PEGylated poly(aspartate-g-OEI) copolymers for effective and prolonged gene transfection.
Two PEGylated poly(aspartate-g-OEI) cationic copolymers, PEG-b-pAsp-g-OEI (DAO) and OEI-g-pAsp-b-PEG-b-pAsp-g-OEI (TAO), were developed for in vivo gene transfer, and a non-PEGylated copolymer (MAO) was utilized as a control. These copolymers exhibited favorable capacities for condensing plasmid DNA (pDNA) into nanosized particles (90-180 nm) with positive surface charges. Gene transfection efficiency of the copolymers (especially DAO) demonstrated improved performance compared to PEI25k in both HeLa and HEK 293 cell lines in the presence of serum. Although MAO and DAO show similar gene transfection efficiency in vitro, DAO is shown to be more effective in vivo. The potential reason is that PEGylation enhances the serum-resistance of the carriers and prolongs gene transfection in vivo. For TAO, despite its PEG segment, the complex of copolymer-pDNA is encompassed by a cation shell and cannot reduce the serum effects. These results suggest that PEGylated diblock copolymers have potential as non-viral gene carriers in gene delivery systems for in vivo application.


Determination of prostatic secretion in rats: effect of neurotransmitters and testosterone.
To study the neuronal and hormonal control of prostatic secretion, the prostatic urethra was cannulated in urethane anesthetized rats. The volume of prostatic secretion was measured following infusion of cholinergic and adrenergic agonists intact animals. Prostatic secretion was elicited by norepinephrine, phenylephrine and carbachol; but not by clonidine, isoproterenol, pilocarpine, or acetylcholine. Phenylephrine and norepinephrine infusions caused a high initial rate of secretion, which then declined rapidly. Carbachol infusion, in contrast, produced a low but constant rate of secretion that was maintained for up to 1 hour. Histological examination of the prostate revealed contraction of smooth muscle surrounding prostatic ducts after infusion of phenylephrine and norepinephrine, but not carbachol. Prostatic secretion was also measured in castrated rats supplemented with various doses of testosterone. Testosterone exerted a dose dependent control of prostatic weight and secretory volume. These results indicate 1) alpha 1 receptor agonists can cause contraction of smooth muscle to expel fluid from the rat prostate, 2) carbachol induces prostatic secretion through a mechanism other than contraction of gland, and 3) testosterone has a primary role in controlling prostatic size.


Priming the immune system of Penaeid shrimp by bacterial HSP70 (DnaK).
This study was conducted to test the effect of DnaK on priming immune responses in Penaeid shrimp. Juvenile-specific pathogen-free (SPF) P. vannamei shrimp were injected with 0.05 μg recombinant DnaK. One hour post-DnaK priming, a non-lethal dose of Vibrio campbellii (10(5) CFU shrimp(-1)) was injected. Other treatments include only DnaK or V. campbellii injection or control with blank inocula. The haemolymph of three shrimp from each treatment was collected at 1.5, 6, 9 and 12 h post-DnaK priming (hpp). It was verified that injection with DnaK and V. campbellii challenge affected the transcription of 3 immune genes, transglutaminase-1 (TGase-1), prophenoloxidase-2 (proPO-2) and endogenous HSP70 (lvHSP70). In P. monodon, shrimp were first injected with DnaK at a dose of 10 μg shrimp(-1) and one hour later with 10(6) CFU of V. harveyi (BB120) shrimp(-1). Shrimp injected with DnaK showed a significant increase in proPO expression compared to the control (P < 0.05). Yet a double injection (DnaK and Vibrio) seemed to cause an antagonistic response at the level of expression, which was not equalled at the level of PO activity. Those results suggest that DnaK is able to modulate immune responses in P. vannamei and P. monodon.


Clinicopathologic correlate of a fresh eyelid pigment implantation.
An eyelid with freshly applied black eyeliner pigment was examined histologically. X-ray microanalysis of the pigment suspension from the manufacturer's vial indicated that its composition was 98% iron and 2% titanium. Transmission electron microscopic examination disclosed that particles were in the extracellular matrix; intracellular particles were not seen. By light microscopy, implant material was detected in various levels of the dermis and was found in dermal lymphatics as well as within and surrounding a hair follicle. Our study suggests that systemic exposure to the implant material is possible and offers explanations for permanent eyelash loss, which we have seen following this procedure.


Are CD44+/CD24- cells the assumed cancer stem cells in breast cancer?
Identification and characterization of the population of cancer stem cells (CSC) depends on several cellular markers, which combination is specific for the phenotype of CSC in the corresponding tumor. Several markers of CSC have already been identified in breast cancer (BC), but there are no universal indicators that could specifically identify the CSC in BC. To determine the validation of the CSC model for cell surface markers such as CD44 and CD24 and their clinical significance. Primary tumor samples of 45 patients with invasive BC without chemotherapy prior to surgery exposure were examined in paraffin blocks. CD44 and CD24 antigens expression was evaluated by the percentage of positive cells using different chromogens and the MultiVision detection system by immunohistochemical method. In this research the evaluation was determined by the following criteria: (-), negative - expression in < 10% of tumor cells; (+), positive - expression in ≥10% of cells. The same scoring system was applied for the expression of CD44+/CD24-. 62.2% of investigated patients are patients older than 50 years and most of them with stage II of disease (71.0%) and luminal tumor subtypes (68.9%). We analysed the expression of CD44, CD24 and CD44+/CD24- for diffe-rent patients with dividing them into two groups. The group A consists of patients with unfavorable prognosis (relapses and metastases have occurred in the first three years after diagnosis), and the group B - with a favourable prognosis (the development of metastases after three years). Median disease-free survival in the group A is 19 months, in the group B - 46 months. The difference between the overall survival (OS) curves in the groups A and B is statistically significant (p < 0.001), the risk of death was higher in the group A (hazard ratio (HR) 5.9; confidence interval (CI) 2.3-15.2). The content of CD44 cells did not differ statistically between groups A and B (p = 0.18), but there was a tendency for increasing in OS with the existence of CD44+ cells (p = 0.056). The distribution of the expression of CD24 marker did not differ between the groups (p = 0.36) as well as the OS curves (p = 0.59). Analysis of the expression of CD44+/CD24- which were considered as possible CSC, revealed a paradoxical increase (p = 0.03) of the frequency in patients of the group B (40.9%) compared to the group A (8.7%). Nevertheless, the comparison of the clinical outcomes did not reveal a statistically significant difference in the survival curves in the groups with existence and absence of CD44+/CD24- expression (p = 0.08). The analysis showed the increasing of the risk of worse clinical outcomes in the cases of expression absence of CD44+/CD24- (HR 2.8; CI 1.1-6.8). As a result of our research, the analysis of the quantity of assumed stem cells of the BC, which were identified by immunohistochemistry as CD44 and CD24 cells, failed to detect a statistically significant relation between groups of patients with different prognosis, and the identification of their expression is not enough for the characteristics of CSC. The obtained data demonstrating the worst clinical outcome in the cases of absence of CD44+/CD24- expression apparently require further investigations and the validation of the immunohistochemical method with the determination of the cut-off line in defining of CD44 and CD24 status.


ClinicaDL: An open-source deep learning software for reproducible neuroimaging processing.
As deep learning faces a reproducibility crisis and studies on deep learning applied to neuroimaging are contaminated by methodological flaws, there is an urgent need to provide a safe environment for deep learning users to help them avoid common pitfalls that will bias and discredit their results. Several tools have been proposed to help deep learning users design their framework for neuroimaging data sets. Software overview: We present here ClinicaDL, one of these software tools. ClinicaDL interacts with BIDS, a standard format in the neuroimaging field, and its derivatives, so it can be used with a large variety of data sets. Moreover, it checks the absence of data leakage when inferring the results of new data with trained networks, and saves all necessary information to guarantee the reproducibility of results. The combination of ClinicaDL and its companion project Clinica allows performing an end-to-end neuroimaging analysis, from the download of raw data sets to the interpretation of trained networks, including neuroimaging preprocessing, quality check, label definition, architecture search, and network training and evaluation. We implemented ClinicaDL to bring answers to three common issues encountered by deep learning users who are not always familiar with neuroimaging data: (1) the format and preprocessing of neuroimaging data sets, (2) the contamination of the evaluation procedure by data leakage and (3) a lack of reproducibility. We hope that its use by researchers will allow producing more reliable and thus valuable scientific studies in our field.


Delineation of agricultural fields in smallholder farms from satellite images using fully convolutional networks and combinatorial grouping.
Accurate spatial information of agricultural fields in smallholder farms is important for providing actionable information to farmers, managers, and policymakers. Very High Resolution (VHR) satellite images can capture such information. However, the automated delineation of fields in smallholder farms is a challenging task because of their small size, irregular shape and the use of mixed-cropping systems, which make their boundaries vaguely defined. Physical edges between smallholder fields are often indistinct in satellite imagery and contours need to be identified by considering the transition of the complex textural pattern between fields. In these circumstances, standard edge-detection algorithms fail to extract accurate boundaries. This article introduces a strategy to detect field boundaries using a fully convolutional network in combination with a globalisation and grouping algorithm. The convolutional network using an encoder-decoder structure is capable of learning complex spatial-contextual features from the image and accurately detects sparse field contours. A hierarchical segmentation is derived from the contours using the oriented watershed transform and by iteratively merging adjacent regions based on the average strength of their common boundary. Finally, field segments are obtained by adopting a combinatorial grouping algorithm exploiting the information of the segmentation hierarchy. An extensive experimental analysis is performed in two study areas in Nigeria and Mali using WorldView-2/3 images and comparing several state-of-the-art contour detection algorithms. The algorithms are compared based on the precision-recall accuracy assessment strategy which is tolerating small localisation errors in the detected contours. The proposed strategy shows promising results by automatically delineating field boundaries with F-scores higher than 0.7 and 0.6 on our two test areas, respectively, outperforming alternative techniques.


