemann's organizer in amphibians is Hensen's node, which lies at the tip of the primitive streak during gastrulation. It is a special site in the embryo that can be defined by the presence of progenitors of several axial tissues (notochord, prechordal mesoderm, somites, gut endoderm), by characteristic cell movements, by specific patterns of gene expression (e.g. goosecoid, HNF-3beta, Sonic hedgehog) and, most importantly, by its ability to induce a complete axis, including host-derived neural tissue, when transplanted to an ectopic site. Here, we show that complete removal not only of the node but also of the anterior 40% of the primitive streak leads to the development of normal embryos containing cells with all the fates normally produced by the node. Cell movement pathways through the regenerated node are identical to those seen in the normal embryo. The patterns of expression of HNF-3beta and Sonic hedgehog are also restored, as is their left/right asymmetry, but goosecoid expression is not. When the regenerated node is transplanted to an ectopic site, it induces a complete embryonic axis that includes a fully patterned, host-derived central nervous system. Analysis of the properties of cells surrounding the site of ablation shows that they acquire these properties gradually. We suggest that the organizer is a region of the embryo that is defined by cell interactions and that the node normally inhibits the organizer state in neighbouring cells.


Dialkylcarbamoyl Chloride Dressings in the Prevention of Surgical Site Infections after Nonimplant Vascular Surgery.
Dressings coated with dialkylcarbamoyl chloride (DACC) are highly hydrophobic and irreversibly bind multiple types of bacteria, trapping them in the dressing and reducing the number of organisms at the wound surface. We aimed to assess the impact of DACC-coated postoperative dressings on the incidence of surgical site infection (SSI) in nonimplant vascular surgery patients. Two hundred patients undergoing nonimplant vascular surgery were prospectively recruited at a single vascular center. The initial 100 patients had their operative wounds dressed with conventional dressings followed by 100 patients who received DACC-coated postoperative dressings. Wounds were reviewed at day 5 and day 30 to determine the presence of SSI using the ASEPSIS scoring system. The variation in outcomes between groups was assessed using chi-squared test and logistic regression analysis to assess the effects of other variables, which may affect healing. Between August 1, 2015 and February 29, 2016, a total of 120 men and 80 women were recruited. The mean age was 63 (range 27-97) years, 92% were current or ex-smokers and 45.5% were diabetic. Rate of SSI at 5 days was significantly lower in the DACC group compared with standard dressings (1% vs. 10%, P < 0.05). There was no difference in the rates of SSI at 30 days. Logistic regression suggested that the type of dressing used was the most prominent predictor variable for the presence of early SSI (P = 0.028, odds ratio = 0.09, 95% confidence interval: 0.01-0.77). DACC-coated dressings were associated with a significant reduction in SSI rates in the early postoperative period.


FAmily-Led RehabiliTaTion aftEr Stroke in INDia: the ATTEND pilot study.
The aim of this pilot study was to determine the feasibility of a multicenter, randomized, controlled trial in India of a family-led, trained caregiver-delivered, home-based rehabilitation intervention vs. routine care. A prospective, randomized (within seven-days of hospital admission), blinded outcome assessor, controlled trial of structured home-based rehabilitation delivered by trained and protocol-guided family caregivers (intervention) vs. routine care alone (control) was conducted in patients with residual disability. Key feasibility measures were recruitment, acceptance and adherence to assessment procedures, and follow-up of participants over six-months. CTRI/2014/10/005133. A total of 104 patients from the stroke unit at Christian Medical College, Ludhiana were recruited over nine-months. Recruitment was feasible and accepted by patients and their carers. Important observations were made regarding potential unblinding of the participants, contamination of therapy between the randomized groups, organization of home visits, and resources required for a multicenter study. The pilot study established the feasibility of conducting a large-scale study of family-led, trained caregiver-delivered, home-based stroke rehabilitation in a low resource setting. The main phase of the trial 'ATTEND' is currently underway in over 10 centers in India.


