Differential effect of actomyosin relaxation on the dynamic properties of focal adhesion proteins.
Treatment of cultured cells with inhibitors of actomyosin contractility induces rapid deterioration of stress fibers, and disassembly of the associated focal adhesions (FAs). In this study, we show that treatment with the Rho kinase inhibitor Y-27632, which blocks actomyosin contractility, induces disarray in the FA-associated actin bundles, followed by the differential dissociation of eight FA components from the adhesion sites. Live-cell microscopy indicated that the drug triggers rapid dissociation of VASP and zyxin from FAs (τ values of 7-8 min), followed by talin, paxillin and ILK (τ ~16 min), and then by FAK, vinculin and kindlin-2 (τ = 25-28 min). Examination of the molecular kinetics of the various FA constituents, using Fluorescence Recovery After Photobleaching (FRAP), in the absence of or following short-term treatment with the drug, revealed major changes in the kon and koff values of the different proteins tested, which are in close agreement with their differential dissociation rates from the adhesion sites. These findings indicate that mechanical, actomyosin-generated forces differentially regulate the molecular kinetics of individual FA-associated molecules, and thereby modulate FA composition and stability.


The role of the mora in the timing of spontaneous Japanese speech.
This study investigates whether the mora is used in controlling timing in Japanese speech, or is instead a structural unit in the language not involved in timing. Unlike most previous studies of mora-timing in Japanese, this article investigates timing in spontaneous speech. Predictability of word duration from number of moras is found to be much weaker than in careful speech. Furthermore, the number of moras predicts word duration only slightly better than number of segments. Syllable structure also has a significant effect on word duration. Finally, comparison of the predictability of whole words and arbitrarily truncated words shows better predictability for truncated words, which would not be possible if the truncated portion were compensating for remaining moras. The results support an accumulative model of variance with a final lengthening effect, and do not indicate the presence of any compensation related to mora-timing. It is suggested that the rhythm of Japanese derives from several factors about the structure of the language, not from durational compensation.


Prevalence of sleep problems in Japanese preschoolers in a medium-sized city: Community-based survey using the Children's Sleep Habits Questionnaire.
Although the mean score of the Children's Sleep Habits Questionnaire (CSHQ) differs between countries, there are no normative data for the CSHQ of Japanese preschoolers based on a community sample. The aims of this study were therefore to present normative data for the CSHQ and determine the prevalence and characteristics of sleep problems in Japanese preschoolers. Parents or the primary caregiver of 482 preschoolers aged 4-5 years completed the CSHQ and the Strength and Difficulties Questionnaire. Approximately 80% of preschoolers scored above the cut-off for sleep disturbance on the CSHQ. In addition, co-sleeping was prevalent in Japanese preschoolers but the habit of co-sleeping contributed little to behavioral and emotional problems. Sleep problems appear to be prevalent in Japanese preschoolers based on the CSHQ, and could be associated with the Japanese sleep habit of co-sleeping.


Targeting Somatostatin Receptors By Functionalized Mesoporous Silica Nanoparticles - Are We Striking Home?
The concept of delivering nanoformulations to desired tissues by means of targeting membrane receptors of high local abundance by ligands anchored to the nanocarrier has gained a lot of attention over the last decade. Currently, there is no unanimous opinion on whether surface functionalization of nanocarriers by targeting ligands translates into any real benefit in terms of pharmacokinetics or treatment outcomes. Having examined the published nanocarriers designed to engage with somatostatin receptors, we realized that in the majority of cases targetability claims were not supported by solid evidence of targeting ligand-targeted receptor coupling, which is the very crux of a targetability concept. Here, we present an approach to characterize targetability of mesoporous silica-based nanocarriers functionalized with ligands of somatostatin receptors. The targetability proof in our case comes from a functional assay based on a genetically-encoded cAMP probe, which allows for real-time capture of receptor activation in living cells, triggered by targeting ligands on nanoparticles. We elaborate on the development and validation of the assay, highlighting the power of proper functional tests in the characterization pipeline of targeted nanoformulations.


Immunization information systems in Canada: Attributes, functionality, strengths and challenges. A Canadian Immunization Research Network study.
Canada does not have a national immunization registry. Diverse systems to record vaccine uptake exist, but these have not been systematically described. Our objective was to describe the immunization information systems (IISs) and non-IIS processes used to record childhood and adolescent vaccinations, and to outline the strengths and limitations of the systems and processes. We collected information from key informants regarding their provincial, territorial or federal organization's surveillance systems for assessing immunization coverage. Information collection consisted of a self-administered questionnaire and a follow-up interview. We evaluated systems against attributes derived from the literature using content analysis. Twenty-six individuals across 16 public health organizations participated over the period of April to August 2015. Twelve of Canada's 13 provinces and territories (P/Ts) and two organizations involved in health service delivery for on-reserve First Nations people participated. Across systems, there were differences in data collection processes, reporting capabilities and advanced functionality. Commonly cited challenges included timeliness and data completeness of records, particularly for physician-administered immunizations. Privacy considerations and the need for data standards were stated as challenges to the goal of information sharing across P/T systems. Many P/Ts have recently implemented new systems and, in some cases, legislation to improve timeliness and/or completeness. Considerable variability exists among IISs and non-IIS processes used to assess immunization coverage in Canada. Although some P/Ts have already pursued legislative or policy initiatives to address the completeness and timeliness of information, many additional opportunities exist in the information technology realm.