Memory and functional brain differences in a national sample of U.S. veterans with Gulf War Illness.
Roughly 26-32% of U. S. veterans who served in the 1991 Persian Gulf War report suffering from chronic health problems. Memory complaints are regularly reported by ill Gulf War veterans (GWV), but limited data verify their complaints. This study investigated episodic memory and brain function in a nationally representative sample of GWV, using a face-name memory task and functional magnetic resonance imaging during encoding. A syndrome classification system was used to subdivide ill GWV into the three major Gulf War Illness syndrome types, "impaired cognition" (GWV-1), "confusion ataxia" (GWV-2), and "central pain" (GWV-3). Memory and brain function of ill GWV were contrasted to deployed and nondeployed well GWV controls (GWV-C). Ill GWV exhibited impaired memory function relative to GWV-C but the patterns of functional brain differences varied. Brain activation differentiated the GWV-C from the ill GWV. The different syndrome types also differed from one another in several brain regions. Additionally, the current study was the first to observe differences in brain function between deployed and nondeployed GWV-C. These results provide (1) evidence of memory impairment in ill GWV and differentiate the syndrome types at a functional neurobiological level, and (2) the role of deployment in the war on brain function.


A De Novo Virus-Like Topology for Synthetic Virions.
A de novo topology of virus-like assembly is reported. The design is a trifaceted coiled-coil peptide helix, which self-assembles into ultrasmall, monodisperse, anionic virus-like shells that encapsulate and transfer both RNA and DNA into human cells. Unlike existing artificial systems, these shells share the same physical characteristics of viruses being anionic, nonaggregating, abundant, hollow, and uniform in size, while effectively mediating gene silencing and transgene expression. These are the smallest virus-like structures reported to date, both synthetic and native, with the ability to adapt and transfer small and large nucleic acids. The design thus offers a promising solution for engineering bespoke artificial viruses with desired functions.


Complex pulmonary aspergilloma treated by cavernostomy.
To evaluate the effectiveness of cavernostomy in patients with complex fungal balls. We analyzed the medical records of patients undergoing cavernostomy between January 2005 and May 2013, evaluating: age, gender, preoperative signs and symptoms, predisposing disease, preoperative tests, location of the aspergilloma, etiologic agent, cavernostomy indication, postoperative outcome. Ten patients were male. The mean age was 42.9 years (34-56). The most frequent symptom was repeated pulmonary bleeding. Cavernostomy was proposed for patients at high risk for lung resection. It was performed in 17 patients and all of them had pulmonary tuberculosis sequelae, with cavitations. The indication in all cases was hemoptysis and elimination of phlegm. The cavernostomies were performed in a single surgical procedure. In all 17 patients the cavity was left open after the withdrawal of the mycetoma. In all patients hemoptysis ceased immediately. Operative mortality was 9.5% (1). cavernostomy is an effective treatment alternative in patients at high risk. It may be useful in some patients with complex aspergilloma, irrespective of lung function or bilateral disease. It is technically easy, has low-risk, saves parenchyma, and may be performed in a single operative time.


A taste of things to come: Effect of temporal order of information and product experience on evaluation of healthy and sustainable plant-based products.
Current patterns of meat consumption are considered unsustainable. Plant-based products are presented as a solution. However, while some plant-based products thrive, others do not make the cut due to the information "framing" effect issues related to the way information is presented to the consumers. Information on the nutrition and health properties of food products are usually made available at the point of purchase, but their effect on consumer product evaluation and subsequent purchase intent can also occur later, during or after consumption. This research demonstrates that the effect of nutrition information on product evaluation and purchase intention depends on when such information is made available-before first tasting or after first tasting-and that the information interacts with the taste experience in its effect on product evaluation and subsequent purchase intent. Using three plant-based products as an example, we conducted a cross-cultural experimental sensory evaluation with temporal order of information as the main between-subject experimental condition (informed before taste vs. informed after taste vs. control condition), and product experience phase (expectation vs. experience vs. post-experience phase) and information content as within-subject conditions. Information content had two levels: lower vs. higher share of oat protein in the product (i.e., source of protein vs. high in protein). The results indicate that information generally increases consumers' purchase intentions with information before tasting having a higher weight when compared to the condition when information was presented after tasting. Presenting the information before tasting also mitigates a drop in the evaluation of taste after tasting, observed in the two other conditions. Further, taste acts as a healthiness cue, but the direction of the inference depends on the availability of health-related information: tasting in the informed condition increased the healthiness perception, whereas tasting in the uninformed condition had the opposite effect. Giving the information before the first tasting also increased the weight of healthiness as compared to taste in the formation of purchase intentions. These findings contribute to a better understanding of the effect of temporal order of information and product tasting have on the consumers' product evaluations of plant-based products from theoretical and managerial perspectives.


Role of the GLT-1 subtype of glutamate transporter in glutamate homeostasis: the GLT-1-preferring inhibitor WAY-855 produces marginal neurotoxicity in the rat hippocampus.
Glutamate is the major excitatory neurotransmitter in the central nervous system and is tightly regulated by cell surface transporters to avoid increases in concentration and associated neurotoxicity. Selective blockers of glutamate transporter subtypes are sparse and so knock-out animals and antisense techniques have been used to study their specific roles. Here we used WAY-855, a GLT-1-preferring blocker, to assess the role of GLT-1 in rat hippocampus. GLT-1 was the most abundant transporter in the hippocampus at the mRNA level. According to [(3)H]-l-glutamate uptake data, GLT-1 was responsible for approximately 80% of the GLAST-, GLT-1-, and EAAC1-mediated uptake that occurs within dissociated hippocampal tissue, yet when this transporter was preferentially blocked for 120 h with WAY-855 (100 microm), no significant neurotoxicity was observed in hippocampal slices. This is in stark contrast to results obtained with TBOA, a broad-spectrum transport blocker, which, at concentrations that caused a similar inhibition of glutamate uptake (10 and 30 microm), caused substantial neuronal death when exposed to the slices for 24 h or longer. Likewise, WAY-855, did not significantly exacerbate neurotoxicity associated with simulated ischemia, whereas TBOA did. Finally, intrahippocampal microinjection of WAY-855 (200 and 300 nmol) in vivo resulted in marginal damage compared with TBOA (20 and 200 nmol), which killed the majority of both CA1-4 pyramidal cells and dentate gyrus granule cells. These results indicate that selective inhibition of GLT-1 is insufficient to provoke glutamate build-up, leading to NMDA receptor-mediated neurotoxic effects, and suggest a prominent role of GLAST and/or EAAC1 in extracellular glutamate maintenance.


Evaluating the Integration of Genomics into Cancer Screening Programmes: Challenges and Opportunities.
As the costs of genomic testing have fallen, and our understanding of genetic susceptibility to cancers has grown, there has been increasing interest in incorporating testing for cancer susceptibility genes, and polygenic risk estimates, into population cancer screening. A growing body of evidence suggests that this would be both clinically and cost-effective. In this article, we aim to explore the frameworks used to evaluate screening programmes, evaluate whether population screening for cancer susceptibility can be assessed using these standards, and consider additional issues and outcomes of importance in this context. There are tensions between traditional approaches of genetic testing (utilising tests with high sensitivity and specificity) and the principles of population screening (in which the screening test typically has low specificity), as well as the frameworks used to evaluate the two. Despite the existence of many screening guidelines, including consensus papers, these often do not align fully with broader considerations of genetic test evaluation. Population screening for genetic risk in cancer shifts the focus from diagnostics to prognostication and has wider implications for personal and familial health than existing screening programmes. In addition, understanding of the prevalence and penetrance of cancer susceptibility genes, required by many screening guidelines, may only be obtainable through population-level testing; prospective multi-disciplinary research alongside implementation will be essential. Appropriate evaluation of genetic screening for cancer risk will require modification of existing screening frameworks to incorporate additional complexity of outcomes and population values. As evidence supporting population screening for cancer susceptibility mounts, development of an appropriate evaluative framework, and expansion of public dialogue will be key to informing policy.


Optimization of kinetics and operating parameters for the bioleaching of heavy metals from sewage sludge, using co-inoculation of two Acidithiobacillus species.
This study explores the potential for synchronous extraction of Cu, Cr, Ni and Zn during sewage sludge bioleaching processes, using three types of bacterial cultures: a pure culture of Acidithiobacillus ferrooxidans (A. ferrooxidans); a pure culture of Acidithiobacillus thiooxidans (A. thiooxidans); and a mixed culture of A. ferrooxidans and A. thiooxidans. Variable operating parameters included initial pH, solids concentration, sulfur concentration and ferrous iron concentration, with optimization via Box-Behnken design of response surface methodology. Results indicate that the mixed culture of A. ferrooxidans and A. thiooxidans, was the most effective at bioleaching heavy metals from sewage sludge. The optimal operating conditions were as follows: an initial pH of 2.0, with concentrations of 3% solids, 6.14 g L-1 sulfur and 4.55 g L-1 ferrous iron. Maximum extraction efficiencies obtained after 14 days of bioleaching under optimal conditions, were 98.54% Cu, 57.99% Cr, 60.06% Ni and 95.60% Zn. Bioleaching kinetics were effectively simulated using a shrinking core model to explain the leaching reaction, with modelling results suggesting that the rate was determined by the diffusion step.


Association between birth weight and educational attainment: an individual-based pooled analysis of nine twin cohorts.
There is evidence that birth weight is positively associated with education, but it remains unclear whether this association is explained by familial environmental factors, genetic factors or the intrauterine environment. We analysed the association between birth weight and educational years within twin pairs, which controls for genetic factors and the environment shared between co-twins. The data were derived from nine twin cohorts in eight countries including 6116 complete twin pairs. The association between birth weight and educational attainment was analysed both between individuals and within pairs using linear regression analyses. In between-individual analyses, birth weight was not associated with educational years. Within-pairs analyses revealed positive but modest associations for some sex, zygosity and birth year groups. The greatest association was found in dizygotic (DZ) men (0.65 educational years/kg birth weight, p=0.006); smaller effects of 0.3 educational years/kg birth weight were found within monozygotic (MZ) twins of both sexes and opposite-sex DZ twins. The magnitude of the associations differed by birth year in MZ women and opposite-sex DZ twins, showing a positive association in the 1915-1959 birth cohort but no association in the 1960-1984 birth cohort. Although associations are weak and somewhat inconsistent, our results suggest that intrauterine environment may play a role when explaining the association between birth weight and educational attainment.