Computational modeling of seizure dynamics using coupled neuronal networks: factors shaping epileptiform activity.
Epileptic seizure dynamics span multiple scales in space and time. Understanding seizure mechanisms requires identifying the relations between seizure components within and across these scales, together with the analysis of their dynamical repertoire. Mathematical models have been developed to reproduce seizure dynamics across scales ranging from the single neuron to the neural population. In this study, we develop a network model of spiking neurons and systematically investigate the conditions, under which the network displays the emergent dynamic behaviors known from the Epileptor, which is a well-investigated abstract model of epileptic neural activity. This approach allows us to study the biophysical parameters and variables leading to epileptiform discharges at cellular and network levels. Our network model is composed of two neuronal populations, characterized by fast excitatory bursting neurons and regular spiking inhibitory neurons, embedded in a common extracellular environment represented by a slow variable. By systematically analyzing the parameter landscape offered by the simulation framework, we reproduce typical sequences of neural activity observed during status epilepticus. We find that exogenous fluctuations from extracellular environment and electro-tonic couplings play a major role in the progression of the seizure, which supports previous studies and further validates our model. We also investigate the influence of chemical synaptic coupling in the generation of spontaneous seizure-like events. Our results argue towards a temporal shift of typical spike waves with fast discharges as synaptic strengths are varied. We demonstrate that spike waves, including interictal spikes, are generated primarily by inhibitory neurons, whereas fast discharges during the wave part are due to excitatory neurons. Simulated traces are compared with in vivo experimental data from rodents at different stages of the disorder. We draw the conclusion that slow variations of global excitability, due to exogenous fluctuations from extracellular environment, and gap junction communication push the system into paroxysmal regimes. We discuss potential mechanisms underlying such machinery and the relevance of our approach, supporting previous detailed modeling studies and reflecting on the limitations of our methodology.


Assessing protein conformational landscapes: integration of DEER data in Maximum Occurrence analysis.
The properties of the conformational landscape of a biomolecule are of capital importance to understand its function. It is widely accepted that a statistical ensemble is far more representative than a single structure, especially for proteins with disordered regions. While experimental data provide the most important handle on the conformational variability that the system is experiencing, they usually report on either time or ensemble averages. Since the available conformations largely outnumber the (independent) available experimental data, the latter can be equally well reproduced by a variety of ensembles. We have proposed the Maximum Occurrence (MaxOcc) approach to provide an upper bound of the statistical weight of each conformation. This method is expected to converge towards the true statistical weights by increasing the number of independent experimental datasets. In this paper we explore the ability of DEER (Double Electron Electron Resonance) data, which report on the distance distribution between two spin labels attached to a biomolecule, to restrain the MaxOcc values and its complementarity to previously introduced experimental techniques such as NMR and Small-Angle X-ray Scattering. We here present the case of Ca2+ bound calmodulin (CaM) as a test case and show that DEER data impose a sizeable reduction of the conformational space described by high MaxOcc conformations.


Fertilizer response and nitrogen use efficiency in African smallholder maize farms.
Improving fertilizer recommendations for farmers is essential to increase food security in smallholder landscapes. Currently, blanket recommendations are provided across agro-ecological zones, although fertilizer response and nutrient use efficiency by maize crop are spatially variable. We aimed to identify factors that could help to refine fertilizer recommendation by analyzing the variability in fertilizer response (FR) and the agronomic nitrogen use efficiency (N-AE). A literature search for on-farm studies across Kenya and Sub-Sahara Africa (SSA), excluding Kenya, yielded 71 publications. The variability in FR was studied using a meta-analysis whereas key factors that influence FR and N-AE were studied with linear regression models. On average, the FR was 2, but it varied considerably from 1 to 28.5 (excluding outliers). In SSA, 18% of the plots were non-responsive plots with an FR < 1. The main factors affecting N-AE for Kenya were P-Olsen, silt content, soil pH, clay and rainfall, whereas only soil pH, exchangeable K and texture were important for SSA. However, our study indicates that available data on soil, climate and management factors could explain only a small part (< 33%) of the variation in FR and N-AE. Soil pH, P-Olsen, silt content, and rainfall had significant but low levels of power in explaining variation in FR and N-AE. Our findings indicate that strategies to refine fertilizer recommendation should include information on soil types and soil properties.