Cardiac response of the fetal rat to carbon monoxide exposure.
Groups of pregnant rats were exposed to 200, 166, and 157 ppm CO for the last 17 out of 22 days of gestation. The number of fetuses per dam or live young per litter were unaffected. Neonatal red blood cell count was depressed, whereas mean corpuscular hemoglobin and volume were elevated. Birth weight was reduced; heart weight, heart weight-to-body weight ratio, placental weight, and placental weight-to-body weight ratio were elevated. Identical results were obtained in studies of fetuses examined daily during the final 4 days of gestation at 200 ppm. Cardiomegaly present at birth was not due to elevated myocardial water content, as dry heart weight and wet heart weight increased proportionately. Heart DNA content (microgram) was increased at both 157 and 200 ppm CO in neonates and fetuses, whereas DNA concentration (microgram/mg dry wt) was similar to the controls. Cardiac hydroxyproline concentration (microgram/mg dry wt) and content (microgram) were unaffected in neonates by fetal CO exposure at 157 and 200 ppm, although the hydroxyproline content was elevated in fetuses at 157 ppm CO. Cardiac lactate dehydrogenase (LDH) M subunit composition was elevated from 4 days before birth, until birth, at 200 ppm CO, whereas total LDH activity was unchanged. Although neonatal myocardial cytochrome c was unaltered by fetal CO exposure, myoglobin concentration (mg/g) and content (mg) were elevated. Prolonged maternal CO inhalation thus exerts significant effects on fetal body and placental weight, heart weight, enzyme constituents, and composition.


Walking while talking: validation in older adults with lower-limb amputation.
Walking while talking (WWT) is a dual-task (cognitive and motor) performance test that has not yet been validated in older adults with lower-limb amputation (LLA). WWT is composed of two sections: WWT-simple (walking while reciting every letter of the alphabet) and WWT-complex (walking while reciting every other letter of the alphabet). To determine the validity, and provide normative data and a new scoring system for the WWT test in older adults with LLA. Baseline cross-sectional data were collected from 56 community-living older adults (≥50 years old) with LLA at rehabilitation hospitals in Vancouver, BC, London, ON, and Edmonton, AB, Canada. Time and number of recited letters and errors during both sections were recorded. A new score was developed based on all these variables. Correlations of the recorded times with the Activities-specific Balance Confidence (ABC) scale and the 2-Minute Walk Test (2MWT) score were used to evaluate the validity of the WWT test. As hypothesized, the times for both sections of the WWT were negatively correlated with both the ABC and 2MWT scores. Positive correlations were observed between the scores developed for both WWT sections with the 2MWT score. Times taken to complete each section of the WWT test were correlated with the 2MWT and the ABC scale scores, providing evidence for the validity of the WWT test. We also provided a scoring method that is more objective and in line with the dual-task nature of the test.


Increases in Australian cutaneous abscess hospitalisations: 1999-2008.
Staphylococcus aureus is the most common cause of skin and soft tissue infections (SSTIs). Such infections have increased in several countries recently and at a time when community-associated methicillin-resistant S. aureus (CA-MRSA) strains have emerged globally. We examined changes in Australian hospitalisations for the treatment of cutaneous abscesses between 1999 and 2008, a period when increased numbers of CA-MRSA infections were being reported. National hospitalisation data for cutaneous abscess treatment (1999-2008) were examined. Hospitalisation numbers were collated and age-specific admission rates calculated and examined for changes over time. Yearly admissions for the treatment of cutaneous abscesses increased by 48%, from 8,849 (1999-2000) to 13,126 (2007-2008). The crude annual hospitalisation rate per 100,000 population rose from 46 to 62 respectively. However, increases in admission rates were limited to the 10 to 54 years age range. Incidence rate ratios (IRRs) for final versus baseline year admission rates for these age groups ranged from 1.36 (95% confidence interval [CI] 1.04-1.78) for those aged 10-14 years to 1.64 (95% CI 1.26-2.12) for those aged 45-49 years; p<0.05. Increases in hospitalisation for cutaneous abscess treatment have occurred in Australia during the last decade. Research into the underlying causes and prevention of these infections is a public health priority.


Obstetric risk factors for early-onset schizophrenia in a Finnish birth cohort.
Although case-control investigations have shown an association between obstetric complications and schizophrenia, particularly among patients with early onsets, cohort studies have mostly failed to confirm this effect. The authors examined whether a history of fetal hypoxia and other obstetric complications elevated risk for early-onset schizophrenia in a 1955 Helsinki birth cohort. The subjects were 80 randomly selected patients with schizophrenia (36 with early and 44 with later onsets) representative of all available probands in the cohort, 61 of their nonschizophrenic siblings, and 56 demographically matched nonpsychiatric comparison subjects. Psychiatric diagnoses were obtained from structured clinical interviews, and obstetric data were taken from standardized, prospectively ascertained obstetric records. A score for hypoxia-associated obstetric complications was entered into logistic regression models, along with measures of prenatal infection and fetal growth retardation. Hypoxia-associated obstetric complications significantly increased the odds of early-onset schizophrenia but not of later-onset schizophrenia or unaffected sibling status, after prenatal infection and fetal growth retardation were taken into account. These findings support an association between obstetric complications and increased risk for early-onset schizophrenia. The authors advance a model whereby the neurotoxic effects of fetal hypoxia may lead to an early onset of schizophrenia due to premature cortical synaptic pruning.


Mice with hyper-long telomeres show less metabolic aging and longer lifespans.
Short telomeres trigger age-related pathologies and shorter lifespans in mice and humans. In the past, we generated mouse embryonic (ES) cells with longer telomeres than normal (hyper-long telomeres) in the absence of genetic manipulations, which contributed to all mouse tissues. To address whether hyper-long telomeres have deleterious effects, we generated mice in which 100% of their cells are derived from hyper-long telomere ES cells. We observe that these mice have longer telomeres and less DNA damage with aging. Hyper-long telomere mice are lean and show low cholesterol and LDL levels, as well as improved glucose and insulin tolerance. Hyper-long telomere mice also have less incidence of cancer and an increased longevity. These findings demonstrate that longer telomeres than normal in a given species are not deleterious but instead, show beneficial effects.


Functional derangements in the regulation of aldosterone secretion in hypertension.
Excess production of aldosterone secondary to an adrenal tumor or bilateral hyperplasia is a known, but infrequent, cause of hypertension. A more frequent adrenal abnormality, observed in 30-40% of hypertensive patients, is a functional derangement in aldosterone secretion. Two such conditions have been described: low renin essential hypertension and non-modulating essential hypertension. Both have in common 1) an abnormality in the interaction of angiotensin II (Ang II) with the adrenal and 2) sodium sensitivity of the blood pressure. However, the pathophysiological mechanisms for the sodium sensitivity and hypertension are different. In normal subjects, the response of the adrenal glomerulosa cell to Ang II varies with the level of sodium intake, with sodium restriction enhancing the response. In one group of hypertensive patients with low plasma renin levels, the normally reduced aldosterone responses to Ang II on the high salt diet do not occur. Thus, these individuals have an enhanced adrenal response to Ang II under circumstances in which it should be reduced, thereby leading to lower renin levels and a tendency toward sodium retention. The second group has the opposite defect; that is, on a low sodium diet, they have a reduced adrenal response to Ang II. This results in a normal or high plasma renin level. The sodium sensitivity of their blood pressure arises not from the adrenal abnormality but from the associated defect in sodium-dependent, Ang II-mediated changes in renal blood flow. Thus, on a high salt diet, these patients, who are termed "non-modulators," fail to increase renal blood flow, thereby leading to a sodium-retaining state.(ABSTRACT TRUNCATED AT 250 WORDS)


Screen-detected multiple primary lung cancers in the ITALUNG trial.
Occurrence of multiple primary lung cancers (MPLC) in individuals undergoing low-dose computed tomography (LDCT) screening has not been thoroughly addressed. We investigated MPLC in subjects recruited in the ITALUNG randomized clinical trial. Cases of cytologically/histologically proven MPLC detected at screening LDCT or follow-up CT were selected and pathologically re-evaluated according to the WHO 2015 classification. Overall 16 MPLC were diagnosed at screening LDCT (n=14, all present at baseline) or follow-up CT (n=2) in six subjects (4 in one subject, 3 in two and 2 in three subjects), representing 0.43% of the 1,406 screenees and 15.8% of the 38 subjects with at least one screen-detected primary lung cancer. MPLC included 9 adenocarcinomas in three subjects and a combination of 7 different tumour histotypes in three subjects. MPLC, mostly adenocarcinomas, are not uncommon in smokers and ex-smokers with at least one LDCT screen detected primary lung cancer.


Postoperative Mycoplasma hominis infections after neurosurgical intervention.
Mycoplasma hominis is a rare cause of infection after neurosurgical procedures. The Mycoplasma genus contains the smallest bacteria discovered to date. Mycoplasma are atypical bacteria that lack a cell wall, a feature that complicates both diagnosis and treatment. The Gram stain and some types of culture media fail to identify these organisms, and typical broad-spectrum antibiotic regimens are ineffective because they act on cell wall metabolism. Mycoplasma hominis commonly colonizes the genitourinary tract in a nonvirulent manner, but it has caused postoperative, postpartum, and posttraumatic infections in various organ systems. The authors present the case of a 17-year-old male with a postoperative intramedullary spinal cord abscess due to M. hominis and report the results of a literature review of M. hominis infections after neurosurgical procedures. Attention is given to time to diagnosis, risk factors for infection, ineffective antibiotic regimens, and final effective antibiotic regimens to provide pertinent information for the practicing neurosurgeon to diagnose and treat this rare occurrence. A PubMed search was performed to identify reports of M. hominis infections after neurosurgical procedures. Eleven cases of postneurosurgical M. hominis infection were found. No other cases of intramedullary spinal cord abscess were found. Initial antibiotic coverage was inadequate in all cases, and diagnosis was delayed in all cases. Multiple surgical interventions were often needed. Once appropriate antibiotics were started, patients typically experienced rapid resolution of their neurological symptoms. In 27% of cases, a suspicious genitourinary source other than urinary catheterization was identified. Postoperative M. hominis infections are rarely seen after neurosurgical procedures. They are typically responsive to appropriate antibiotic therapy. Mycoplasma infection may cause prolonged hospitalization and multiple returns to the operating room due to delay in diagnosis. Early clinical suspicion with appropriate antibiotic coverage could help prevent these significant complications.


Comparative study between partial inferior turbinotomy and microdebrider-assisted inferior turbinoplasty.
The purpose of our study was to compare the inferior turbinotomy and the microdebrider-assisted inferior turbinoplasty in patients with hypertrophy of the inferior turbinate. We carried out a retrospective review of 205 patients, 96 women and 109 men, with a mean age of 48 years, operated on for hypertrophy of the inferior turbinate between May 2005 and May 2012. Forty-seven patients were excluded from our study because in these patients, nasal obstruction was caused by a specific pathologic condition (allergy, tumors or polyps, recurrent rhinosinusitis, etc). The remaining 158 patients were randomly assigned to undergo partial inferior turbinoplasty through the use of microdebrider (group A, n = 79) or partial inferior turbinotomy (group B, n = 79). Surgical outcome was evaluated according to 4 distinct parameters: nasal endoscopic findings, nasal subjective symptoms, anterior rhinomanometry, and nasal mucociliary transport time. These evaluations were made before surgery and 1 week and 3 months after surgery. The follow-up was a minimum of 24 months and a maximum of 60 months, with a mean follow-up of 42 months. Turbinate edema and secretions decreased significantly (P < 0.05) in groups A and B 3 months after surgery. In group A, crusting was not observed after surgery. In group B, crusting had increased significantly (P < 0.005) 1 week after surgery and then decreased significantly at the third month after surgery. Subjective nasal symptoms including nasal obstruction, sneezing, snoring, itchy nose, hyposmia, headache, and dryness were significantly improved in both groups from the third month after surgery (P < 0.05). Rhinomanometric measurements demonstrated a significant nasal flow increase at 3 months (P < 0.05). The mean nasal mucociliary transport time slightly increased in both groups 1 week after surgery, and then restabilized to preoperative values at the third-month follow-up in both groups (difference not significant). Microdebrider-assisted inferior turbinoplasty and partial inferior turbinotomy are very effective surgical techniques for solving hypertrophy of the inferior turbinates and therefore related problems of nasal obstruction. Microdebrider-assisted inferior turbinoplasty compared to partial inferior turbinotomy ensures a greater preservation of the nasal mucosa to prevent nasal bleeding.


On repetition. Its relationship to the depressive position.
Thinking is painful as it progresses. Something of what is being achieved has to be left behind. The loss is being compensated by repetition in variations, as if the unconscious tries to restore what has been left behind. Looking back on the steps of thinking, one gains a feeling of security in one's conclusions if these steps are restored.


Expression of the sodium iodide symporter in human kidney.
The human sodium iodide symporter (hNIS) is a transmembrane protein that mediates the active transport of iodide in the thyroid gland. Following cloning of NIS, NIS expression has been detected in a broad range of nonthyroidal tissues, suggesting that iodide transport in these tissues is conferred by the expression of functional NIS protein. The aim of this study was to examine functional hNIS expression in kidney by reverse transcription-polymerase chain reaction (RT-PCR), ribonuclease protection assay (RPA), immunohistochemistry, and Western blot analysis accompanied by iodide accumulation studies in kidney cells. Using a pair of full-length hNIS-specific oligonucleotide primers, RT-PCR followed by Southern hybridization revealed hNIS mRNA expression in normal human kidney tissue. The PCR products were subjected to automated sequencing and revealed full identity with the published human thyroid-derived NIS cDNA sequence. Furthermore, positive protected bands indicating the presence of hNIS mRNA were apparent in RPA gel lanes corresponding to human kidney cells as well as Chinese hamster ovary (CHO) cells stably transfected with hNIS cDNA and Graves' thyroid tissue. Immunohistochemical analysis of normal human kidney tissue using a mouse monoclonal hNIS-specific antibody showed marked hNIS-specific immunoreactivity confined to tubular cells, while no hNIS-specific immunoreactivity was detected in the glomeruli. NIS protein expression in human kidney cells was further confirmed by Western blot analysis. In addition, accumulation of (125)I was detected in human kidney cells in vitro and was shown to be sodium dependent and sensitive to perchlorate. Functional hNIS expression was demonstrated in the renal tubular system, suggesting that renal iodide transport may be, at least in part, an active process driven by NIS.


Absence of [125I] alpha-bungarotoxin binding to motor nerve terminals of frog, lizard and mouse muscle.
The existence of nicotinic acetylcholine receptors (AChRs) on the motor nerve terminals of vertebrates has long been controversial. We have re-examined this issue by electron microscope autoradiography with [125I] alpha-bungarotoxin, following separation of nerve terminals from muscle fibers by collagenase and protease treatment. We found no label over nerve terminal membranes other than that due to background, and we calculate upper limits of less than 0.1% of the postsynaptic AChR density for nerve terminals in frogs, lizards, and mice. We conclude that there are essentially no presynaptic acetylcholine receptors that bind alpha-bungarotoxin at vertebrate neuromuscular junctions.


Photocatalytic Reduction of CO2 to HCOOH and CO by a Phosphine-Bipyridine-Phosphine Ir(III) Catalyst: Photophysics, Nonadiabatic Effects, Mechanism, and Selectivity.
Photocatalytic CO2 reduction is one of the best solutions to solve the global energy crisis and to realize carbon neutralization. The tetradentate phosphine-bipyridine (bpy)-phosphine (PNNP)-type Ir(III) photocatalyst, Mes-IrPCY2, was reported with a high HCOOH selectivity but the photocatalytic mechanism remains elusive. Herein, we employ electronic structure methods in combination with radiative, nonradiative, and electron transfer rate calculations, to explore the entire photocatalytic cycle of Mes-IrPCY2 to either HCOOH or CO, based on which a new mechanistic scenario is proposed. The catalytic reduction reaction starts from the generation of the precursor 3MLCT state. Subsequently, the divergence happens from the 3MLCT state, the single electron transfer and deprotonation process lead to the formation of one-electron-reduced species and Ir(I) species, which initiate the reduction reaction to HCOOH and CO, respectively. Interestingly, the efficient occurrence of proton or electron transfer reduces barriers of critical steps. In addition, nonadiabatic transitions play a nonnegligible role in the cycle. We suggest a lower free-energy barrier in the reaction-limiting step and the very efficient SET in 3MLCT are cooperatively responsible for a high HCOOH selectivity. The gained mechanistic insights could help chemists to understand, regulate, and design photocatalytic CO2 reduction reaction of similar function-integrated molecular photocatalyst.


Evidence for gamma-aminobutyric acid specific binding sites on human spermatozoa.
The possible presence of gamma-aminobutyric acid (GABA) specific binding sites on human spermatozoa was investigated. Swim-up preparations of human spermatozoa were incubated with radiolabelled GABA in the presence of unlabelled GABA, alternatively displacers of GABAA/B receptors and GABA transport proteins. The results indicate that GABA specific binding sites are present on the surface of human spermatozoa, and that these binding sites possibly indicate the presence of GABA transport proteins. Furthermore, GABA at different concentrations was added to swim-up preparations of human spermatozoa. Possible effects of GABA on sperm motility, hyperactivation and acrosome reaction were explored. No significant differences were observed between treated groups and controls concerning motility parameters and hyperactivation. Incubation with GABA did not cause any increase in spontaneous acrosome reaction. However, spermatozoa treated with the calcium ionophore A-23187 showed a small but significantly increased ability to undergo the acrosome reaction following preincubation in 10(-4) M GABA (P < 0.05).


Use of Six Sigma for eliminating missed opportunities for prevention services.
Delivery of primary care preventative services can be significantly increased utilizing Six Sigma methods. Missed preventative service opportunities were compared in the study clinic with the community clinic in the same practice. The study clinic had 100% preventative services, compared with only 16.3% in the community clinic. Preventative services can be enhanced to Six Sigma quality when the nurse executive and medical staff agree on a single standard of nursing care executed via standing orders.


Estrogen Receptor α Regulates Ethanol Excitation of Ventral Tegmental Area Neurons and Binge Drinking in Female Mice.
Elevations in estrogen (17β-estradiol, E2) are associated with increased alcohol drinking by women and experimentally in rodents. E2 alters the activity of the dopamine system, including the VTA and its projection targets, which plays an important role in binge drinking. A previous study demonstrated that, during high E2 states, VTA neurons in female mice are more sensitive to ethanol excitation. However, the mechanisms responsible for the ability of E2 to enhance ethanol sensitivity of VTA neurons have not been investigated. In this study, we used selective agonists and antagonists to examine the role of ER subtypes (ERα and ERβ) in regulating the ethanol sensitivity of VTA neurons in female mice and found that ERα promotes the enhanced ethanol response of VTA neurons. We also demonstrated that enhancement of ethanol excitation requires the activity of the metabotropic glutamate receptor, mGluR1, which is known to couple with ERα at the plasma membrane. To investigate the behavioral relevance of these findings, we administered lentivirus-expressing short hairpin RNAs targeting either ERα or ERβ into the VTA and found that knockdown of each receptor in the VTA reduced binge-like ethanol drinking in female, but not male, mice. Reducing ERα in the VTA had a more dramatic effect on binge-like drinking than reducing ERβ, consistent with the ability of ERα to alter ethanol sensitivity of VTA neurons. These results provide important insight into sex-specific mechanisms that drive excessive alcohol drinking.SIGNIFICANCE STATEMENT Estrogen has potent effects on the dopamine system and increases the vulnerability of females to develop addiction to substances, such as alcohol. We investigated the mechanisms by which estrogen increases the response of neurons in the VTA to ethanol. We found that activation of the ERα increased the ethanol-induced excitation of VTA neurons. 17β-Estradiol-mediated enhancement of ethanol-induced excitation required the metabotropic glutamate receptor mGluR1. We also demonstrated that ERs in the VTA regulate binge-like alcohol drinking by female, but not male, mice. The influence of ERs on binge drinking in female mice suggests that treatments for alcohol use disorder in women may need to account for this sex difference.


[Endoscopic ambulatory electroexcision of gastric polyps].
An analysis of observations of 68 patients has shown that in certain patients the endoscopic electroexcision of gastric polyps can be fulfilled under conditions of the outpatient clinic. The safety of the operation depends on the patient's state and the preliminary assessment of the following factors: the anatomic shape, polyp size and width of its base. Electroexcisions can not be performed endoscopically for polyps on a false pedicle (due to high risk of bleedings from the vessels of the submucous layer) and plaque-shaped polyps (due to the absence of possibility to put a diathermic loop).