Data for tracking SDGs: challenges in capturing neonatal data from hospitals in Kenya.
Target 3.2 of the United Nations Sustainable Development Goals (SDGs) is to reduce neonatal mortality. In low-income and middle-income countries (LMICs), the District Health Information Software, V.2 (DHIS2) is widely used to help improve indicator data reporting. There are few reports on its use for collecting neonatal hospital data that are of increasing importance as births within facilities increase. To address this gap, we investigated implementation experiences of DHIS2 in LMICs and mapped the information flow relevant for neonatal data reporting in Kenyan hospitals. A narrative review of published literature and policy documents from LMICs was conducted. Information gathered was used to identify the challenges around DHIS2 and to map information flows from healthcare facilities to the national level. Two use cases explore how newborn data collection and reporting happens in hospitals. The results were validated, adjusted and system challenges identified. Literature and policy documents report that DHIS2 is a useful tool with strong technical capabilities, but significant challenges can emerge with the implementation. Visualisations of information flows highlight how a complex, people-based and paper-based subsystem for inpatient information capture precedes digitisation. Use cases point to major challenges in these subsystems in accurately identifying newborn deaths and appropriate data for the calculation of mortality even in hospitals. DHIS2 is a tool with potential to improve availability of health information that is key to health systems, but it critically depends on people-based and paper-based subsystems. In hospitals, the subsystems are subject to multiple micro level challenges. Work is needed to design and implement better standardised information processes, recording and reporting tools, and to strengthen the information system workforce. If the challenges are addressed and data quality improved, DHIS2 can support countries to track progress towards the SDG target of improving neonatal mortality.


Defect solitons in kagome optical lattices.
We report the existence and stability of solitons in kagome optical lattices with a defect in photorefractive crystal under focusing saturable nonlinearity. For different types of defects, solitons will exist in different gaps. For a positive defect, the solitons only exist in the semi-infinite gap and only stably exist in the low power region. For a negative defect, the solitons exist both in the semi-infinite gap and the first gap. With an increasing of the negative defect depth, the stable region in the semi-infinite will be narrowed, while solitons will be firstly unstable in the high power region of the first gap, and finally solitons will be not stable in the whole first gap.


Chitosan binding onto the epigallocatechin-loaded ferritin nanocage enhances its transport across Caco-2 cells.
The effect of chitosan decoration on the transport of epigallocatechin (EGC)-encapsulated ferritin cage across the Caco-2 cells was investigated. After the encapsulation of EGC in apo-red bean (adzuki) ferritin (apoRBF), the EGC-loaded apoRBF nanoparticle (ER) was fabricated with an encapsulation ratio of 11.6% (w/w). The results indicated that different chitosan molecules (with molecular weights of 980, 4600, 46 000, and 210 000 Da) could attach onto the apoRBF via electrostatic interactions to form ER-chitosan complexes (ERCs) (ERCs980, ERCs4600, ERCs46000, and ERCs210000). ERCs980 and ERCs4600 retained the typical shell-like morphology of ferritin with a size distribution of 12 nm and showed weak negative zeta-potentials at pH 6.7, while ERCs46000 and ERCs210000 significantly aggregated. Furthermore, the transport of EGC in ERCs980 and ERCs4600 across the Caco-2 cells was enhanced by the transferrin receptor 1 (TfR-1)-mediated absorption pathway, demonstrating that chitosan molecules with low molecular weights of 980 and 4600 Da were beneficial to the absorption of EGC based on the ferritin cage. This study will facilitate the application of ferritin-chitosan materials for fabricating the core-shell platform for encapsulation and bioavailability enhancement of bioactive molecules.


Antioxidant activity of cysteine, tryptophan, and methionine residues in continuous phase beta-lactoglobulin in oil-in-water emulsions.
Proteins dispersed in the continuous phase of oil-in-water emulsions are capable of inhibiting lipid oxidation reactions. The antioxidant activity of these proteins is thought to encompass both free radical scavenging by amino acid residues and chelation of prooxidative transition metals; however, the precise mechanism by which this occurs remains unclear. In this study, the oxidative stability of cysteine, tryptophan, and methionine residues in continuous phase beta-lactoglobulin (beta-Lg) in a Brij-stabilized menhaden oil-in-water emulsion was determined. The presence of low concentrations of continuous phase beta-Lg (250 and 750 microg/mL) significantly inhibited lipid oxidation as determined by lipid hydroperoxides and thiobarbituric acid reactive substances analysis. It was observed that cysteine oxidized before tryptophan in beta-Lg, and both residues oxidized before lipid oxidation could be detected. No oxidation of the methionine residues of beta-Lg was observed despite its reported high oxidative susceptibility. It is conceivable that surface exposure of amino acid residues greatly affects their oxidation kinetics, which may explain why some residues are preferentially oxidized relative to others. Further elucidation of the mechanisms governing free radical scavenging of amino acids could lead to more effective applications of proteins as antioxidants within oil-in-water food emulsions.


A conditional allele of the Saccharomyces cerevisiae HOP1 gene is suppressed by overexpression of two other meiosis-specific genes: RED1 and REC104.
The HOP1 gene of Saccharomyces cerevisiae is believed to encode a protein component of the synaptonemal complex, the structure formed when homologous chromosomes synapse during meiotic prophase. Five new mutant alleles (three conditional, two nonconditional) of HOP1 were identified by screening EMS-mutagenized cells for a failure to complement the spore viability defect of a hop1 null allele. Two high copy plasmids were found that partially suppress the temperature-sensitive spore inviability phenotype of one of these alleles, hop1-628. The suppression is allele-specific; no effect of the plasmids is observed in hop1 null diploids. Mutation of either of the two suppressor genes results in recessive spore lethality, indicating that these genes play important roles during meiosis. The DNA sequence of one high copy suppressor gene matched that of RED1, a previously identified meiosis-specific gene. Our data strongly support the idea that RED1 protein is also a component of the synaptonemal complex and further suggest that the RED1 and HOP1 gene products may interact. The second suppressor maps to the right arm of chromosome VIII distal to CDC12 and is REC104, a meiosis-specific gene believed to act early in meiosis.


Anteroposterior atlantoaxial subluxation in cervical spine osteoarthritis: case reports and review of the literature.
Nontraumatic anteroposterior atlantoaxial subluxation (AAS) has been described in several rheumatic or inherited disorders, especially rheumatoid arthritis and to a lesser extent the inflammatory spondyloarthropathies. We describe AAS secondary to osteoarthritis (OA) of the cervical spine in a 76-year-old man and a 73-year-old woman with severe cervical OA, symptomatic C1-C2 facet joints, and signs of generalized OA. Only 6 similar cases exist in the literature. OA should be added to the causes of AAS, and conversely AAS should be assessed in cases with severe OA of the upper cervical spine.


Genomic repeats, misassembly and reannotation: a case study with long-read resequencing of Porphyromonas gingivalis reference strains.
Without knowledge of their genomic sequences, it is impossible to make functional models of the bacteria that make up human and animal microbiota. Unfortunately, the vast majority of publicly available genomes are only working drafts, an incompleteness that causes numerous problems and constitutes a major obstacle to genotypic and phenotypic interpretation. In this work, we began with an example from the class Bacteroidia in the phylum Bacteroidetes, which is preponderant among human orodigestive microbiota. We successfully identify the genetic loci responsible for assembly breaks and misassemblies and demonstrate the importance and usefulness of long-read sequencing and curated reannotation. We showed that the fragmentation in Bacteroidia draft genomes assembled from massively parallel sequencing linearly correlates with genomic repeats of the same or greater size than the reads. We also demonstrated that some of these repeats, especially the long ones, correspond to misassembled loci in three reference Porphyromonas gingivalis genomes marked as circularized (thus complete or finished). We prove that even at modest coverage (30X), long-read resequencing together with PCR contiguity verification (rrn operons and an integrative and conjugative element or ICE) can be used to identify and correct the wrongly combined or assembled regions. Finally, although time-consuming and labor-intensive, consistent manual biocuration of three P. gingivalis strains allowed us to compare and correct the existing genomic annotations, resulting in a more accurate interpretation of the genomic differences among these strains. In this study, we demonstrate the usefulness and importance of long-read sequencing in verifying published genomes (even when complete) and generating assemblies for new bacterial strains/species with high genomic plasticity. We also show that when combined with biological validation processes and diligent biocurated annotation, this strategy helps reduce the propagation of errors in shared databases, thus limiting false conclusions based on incomplete or misleading information.