What do we know about preventing school violence? A systematic review of systematic reviews.
Many children across the world are exposed to school violence, which undermines their right to education and adversely affects their development. Studies of interventions for school violence suggest that it can be prevented. However, this evidence base is challenging to navigate. We completed a systematic review of interventions to reduce four types of school violence: (a) peer violence; (b) corporal punishment; (c) student-on-teacher violence and (d) teacher-on-student violence. Reviewers independently searched databases and journals. Included studies were published between 2005 and 2015; in English; considered school-based interventions for children and measured violence as an outcome. Many systematic reviews were found, thus we completed a systematic review of systematic reviews. Only systematic reviews on interventions for intimate partner violence (IPV) and peer aggression were found. These reviews were generally of moderate quality. Research on both types of violence was largely completed in North America. Only a handful of programmes demonstrate promise in preventing IPV. Cognitive behavioral, social-emotional and peer mentoring/mediation programmes showed promise in reducing the levels of perpetration of peer aggression. Further research needs to determine the long-term effects of interventions, potential moderators and mediators of program effects, program effects across different contexts and key intervention components.


[Pathogenetic principle of substantiation of indications and programs for transfusion therapy in surgical practice].
On the basis of personal clinical experience and literature data the authors show the necessity to formulate indications for transfusion therapy and its prognosis not by nosological but by pathogenetic principle, i. e. in relation to pathophysiological changes in the patient, similar in different diseases and traumas.


Enhancing retention through reconsolidation: negative emotional arousal following retrieval enhances later recall.
When information is retrieved from memory, it enters a labile state rendering it amenable to change. This process of reconsolidation may explain, in part, the benefits that are observed in later retention following retrieval of information on an initial test. We examined whether the benefits of retrieval could be modulated by an emotional event occurring after retrieval. Participants studied Swahili-English vocabulary pairs. On a subsequent cued-recall test, each retrieval was followed by a blank screen, a neutral picture, or a picture inducing negative affect. Performance on a final cued-recall test was best for items whose initial retrieval was followed by negative pictures. This outcome occurred when a negative picture was presented immediately after (Experiment 1) or 2 s after (Experiment 2) successful retrieval, but not when it was presented after restudy of the vocabulary pair (Experiment 3). Postretrieval reconsolidation via emotional processing may enhance the usual positive effects of retrieval.


Estimating hypermutation rates from clonal tree data.
To understand the mechanisms underlying the varying patterns of mutations that occur during immune and autoimmune responses, estimates of the somatic hypermutation rate are critical. However, despite its significance, precise estimates of the mutation rate do not currently exist. Microdissection studies of mutating B cell clones provide an opportunity to measure this rate more accurately than previously possible. Each microdissection provides a number of clonally related sequences that, through the analysis of shared mutations, can be genealogically related to each other. The shape of these clonal trees is influenced by many processes, including the hypermutation rate. We have developed two different methods to estimate the mutation rate based on these data. These methods are applied to two sets of experimental data, one from an autoimmune response and one from the antihapten response to (4-hydroxy-3-nitrophenyl)acetyl (NP). Comparable mutation rates are estimated for both responses, 0.7-0.9 x 10(-3) and 0.9-1.1 x 10(-3) bp(-1) division(-1) for the autoimmune and NP responses, respectively. In addition to comparing the results of the two procedures, we investigate the effect on our estimate of assumptions, such as the fraction of lethal mutations.


Usefulness of preheparin lipoprotein lipase mass as a parameter for predicting the efficacy of colestimide.
This study was conducted to clarify the characteristics of colestimide responders. Forty-seven non-diabetic patients with high levels of low-density lipoprotein cholesterol (LDL-C) received colestimide at 3,000 mg/day and were followed up for 4 months. After 4 months, body weight was reduced but the change was not statistically significant. Total serum cholesterol (TC) and LDL-C levels significantly decreased from 280 to 232 mg/dl and from 195 to 150 mg/dl, respectively (p<0.01 versus before colestimide was administered). Serum triglyceride (TG) levels increased, but the change was not significant. Preheparin lipoprotein lipase mass (preheparin LPL mass) at baseline was significantly higher in colestimide responders (greater than a 20% decrease of LDL-C: n=28) than non-responders (76.2 ng/ml versus 50.3 ng/ml, p<0.05: n=19). Next, the subjects were divided into those with a high (n=33) and low (n=14) preheparin LPL mass at baseline. LDL-C levels were significantly decreased in patients with a high preheparin LPL mass while TG levels were significantly increased in patients with a low preheparin LPL mass. These results suggest that baseline preheparin LPL mass may be a marker of the response to colestimide.


Contrast-enhanced ultrasound ventriculography.
During external ventricular drainage (EVD) weaning, cranial computed tomography (cCT) is necessary to evaluate ventricle width. Because intrahospital transfer of critically ill patients is associated with higher mortality, bedside techniques are necessary to evaluate ventricle width. Transcranial sonography is able to show the ventricles in patients with sufficient temporal acoustic window. Contrast-enhanced ultrasound (CEUS) is able to overcome the limitations of insufficient insonation. We demonstrate the feasibility of bedside transcranial CEUS ventriculography to measure ventricles and verify the passage of cerebrospinal fluid (CSF) through the foramen of Magendie into the subarachnoid space during EVD weaning in critically ill patients. Six patients were examined by transcranial and transnuchal CEUS. Harmonic imaging with low mechanical index was used. One milliliter of an ultrasound contrast agent was administered via EVD line. Comparison with the cCT scans at the time of discharge was used to confirm CEUS-ventriculography results. Ventricles were visualized in all patients. CSF transmission via the foramen of Magendie was demonstrated in 5 patients. Mean ventricle width (centimeters) was 0.67 (CEUS) vs 0.73 (cCT) (standard deviation 0.43, 0.45, P = .116) [third ventricle], 0.88 vs 1.02 (0.28, 0.22, P = .055) [fourth ventricle], 1.40 vs 1.37 (0.56, 0.54, P = .620) [left lateral ventricle], 1.37 vs 1.37 (0.55, 0.54, P = .952) [right lateral ventricle], 2.33 vs 2.23 (0.51, 0.58, P = .169) [left anterior horn], and 2.25 vs 2.07 (0.56, 0.64, P = .204) [right anterior horn]. Mean duration for CEUS ventriculography was 3:15 minutes. CEUS ventriculography is an effective bedside procedure in critically ill patients with EVD. CEUS allows measurement of ventricle width, ventricle communication, and CSF transfer to the subarachnoidal space through the cisternal foramina.


Determining the localization of premolar zenith positions according to the gingival line.
The gingival zenith (GZ) positions according to a reference line in the premolar (PM) area remain concern, especially for the clinicians in placing the gingival contours during surgery. The objectives of this study are to determine the maxillary PM GZ positions according to GZ line (GZL). A sample population of 63 patients with healthy gingival tissue was studied. The GZ was determined at the most apical point of the gingival marginal scallop. A horizontal-zenith line (ZL) was drawn connecting the GZ from the ipsilateral canine (C) and central incisor teeth. Reference lines were drawn, and bilateral measurements were taken in the respective stone casts in the PM area. No statistically significant differences were found between bilateral first premolars (FPM) and second premolars (SPM). When considering ipsilateral FPM and SPM, statistically significant differences were found between them. For all PM teeth, the mean distance value of GZ to GZL was approximately 1.32 mm. The present study results showed that GZs of FPM and SPM teeth for both left and right sight was coronally located according to ZL.


The yan gene is highly conserved in Drosophila and its expression suggests a complex role throughout development.
Competence for cell fate determination and cellular differentiation is under tight control of regulatory genes. Yan, a nuclear target of receptor tyrosine kinase (RTK) signaling, is an E twenty six (ETS) DNA-binding protein that functions as a negative regulator of cell differentiation and proliferation in Drosophila. Most members of RTK signaling pathways are highly conserved through evolution, yet no yan orthologues have been identified to date in vertebrates. To investigate the degree of yan conservation during evolution, we have characterized a yan homologue from a sibling species of D. melanogaster, D. virilis. Our results show that the organization, primary structure and expression pattern of yan are highly conserved. Both genes span over 20 kb and contain four exons with introns at identical positions. The areas with highest amino acid similarity include the Pointed and ETS domain but there are other discrete regions with a high degree of similarity. Phylogenetic analysis reveals that yan's closest relative is the human tel gene, a negative regulator of differentiation in hematopoetic precursors. In both species, Yan is dynamically expressed beginning as early as stage 4/5 and persisting throughout embryogenesis. In third instar larvae, Yan is expressed in and behind the morphogenetic furrow of the eye imaginal disc as well as in the laminar precursor cells of the brain. Ovarian follicle cells also contain Yan protein. Conservation of the structure and expression patterns of yan genes strongly suggests that regulatory mechanisms for their expression are also conserved in these two species.


Metastatic Neoplasms to the Breast.
When the clinical presentation is related to the metastatic mass and a radiologically solitary tumor focus is detected, especially in cases where clinical information is not taken into account or is insufficient, if a possible metastatic neoplasia is not kept in mind then it is possible to evaluate the tumor as a primary breast neoplasm. In this study, it is aimed to present our cases of non-hematopoietic metastatic neoplasms and to evaluate the clinicopathological features that may aid in distinguishing metastatic from primary neoplasms. This study includes cases diagnosed with metastatic non-hematopoietic breast neoplasm in breast resection materials in our center, between the years 2010-2023. All cases were analyzed retrospectively by evaluating clinicopathological features. Of the 15 subjects included in the study, 11 (73%) were female and 4 (27%) were male. The mean age of the patients were 46.9 ranged from 22 to 63 years. The most frequent metastatic malignancy was carcinoma (60%), followed by melanoma (33%) and sarcoma (7%). Of the 9 patients with metastatic carcinoma, the primary tumor originated from the lungs in 4, from gastrointestinal system in 2, female genital tract in 2, and kidney in 1 patient. Sarcoma diagnosis was given in a single patient and the histology was a leiomyosarcoma originating from kidney. A careful histomorphological and immunohistochemical evaluation and a detailed examination of the clinicoradiological data are critical to establish the right course in patient management, treatment plan and to correctly predict the prognosis.