Risk factors for coliform bacteria in backcountry lakes and streams in the Sierra Nevada mountains: a 5-year study.
To provide a 5-year longitudinal assessment of risk of acquiring disease from Sierra Nevada Wilderness area lakes and streams. This study examines the relative risk factors for harmful water microorganisms, using coliforms as an indicator. Streams and lakes in the backcountry of Yosemite and Kings Canyon National Parks and neighboring wilderness areas were selected and water was analyzed each year over a 5-year period. A total of 364 samples from lakes or streams were chosen to statistically differentiate the risk categories based on land usage, as follows: 1) areas rarely visited by humans (Wild), 2) human day-use-only areas (Day Hike), 3) areas used by backpackers with overnight camping allowed (Backpack), 4) areas primarily impacted by horses or pack animals (Pack Animal), and 5) cattle and sheep grazing tracts (Cattle). Water was collected in sterile test tubes and Millipore coliform samplers. Water was analyzed at the university microbiology lab, where bacteria were harvested and then subjected to analysis using standardized techniques. Statistical analysis to compare site categories was performed utilizing Fisher exact test and analysis of variance. A total of 364 sampling sites were analyzed. Coliforms were found in 9% (4/47) of Wild site samples, 12% (5/42) of Day Hike site samples, and 18% (20/111) of Backpacker site samples. In contrast, 63% (70/111) of Pack Animal site samples yielded coliforms, and 96% (51/53) of samples from the Cattle areas grew coliforms. Differences between Backpacker vs Cattle or Pack Animal areas were significant at P <or= .05. All samples grew normal aquatic bacteria. Surface water from watersheds below cattle areas and those used by pack animals is at high risk for containing coliform organisms. Water from Wild, Day Hike, or Backpack sites poses far less risk for contamination by coliforms.


Parenthood, information and support on the internet. A literature review of research on parents and professionals online.
The aim of this article was to address questions on how parents use the internet to find information and support regarding children, health and family life. Another aim was to find out how professionals use the internet to provide support and information to parents. This was done by a literature review. Articles were searched for in five databases with a search strategy called "building block" approach. The review showed that the majority of today's parents search for both information and social support on the internet. However, there are considerable differences due to gender, age and socio-economic differences. First time middle class mothers aged 30-35 are most active in looking up health and parent information on the internet. In the same time, several studies report diminishing class differences on parent web sites. An important reason to the increasing number of parents who turn to the internet for information and interaction has shown to be the weakened support many of today's parents experience from their own parents, relatives and friends. Professionals have recognized the parents' great interest for going online and offer both information and support on the net. Many benefits are reported, for example the possibility to reach out to a wider audience and to increase access to organisations without an increase in costs. Other benefits include the possibility for parents to remain anonymous in their contacts with professionals and that parents' perceived need for information can be effectively met around the clock. Interventions for wider groups of parents, such as parent training on the net, are still very rare and more research is needed to evaluate different types of interventions on the net. However, most studies were empirical and lacked theoretical frameworks which leave questions on how we can more fully understand this phenomenon unanswered.