How Plants Sense and Respond to Stressful Environments.
Plants are exposed to an ever-changing environment to which they have to adjust accordingly. Their response is tightly regulated by complex signaling pathways that all start with stimulus perception. Here, we give an overview of the latest developments in the perception of various abiotic stresses, including drought, salinity, flooding, and temperature stress. We discuss whether proposed perception mechanisms are true sensors, which is well established for some abiotic factors but not yet fully elucidated for others. In addition, we review the downstream cellular responses, many of which are shared by various stresses but result in stress-specific physiological and developmental output. New sensing mechanisms have been identified, including heat sensing by the photoreceptor phytochrome B, salt sensing by glycosylinositol phosphorylceramide sphingolipids, and drought sensing by the specific calcium influx channel OSCA1. The simultaneous occurrence of multiple stress conditions shows characteristic downstream signaling signatures that were previously considered general signaling responses. The integration of sensing of multiple stress conditions and subsequent signaling responses is a promising venue for future research to improve the understanding of plant abiotic stress perception.


The flagellar apparatus of the glaucophyte Cyanophora cuspidata.
Glaucophytes are a kingdom-scale lineage of unicellular algae with uniquely underived plastids. The genus Cyanophora is of particular interest because it is the only glaucophyte that is a flagellate throughout its life cycle, making its morphology more directly comparable than other glaucophytes to other eukaryote flagellates. The ultrastructure of Cyanophora has already been studied, primarily in the 1960s and 1970s. However, the usefulness of that work has been undermined by its own limitations, subsequent misinterpretations, and a recent taxonomic revision of the genus. For example, Cyanophora's microtubular roots have been widely reported as cruciate, with rotationally symmetrical wide and thin roots, although the first ultrastructural work described it as having three wide and one narrow root. We examine Cyanophora cuspidata using scanning and transmission electron microscopy, and construct a model of its cytoskeleton using serial-section TEM. We confirm the earlier model, with asymmetric roots. We describe previously unknown and unsuspected features of its microtubular roots, including (i) a rearrangement of individual microtubules within the posterior right root, (ii) a splitting of the posterior left root into two subroots, and (iii) the convergence and termination of the narrow roots against wider ones in both the anterior and posterior subsystems of the flagellar apparatus. We also describe a large complement of nonmicrotubular components of the cytoskeleton, including a substantial connective between the posterior right root and the anterior basal body. Our work should serve as the starting point for a re-examination of both internal glaucophyte diversity and morphological evolution in eukaryotes.


Immunization for adolescents.
The current status of immunization practice and recommendations for adolescents is reviewed. Vaccines for diptheria, tetanus, pertussis, measles, mumps and rubella are discussed in detail and vaccines for influenza, the pneumococci, meningococci, varicella, rabies, smallpox and tuberculosis briefly reviewed. Special attention is paid to those aspects of each vaccine and disease particularly appropriate to the adolescent age period.


Expressed emotion-criticism and risk of depression onset in children.
The primary goal of the current study was to examine the impact of maternal criticism (expressed emotion-criticism; EE-Crit) on the prospective development of depressive episodes in children. In addition to examining baseline levels of EE-Crit, we also sought to determine whether distinct subgroups (latent classes) of mothers could be identified based on the levels of EE-Crit they exhibited over a multiwave assessment and whether that latent class membership would predict depression onset in children. Finally, we examined whether EE-Crit and maternal depression would independently predict children's depression risk or whether EE-Crit would moderate the link between maternal depression and children's depression onset. Children of mothers with or without a history of major depression (N = 100) were assessed 5 times over 20 months. Children completed the Children's Depression Inventory and mothers completed the Five Minute Speech Sample and the Beck Depression Inventory at the baseline assessment, and at 2-, 4-, and 6-month follow-up assessments. Children and mothers completed diagnostic interviews assessing children's onsets of depressive episodes at the 20-month follow-up. Latent class analysis of the 4 waves of EE-Crit assessments revealed two distinct groups, exhibiting relatively lower versus higher levels of EE-Crit across the first 6 months of follow-up. EE-Crit latent class membership predicted children's depression onset over the subsequent 14 months. This finding was maintained after controlling for mother's and children's depressive symptoms during the initial 6 months of follow-up. Finally, maternal depression did not moderate the link between EE-Crit and childhood depression onset. Continued exposure to maternal criticism appears to be an important risk factor for depression in children, risk that is at least partially independent of the risk conveyed by maternal depression. These results highlight the importance of a modifiable risk factor for depression-repeated exposure to maternal criticism.


[A case of thiamine deficiency with psychotic symptoms--blood concentration of thiamine and response to therapy].
We report the case of a 63-year-old woman with thiamine deficiency who showed auditory hallucinations, a delusion of persecution, catatonic stupor, and catalepsy but no neurological symptoms including oculomotor or gait disturbance. Brain MRI did not show high-intensity T2 signals in regions including the thalami, mamillary bodies, or periaqueductal area. Her thiamine concentration was 19 ng/mL, only slightly less than the reference range of 20-50 ng/mL. Her psychosis was unresponsive to antipsychotics or electroconvulsive therapy, but was ameliorated by repetitive intravenous thiamine administrations at 100-200 mg per day. However, one month after completing intravenous treatment, her psychosis recurred, even though she was given 150 mg of thiamine per day orally and her blood concentration of thiamine was maintained at far higher than the reference range. Again, intravenous thiamine administration was necessary to ameliorate her symptoms. The present patient indicates that the possibility of thiamine deficiency should be considered in cases of psychosis without neurological disturbance and high-intensity T2 MRI lesions. Also, this case suggests that a high blood thiamine concentration does not necessarily correspond to sufficient thiamine levels in the brain. Based on this, we must reconsider the importance of a high dose of thiamine administration as a therapy for thiamine deficiency. The validity of the reference range of the thiamine concentration, 20-50 ng/mL, is critically reviewed.


Cell-Permeable Succinate Rescues Mitochondrial Respiration in Cellular Models of Amiodarone Toxicity.
Amiodarone is a potent antiarrhythmic drug and displays substantial liver toxicity in humans. It has previously been demonstrated that amiodarone and its metabolite (desethylamiodarone, DEA) can inhibit mitochondrial function, particularly complexes I (CI) and II (CII) of the electron transport system in various animal tissues and cell types. The present study, performed in human peripheral blood cells, and one liver-derived human cell line, is primarily aimed at assessing the concentration-dependent effects of these drugs on mitochondrial function (respiration and cellular ATP levels). Furthermore, we explore the efficacy of a novel cell-permeable succinate prodrug in alleviating the drug-induced acute mitochondrial dysfunction. Amiodarone and DEA elicit a concentration-dependent impairment of mitochondrial respiration in both intact and permeabilized platelets via the inhibition of both CI- and CII-supported respiration. The inhibitory effect seen in human platelets is also confirmed in mononuclear cells (PBMCs) and HepG2 cells. Additionally, amiodarone elicits a severe concentration-dependent ATP depletion in PBMCs, which cannot be explained solely by mitochondrial inhibition. The succinate prodrug NV118 alleviates the respiratory deficit in platelets and HepG2 cells acutely exposed to amiodarone. In conclusion, amiodarone severely inhibits metabolism in primary human mitochondria, which can be counteracted by increasing mitochondrial function using intracellular delivery of succinate.


Influence of Baseline Diastolic Blood Pressure on Effects of Intensive Compared With Standard Blood Pressure Control.
In individuals with a low diastolic blood pressure (DBP), the potential benefits or risks of intensive systolic blood pressure (SBP) lowering are unclear. SPRINT (Systolic Blood Pressure Intervention Trial) was a randomized controlled trial that compared the effects of intensive (target <120 mm Hg) and standard (target <140 mm Hg) SBP control in 9361 older adults with high blood pressure at increased risk of cardiovascular disease. The primary outcome was a composite of cardiovascular disease events. All-cause death and incident chronic kidney disease were secondary outcomes. This post hoc analysis examined whether the effects of the SBP intervention differed by baseline DBP. Mean baseline SBP and DBP were 139.7±15.6 and 78.1±11.9 mm Hg, respectively. Regardless of the randomized treatment, baseline DBP had a U-shaped association with the hazard of the primary cardiovascular disease outcome. However, the effects of the intensive SBP intervention on the primary outcome were not influenced by baseline DBP level (P for interaction=0.83). The primary outcome hazard ratio for intensive versus standard treatment was 0.78 (95% confidence interval, 0.57-1.07) in the lowest DBP quintile (mean baseline DBP, 61±5 mm Hg) and 0.74 (95% confidence interval, 0.61-0.90) in the upper 4 DBP quintiles (mean baseline DBP, 82±9 mm Hg), with an interaction P value of 0.78. Results were similar for all-cause death and kidney events. Low baseline DBP was associated with increased risk of cardiovascular disease events, but there was no evidence that the benefit of the intensive SBP lowering differed by baseline DBP. URL: https://www.clinicaltrials.gov. Unique identifier: NCT01206062.


A randomized trial of pregabalin in patients with neuropathic pain due to spinal cord injury.
To assess the efficacy and tolerability of pregabalin for the treatment of central neuropathic pain after spinal cord injury (SCI). Patients with chronic, below-level, neuropathic pain due to SCI were randomized to receive 150 to 600 mg/d pregabalin (n = 108) or matching placebo (n = 112) for 17 weeks. Pain was classified in relation to the neurologic level of injury, defined as the most caudal spinal cord segment with normal sensory and motor function, as above, at, or below level. The primary outcome measure was duration-adjusted average change in pain. Key secondary outcome measures included the change in mean pain score from baseline to end point, the percentage of patients with ≥30% reduction in mean pain score at end point, patient global impression of change scores at end point, and the change in mean pain-related sleep interference score from baseline to end point. Additional outcome measures included the medical outcomes study-sleep scale and the Hospital anxiety and depression scale. Pregabalin treatment resulted in statistically significant improvements over placebo for all primary and key secondary outcome measures. Significant pain improvement was evident as early as week 1 and was sustained throughout the treatment period. Adverse events were consistent with the known safety profile of pregabalin and were mostly mild to moderate in severity. Somnolence and dizziness were most frequently reported. This study demonstrates that pregabalin is effective and well tolerated in patients with neuropathic pain due to SCI. This study provides class I evidence that pregabalin, 150 to 600 mg/d, is effective in reducing duration-adjusted average change in pain compared with baseline in patients with SCI over a 16-week period (p = 0.003, 95% confidence interval = -0.98, -0.20).