Immediate-early genes of murine cytomegalovirus: location, transcripts, and translation products.
Cloned genomic fragments from the region (0.769 to 0.818 map units) coding for immediate-early (IE) transcripts of murine cytomegalovirus (MCMV) were used to analyze the physical organization of this region, the direction of transcription, and the proteins synthesized in vitro. Three IE transcription units could be identified. From IE coding region 1 (ie1; 0.781 to 0.796 map units) a dominant 2.75-kilobase (kb) RNA was transcribed from right to left on the prototype arrangement of the MCMV genome which directed the synthesis of an 89,000-molecular-weight polypeptide (89K polypeptide), the major IE protein. This phosphoprotein (pp89) has been shown to be active in the regulation of transcription. Upstream of ie1 and separated by the MCMV enhancer sequence was a second IE coding region, ie2, which was mapped at 0.803 to 0.817 map units. From ie2 a 1.75-kb RNA of moderate abundance was transcribed in the direction opposite to that of the ie1 RNA. After hybrid selection of the ie2 transcript, a 43,000-molecular-weight translation product was detected. A third coding region, ie3, was located directly downstream of ie1 (0.773 to 0.781 map units). The series of RNAs with low abundance, terminating in ie3, probably used the ie1 transcription start site and ranged from 1.0 to 5.1 kb in size. The 5.1-kb RNA apparently represents the nonspliced transcript from both coding regions ie1 and ie3. A 15K polypeptide was translated in vitro from RNA that was hybrid selected by ie3 sequences. Immunoprecipitation with monoclonal antibody revealed that 31K to 67K polypeptides were related to pp89. Some of these proteins were translated from RNAs that were smaller than 2.75 kb. Polypeptides related to pp89 were also synthesized in vivo. Because polypeptides unrelated to pp89 that were translated from RNA that was selected by ie2 and ie3 sequences were not immunoprecipitated by murine antisera, we assumed that the amount of these proteins synthesized in vivo during infection was probably very low.


Hospital Costs of Foreign Non-Resident Patients: A Comparative Analysis in Catalonia, Spain.
Although patient mobility has increased over the world, in Europe there is a lack of empirical studies. The aim of the study was to compare foreign non-resident patients versus domestic patients for the particular Catalan case, focusing on patient characteristics, hospitalisation costs and differences in costs depending on the typology of the hospital they are treated. We used data from the 2012 Minimum Basic Data Set-Acute Care hospitals (CMBD-HA) in Catalonia. We matched two case-control groups: first, foreign non-resident patients versus domestic patients and, second, foreign non-resident patients treated by Regional Public Hospitals versus other type of hospitals. Hospitalisation costs were modelled using a GLM Gamma with a log-link. Our results show that foreign non-resident patients were significantly less costly than domestic patients (12% cheaper). Our findings also suggested differences in the characteristics of foreign non-resident patients using Regional Public Hospitals or other kinds of hospitals although we did not observe significant differences in the healthcare costs. Nevertheless, women, 15-24 and 35-44 years old patients and the days of stay were less costly in Regional Public Hospitals. In general, acute hospitalizations of foreign non-resident patients while they are on holiday cost substantially less than domestic patients. The typology of hospital is not found to be a relevant factor influencing costs.


Effects of elevated magnesium on discharge of myenteric neurons of cat small bowel.
Electrical discharge of single units in myenteric ganglia of cat intestine was recorded extracellularly, and the effects on the electrical discharge of elevating the concentration of Mg++ in the Tyrode solution from 0.2 to 10.2 mM were determined. The ongoing discharge of 83% of the burst-type units was blocked by elevation of Mg++. The remainder of the burst-type units and all of the single-spike units tested continued to discharge in elevated Mg++. Frequency distribution histograms of interburst intervals of burst units that were unaffected by elevated Mg++ showed low variance of interburst interval, and multimodes on the histograms were multiples of the first mode. The variance of interburst intervals of burst-type neurons that were blocked by elevated Mg++ was greater than variance of the burst-type neurons that were unaffected by increased Mg++. If it is assumed that the action of elevated Mg++ is blockade of synaptic transmission, then the results indicated that the ongoing discharge of the neurons that were blocked by elevated Mg++ was dependent on synaptic input to the cell. The burst-type units that were unaffected by elevated Mg++ may be endogenous oscillators that do not receive synaptic input. The burst-type units that were blocked by elevated Mg++ may be driven by synaptic input from the burst-type oscillators.