Cutaneotrichosporon curvatum and Yarrowia lipolytica as key players for green chemistry: efficient oil producers from food waste via the carboxylate platform.
Cutaneotrichosporon curvatum and Yarrowia lipolytica can accumulate microbial oils using short-chain fatty acids (SCFA) as carbon sources. SCFAs-rich media often contain significant amounts of nitrogen that prevent high carbon:nitrogen (C:N) ratios necessary to boost lipid production. This work assessed the intrinsic ability of C. curvatum and Y. lipolytica to produce high amounts of microbial oils from these unusual carbon sources. Results demonstrated that minor differences in SCFA concentration (only 2 g/L) had a significant effect on yeast growth and lipid production. A C:N of 80 promoted yeast growth at all SCFA concentrations and favored SCFA consumption at 19 g/L SCFAs. The different SCFA uptake preferences in C. curvatum and Y. lipolytica highlighted the importance of considering the SCFA profile to select a suitable yeast strain for microbial oils production. At the most challenging SCFA concentration (19 g/L), 57.2% ±1.6% (w/w) and 78.4 ± 0.6% (w/w) lipid content were obtained in C. curvatum and Y. lipolytica, respectively. These values are among the highest reported for wild-type strains. To circumvent the challenges associated with media with high nitrogen content, this report also proved struvite precipitation as an effective method for increasing lipid production (from 17.9 ± 3.9% (w/w) to 41.9 ± 2.6% (w/w)) after nitrogen removal in food waste-derived media.


Emotion regulation in children with behavior problems: linking behavioral and brain processes.
Past studies have shown that aggressive children exhibit rigid (rather than flexible) parent-child interactions; these rigid repertoires may provide the context through which children fail to acquire emotion-regulation skills. Difficulties in regulating emotion are associated with minimal activity in dorsal systems in the cerebral cortex, for example, the anterior cingulate cortex. The current study aimed to integrate parent-child and neurocognitive indices of emotion regulation and examine their associations for the first time. Sixty children (8-12 years old) referred for treatment for aggression underwent two assessments. Brain processes related to emotion regulation were assessed using dense-array EEG with a computerized go/no-go task. The N2 amplitudes thought to tap inhibitory control were recorded, and a source analysis was conducted. In the second assessment, parents and children were videotaped while trying to solve a conflict topic. State space grids were used to derive two dynamic flexibility parameters from the coded videotapes: (a) the number of transitions between emotional states and (b) the dispersion of emotional states, based on proportional durations in each state. The regression results showed that flexibility measures were not related to N2 amplitudes. However, flexibility measures were significantly associated with the ratio of dorsal to ventral source activation: for transitions, ΔR 2 = .27, F (1, 34) = 13.13, p = .001; for dispersion, ΔR 2 = .29, F (1, 35) = 14.76, p < .001. Thus, in support of our main hypothesis, greater dyadic flexibility was associated with a higher ratio of dorsomedial to ventral activation, suggesting that children with more flexible parent-child interactions are able to recruit relatively more dorsomedial activity in challenging situations.


State helmet laws and helmet use among fatally injured moped riders in the United States, 2011-2015.
Research has found that mandatory motorcycle helmet laws increase helmet use and reduce motorcycle-related fatalities. However, the association between state moped helmet laws and helmet use in the United States has not been examined. This study investigated this association among a census of fatally injured moped riders in the United States. A logistic regression model was constructed to analyze data extracted from the Fatality Analysis Reporting System (FARS) to examine risk factors for helmet nonuse among 572 moped riders fatally injured between 2011 and 2015. Fatally injured moped riders in states with universal helmet laws had 69 times the odds of wearing a helmet (P < .001). Findings suggest that universal moped helmet laws increase helmet use. However, additional research is needed to examine helmet laws and use among nonfatally injured moped riders.


Time-resolved X-ray excited optical luminescence from tris(2-phenyl pyridine)iridium [corrected].
Time-resolved X-ray Excited Optical Luminescence (TRXEOL) has been developed to investigate the optical properties of a green organometallic phosphor, tris(2-phenyl pyridine)iridium, Ir(ppy)3. Using time-gated measurements, we find that the characteristic luminescence band from a neat Ir(ppy)3 film is composed of a fast channel at approximately 534 nm and a slower channel at approximately 580 nm. The implication of this study and the applicability of the technique in the study of light emitting materials are noted.


Electrochemically powered self-propelled electrophoretic nanosubmarines.
In the past few years, we have witnessed rapid developments in the realization of the old nanotechnology dream, autonomous nanosubmarines. These nanomachines are self-powered, taking energy from their environment by electrocatalytic conversion of chemicals present in the solution, self-propelled by flux of the electrons within the submarine and the hydronium ions on the surface of the nanosub, powering it in the direction opposite to that of the flux of the hydronium. These nanosubmarines are responsive to external fields, able to follow complex magnetic patterns, navigate themselves in complex microfluidic channels, follow chemical gradients, carry cargo, and communicate with each other. This minireview focuses on a discussion of the fundamentals of the electrophoretic mechanism underlying the propulsion of this sort of nanosub, as well as a demonstration of the proof-of-concept capabilities of nanosubmarines.


Patterns of corticotropic cells in the adult human pituitary in Cushing's disease.
The overall anatomical distribution of specifically stained corticotropic cells has been studied in pituitaries obtained at autopsy from 9 patients with Cushing's disease. Three patterns have been demonstrated consistent with the theory that it is not a single entity, but that some cases are of primary pituitary aetiology, whereas others are the result of hypothalamic or central nervous system dysfunction. The junctional corticotropic cells appear to react differently from those in the anterior pituitary to some stimuli, supporting the hypothesis that these cells may represent the remnants of the pars intermedia in the human adult, and suggesting that they may have some as yet unidentified physiological function.


Increased numbers of orexin/hypocretin neurons in a genetic rat depression model.
The Flinders Sensitive Line (FSL) rat is a genetic animal model of depression that displays characteristics similar to those of depressed patients including lower body weight, decreased appetite and reduced REM sleep latency. Hypothalamic neuropeptides such as orexin/hypocretin, melanin-concentrating hormone (MCH) and cocaine and amphetamine regulated transcript (CART), that are involved in the regulation of both energy metabolism and sleep, have recently been implicated also in depression. We therefore hypothesized that alterations in these neuropeptide systems may play a role in the development of the FSL phenotype with both depressive like behavior, metabolic abnormalities and sleep disturbances. In this study, we first confirmed that the FSL rats displayed increased immobility in the Porsolt forced swim test compared to their control strain, the Flinders Resistant Line (FRL), which is indicative of depressive-like behavior. We then examined the number of orexin-, MCH- and CART-immunopositive neurons in the hypothalamus using stereological analyses. We found that the total number of orexin-positive neurons was higher in the hypothalamus of female FSL rats compared to female FRL rats, whereas no changes in the MCH or CART populations could be detected between the strains. Chronic treatment with the selective serotonin reuptake inhibitor (SSRI) escitalopram reduced immobility only in the FRL rats where it also increased the number of MCH positive neurons compared to untreated rats. These findings support the view that orexin may be involved in depression and strengthen the notion that the "depressed" brain responds differently to pharmacological interventions than the normal brain.


Prevalence of iron deficiency in pregnant women: A prospective cross-sectional Austrian study.
The aim of the study was to determine, for the first time, in a prospective cross-sectional multicenter study, the prevalence of iron deficiency (ID) in an Austrian pregnant population. A cohort of 425 pregnant women was classified into four groups of different weeks of gestation. Group 1 was monitored longitudinally, while groups 2-4, iron status, were sampled only once. Evaluation of the prevalence of ID was performed by comparing the diagnostic criteria of the WHO to the cutoff proposed by Achebe MM and Gafter-Gvili A (Achebe) and the Austrian Nutrition Report (ANR). In comparison with the ANR, the prevalence of ID was lower in group 1 and higher in groups 2-4 (17.2% vs. 12.17%, 25.84%, 35.29%, and 41.76%, respectively) (p-values < .01 except group 1). According to WHO, the prevalence in group 1 was 12.17% at inclusion, 2 months later 31.7%, and further 2 months later 65.71%, respectively. According to Achebe, the number of cases doubled; for group 1, the number of cases rose from 13 to 42 (115 patients total); for groups 2-4, we observed an increase from 112 to 230 (340 patients total). This study reported a prevalence of around 12% at the beginning of pregnancy, which increased during pregnancy up to 65%. ID can have a massive impact on quality of life, justifying screening, as iron deficiency would be easy to diagnose and treat.


Ecosystem consequences of multi-trait response to environmental changes in Japanese medaka, Oryzias latipes.
Intraspecific trait variation has large effects on the ecosystem and is greatly affected by human activities. To date, most studies focused on single-trait analyses, while considering multiple traits is expected to better predict how an individual interacts with its environment. Here, we used a mesocosm experiment with fish Oryzias latipes to test whether individual growth, boldness and functional traits (feeding rate and stoichiometric traits) formed one functional pace-of-life syndrome (POLS). We then tested the effects of among-individual mean and variance of fish functional POLSs within mesocosms on invertebrate community (e.g. zoobenthos and zooplankton abundances) and ecosystem processes (e.g. ecosystem metabolism, algae stock, nutrient concentrations). Stoichiometric traits correlated with somatic growth and behaviours, forming two independent functional POLS (i.e. two major covariance axes). Mean values of the first syndrome were sex- and environment-dependent and were associated with (i) long-term (10 generations; 4 years) selection for small or large body size resulting in contrasting life histories and (ii) short-term (6 weeks) effects of experimental treatments on resource availability (through manipulation of light intensity and interspecific competition). Specifically, females and individuals from populations selected for a small body size presented fast functional POLS with faster growth rate, higher carbon body content and lower boldness. Individuals exposed to low resources (low light and high competition) displayed a slow functional POLS. Higher mesocosm mean and variance values in the second functional POLS (i.e. high feeding rate, high carbon:nitrogen body ratio, low ammonium excretion rate) were associated to decreased prey abundances, but did not affect any of the ecosystem processes. We highlighted the presence of functional multi-trait covariation in medaka, which were affected by sex, long-term selection history and short-term environmental conditions, that ultimately had cascading ecological consequences. We stressed the need for applying this approach to better predict ecosystem response to anthropogenic global changes.


Correlation at two-dimensional charge-transfer FeSe interface.
The charge transfer and spin coupling effects are explored at the interface of two-dimensional (2D) superconducting FeSe nanosheets and molecular photochromic potassium-7,7,8,8-tetracyanoquinodimethane (KTCNQ). Light-induced conductivity in 2D FeSe nanosheets is enhanced by the electron doping from KTCNQ by the destabilized spin-Peierls phase through their interface. Furthermore, the spin coupling at the interface of FeSe and KTCNQ shifts the dimerization transition temperature of KTCNQ. Our results suggest 2D exfoliated FeSe nanosheets as a versatile strongly correlated platform for the study of interfacial electron doping and spin coupling.


Charge Carrier Mobility Improvement in Diketopyrrolopyrrole Block-Copolymers by Shear Coating.
Shear coating is a promising deposition method for upscaling device fabrication and enabling high throughput, and is furthermore suitable for translating to roll-to-roll processing. Although common polymer semiconductors (PSCs) are solution processible, they are still prone to mechanical failure upon stretching, limiting applications in e.g., electronic skin and health monitoring. Progress made towards mechanically compliant PSCs, e.g., the incorporation of soft segments into the polymer backbone, could not only allow such applications, but also benefit advanced fabrication methods, like roll-to-roll printing on flexible substrates, to produce the targeted devices. Tri-block copolymers (TBCs), consisting of an inner rigid semiconducting poly-diketo-pyrrolopyrrole-thienothiophene (PDPP-TT) block flanked by two soft elastomeric poly(dimethylsiloxane) (PDMS) chains, maintain good charge transport properties, while being mechanically soft and flexible. Potentially aiming at the fabrication of TBC-based wearable electronics by means of cost-efficient and scalable deposition methods (e.g., blade-coating), a tolerance of the electrical performance of the TBCs to the shear speed was investigated. Herein, we demonstrate that such TBCs can be deposited at high shear speeds (film formation up to a speed of 10 mm s-1). While such high speeds result in increased film thickness, no degradation of the electrical performance was observed, as was frequently reported for polymer-based OFETs. Instead, high shear speeds even led to a small improvement in the electrical performance: mobility increased from 0.06 cm2 V-1 s-1 at 0.5 mm s-1 to 0.16 cm2 V-1 s-1 at 7 mm s-1 for the TBC with 24 wt% PDMS, and for the TBC containing 37 wt% PDMS from 0.05 cm2 V-1 s-1 at 0.5 mm s-1 to 0.13 cm2 V-1 s-1 at 7 mm s-1. Interestingly, the improvement of mobility is not accompanied by any significant changes in morphology.


Cholesterol inhibits M-type K+ channels via protein kinase C-dependent phosphorylation in sympathetic neurons.
M-type (KCNQ) potassium channels play an important role in regulating the action potential firing in neurons. Here, we investigated the effect of cholesterol on M current in superior cervical ganglion (SCG) sympathetic neurons, using the patch clamp technique. M current was inhibited in a dose-dependent manner by cholesterol loading with a methyl-beta-cyclodextrin-cholesterol complex. This effect was prevented when membrane cholesterol level was restored by including empty methyl-beta-cyclodextrin in the pipette solution. Dialysis of cells with AMP-PNP instead of ATP prevented cholesterol action on M currents. Protein kinase C (PKC) inhibitor, calphostin C, abolished cholesterol-induced inhibition whereas the PKC activator, PDBu, mimicked the inhibition of M currents by cholesterol. The in vitro kinase assay showed that KCNQ2 subunits of M channel can be phosphorylated by PKC. A KCNQ2 mutant that is defective in phosphorylation by PKC failed to show current inhibition not only by PDBu but also by cholesterol. These results indicate that cholesterol-induced inhibition of M currents is mediated by PKC phosphorylation. The inhibition of M currents by PDBu and cholesterol was completely blocked by PIP(2) loading, indicating that the decrease in PIP(2)-channel interaction underlies M channel inhibition by PKC-mediated phosphorylation. We conclude that cholesterol specifically regulates M currents in SCG neurons via PKC activation.


Validating alcohol use measures among male drinkers in Goa: implications for research on alcohol, sexual risk, and HIV in India.
Assessment of heavy drinking patterns is vital for HIV/AIDs studies in India and developing countries. A population survey in northern Goa included urban and rural male drinkers (n = 743) who completed a new Fractional Graduated Frequencies (F-GF) alcohol patterns measure assessing seven beverage types and drink sizes for the largest daily amount, then drinking frequencies at fractional amounts. The new measure was compared to a simpler quantity-frequency (QF) summary and, in a validity subsample of hazardous drinkers (n = 56), 28-day diaries of drinking events. Approximately 56% of total volume came from peak drinking (averaging 60 g ethanol/day). For AUDIT-based Hazardous Drinkers, QF and F-GF volumes (drinks/day) were not significantly different from diary volume (correlations 0.65 and 0.57, respectively). F-GF well captured the profile of daily amounts in drinking event data. In addition, the F-GF showed evidence of better predicting any sexual risk behavior or partner violence perpetration than the QF measure. Summary drinking pattern measures, especially the new F-GF, are more cost efficient than intensive event records, and appear valid when carefully assessing quantities with local beverage types and drink ethanol content.


A randomized, double-blind, placebo-controlled crossover study of the effect of exogenous melatonin on delayed sleep phase syndrome.
The effects of exogenous melatonin on sleep, daytime sleepiness, fatigue, and alertness were investigated in 22 patients with delayed sleep phase syndrome whose nocturnal sleep was restricted to the interval from 24:00 to 08:00 hours. This study was a randomized, double-blind, placebo-controlled crossover trial. Subjects received either placebo or melatonin (5 mg) daily for 4 weeks, underwent a 1-week washout period, and then were given the other treatment for an additional 4 weeks. Patients could take the melatonin between 19:00 and 21:00 hours, which allowed them to select the time they felt to be most beneficial for the phase-setting effects of the medication. Two consecutive overnight polysomnographic recordings were performed on three occasions: at baseline (before treatment), after 4 weeks of melatonin treatment, and after 4 weeks of placebo treatment. In the 20 patients who completed the study, sleep onset latency was significantly reduced while subjects were taking melatonin as compared with both placebo and baseline. There was no evidence that melatonin altered total sleep time (as compared with baseline total sleep time), but there was a significant decrease in total sleep time while patients were taking placebo. Melatonin did not result in altered scores on subjective measures of sleepiness, fatigue, and alertness, which were administered at different times of the day. After an imposed conventional sleep period (from 24:00 to 08:00), subjects taking melatonin reported being less sleepy and fatigued than they did while taking placebo. Melatonin ameliorated some symptoms of delayed sleep phase syndrome, as confirmed by both objective and subjective measures. No adverse effects of melatonin were noted during the 4-week treatment period.


The influence of school-based natural mentoring relationships on school attachment and subsequent adolescent risk behaviors.
A relatively new area of research suggests that naturally occurring mentoring relationships may influence the development of adolescents by protecting against risk behaviors. Few studies have explored how these relationships function to reduce risk behavior among youth, especially in the school context. Based on previous research and theory, we proposed and tested a mediation model, which hypothesized that school attachment mediated the longitudinal association between school-based natural mentoring relationships and risk behaviors, including eight indicators of substance use and violence. Students (N = 3320) from 65 high schools across eight states completed a self-report questionnaire at baseline and 1-year follow-up. The sample was comprised of youth with an average age of 14.8 years and an almost equal percentage of females (53%) and males from various ethnic backgrounds. Tests for mediation were conducted in Mplus using path analysis with full information maximum likelihood procedures and models adjusted for demographic covariates and baseline level of the dependent variable. Results suggested that natural mentoring relationships had a protective indirect influence on all eight risk behaviors through its positive association on the school attachment mediator. Implications are discussed for strengthening the association between school-based natural mentoring and school attachment to prevent risk behaviors among youth.


Interactions among p22, glyceraldehyde-3-phosphate dehydrogenase and microtubules.
Previously, we have shown that p22, an EF-hand Ca2+-binding protein, interacts indirectly with microtubules in an N-myristoylation-dependent and Ca2+-independent manner. In the present study, we report that N-myristoylated p22 interacts with several microtubule-associated proteins within the 30-100 kDa range using overlay blots of microtubule pellets containing cytosolic proteins. One of those p22-binding partners, a 35-40 kDa microtubule-binding protein, has been identified by MS as GAPDH (glyceraldehyde-3-phosphate dehydrogenase). Several lines of evidence suggest a functional relationship between GAPDH and p22. First, endogenous p22 interacts with GAPDH by immunoprecipitation. Secondly, p22 and GAPDH align along microtubule tracks in analogous punctate structures in BHK cells. Thirdly, GAPDH facilitates the p22-dependent interactions between microtubules and microsomal membranes, by increasing the ability of p22 to bind microtubules but not membranes. We have also shown a direct interaction between N-myristoylated p22 and GAPDH in vitro with a K(D) of approximately 0.5 microM. The removal of either the N-myristoyl group or the last six C-terminal amino acids abolishes the binding of p22 to GAPDH and reduces the ability of p22 to associate with microtubules. In summary, we report that GAPDH is involved in the ability of p22 to facilitate microtubule-membrane interactions by affecting the p22-microtubule, but not the p22-membrane, association.


Contribution of endoplasmic reticulum to Ca(2+) signals in Dictyostelium depends on extracellular Ca(2+).
We recently reported the first molecular genetic evidence that Dictyostelium Ca(2+) responses to chemoattractants include a contribution from the endoplasmic reticulum (ER) - responses are enhanced in mutants lacking calreticulin or calnexin, two major Ca(2+)-binding proteins in the ER, even though the influx of Ca(2+) into the mutants is reduced. Compared with wild-type cells, the ER in the mutants contributes at least 30-70 nM additional Ca(2+) to the responses. Here we report that this additional ER contribution to the cytosolic Ca(2+) signal depends upon extracellular Ca(2+)- it does not occur in the absence of extracellular Ca(2+), increases to a maximum as the extracellular Ca(2+) levels rise to 10 microM and then remains constant at extracellular Ca(2+) concentrations up to at least 250 microM. These results suggest that Ca(2+) influx causes the intracellular release, in the simplest scenario by a mechanism involving Ca(2+)-induced Ca(2+) release from the ER. By way of contrast, we show that Ca(2+) responses to mechanical stimulation are reduced, but still occur in the absence of extracellular Ca(2+). Unlike the responses to chemoattractants, mechanoresponses thus include contributions from the ER that are independent of extracellular Ca(2+).