Identification and characterization of SSRs from soybean (Glycine max) ESTs.
Microsatellites, or simple sequence repeats (SSRs), are very useful molecular markers for a number of plant species. We used a new publicly available module (TROLL) to extract microsatellites from the public database of soybean expressed sequence tag (EST) sequences. A total of 12,833 sequences containing di- to penta-type SSRs were identified from 200,516 non-redundant soybean ESTs. On average, one SSR was found per 7.25 kb of EST sequences, with the tri-nucleotide motifs being the most abundant. Primer sequences flanking the SSR motifs were successfully designed for 9,638 soybean ESTs using the software primer3.0 and only 59 pairs of them were found in earlier studies. We synthesized 124 pairs of the primers to determine the polymorphism and heterozygosity among eight genotypes of soybean cultivars, which represented a wide range of the cultivated soybean cultivars. PCR amplification products with anticipated SSRs were obtained with 81 pairs of primers; 36 PCR products appeared to be homozygous and the remaining 45 PCR products appeared to be heterozygous and displayed polymorphism among the eight cultivars. We further analysed the EST sequences containing 45 polymorphic EST-SSR markers using the programs BLASTN and BLASTX. Sequence alignment showed that 29 ESTs have homologous sequences and 15 ESTs could be classified into a Uni-gene cluster with comparatively convincing protein products. Among these 15 ESTs belonging to a Uni-gene cluster, 9 SSRs were located in 3'-UTR, 4 SSRs were located in the intron region and 2 SSRs were located in the CDS region. None of these SSRs was located in the 5'-UTR. These novel SSRs identified in the ESTs of soybean provide useful information for gene mapping and cloning in future studies.


Abnormal cardiac structure and function in mice expressing nonphosphorylatable cardiac regulatory myosin light chain 2.
A role for myosin phosphorylation in modulating normal cardiac function has long been suspected, and we hypothesized that changing the phosphorylation status of a cardiac myosin light chain might alter cardiac function in the whole animal. To test this directly, transgenic mice were created in which three potentially phosphorylatable serines in the ventricular isoform of the regulatory myosin light chain were mutated to alanines. Lines were obtained in which replacement of the endogenous species in the ventricle with the nonphosphorylatable, transgenically encoded protein was essentially complete. The mice show a spectrum of cardiovascular changes. As previously observed in skeletal muscle, Ca(2+) sensitivity of force development was dependent upon the phosphorylation status of the regulatory light chain. Structural abnormalities were detected by both gross histology and transmission electron microscopic analyses. Mature animals showed both atrial hypertrophy and dilatation. Echocardiographic analysis revealed that as a result of chamber enlargement, severe tricuspid valve insufficiency resulted in a detectable regurgitation jet. We conclude that regulated phosphorylation of the regulatory myosin light chains appears to play an important role in maintaining normal cardiac function over the lifetime of the animal.


Increased risk of pulmonary embolism among patients with hyperthyroidism: a 5-year follow-up study.
Although studies have indicated that hyperthyroidism is associated with hypercoagulability, most such studies have focused only on examining the incidence of venous thrombosis. As far as we know, no study has attempted to explore the risk of pulmonary embolism (PE) among patients with hyperthyroidism. Using a nationwide population-based dataset, this study was aimed at estimating the risk of PE among hyperthyroidism patients during a 5-year period, as compared with non-hyperthyroidism patients during the same period. Data sourced from the Taiwan Longitudinal Health Insurance Database were analyzed. The study included 8903 patients with hyperthyroidism as a study cohort and 44,515 randomly selected patients without hyperthyroidism as a comparison cohort. Stratified Cox proportional hazard regressions were used to compute the 5-year PE-free survival rate between these two cohorts. Of the total of 53,418 patients, 41 patients (0.08%) were identified as having PE during the follow-up period, 14 from the study cohort (0.16% of the hyperthyroidism patients) and 27 comparison patients (0.06% of patients from the comparison cohort). After adjustment for geographic region, monthly income, hypertension, diabetes, hyperlipidemia, peripheral vascular disease, coronary heart disease, cancer, recent surgery, recent fracture, pregnancy and the use of anticoagulants, the risk of having PE during the 5-year follow-up period was 2.31 times greater (95% confidence interval 1.20-4.45, P=0.012) for patients with hyperthyroidism than for patients in the comparison cohort. We found an increased risk of PE in patients with hyperthyroidism. Clinicians should be aware of this increased risk.


Prognostic value of circulating chromogranin A levels in acute coronary syndromes.
To determine whether circulating levels of chromogranin A (CgA) provide prognostic information independently of conventional risk markers in acute coronary syndromes (ACSs). We measured circulating CgA levels on day 1 in 1268 patients (median age 67 years, 70% male) with ACS admitted to a single coronary care unit of a Scandinavian teaching hospital. The merit of CgA as a biomarker was evaluated after adjusting for conventional cardiovascular risk factors. During a median follow-up of 92 months, 389 patients (31%) died. The baseline CgA concentration was strongly associated with increased long-term mortality [hazard ratio per 1 standard deviation increase in logarithmically transformed CgA level: 1.57 (1.44-1.70), P < 0.001], heart failure hospitalizations [1.54 (1.35-1.76), P < 0.001], and recurrent myocardial infarction (MI) [1.27 (1.10-1.47), P < 0.001], but not stroke. After adjustment for conventional cardiovascular risk markers, the association remained significant for mortality [hazard ratio 1.28 (1.15-1.42), P < 0.001] and heart failure hospitalization [hazard ratio 1.24 (1.04-1.47), P = 0.02], but not recurrent MI. CgA is an independent predictor of long-term mortality and heart failure hospitalizations across the spectrum of ACSs and provides incremental prognostic information to conventional cardiovascular risk markers.


The effects of shear on the delay time for gelation of hemoglobin S.
Intraerythrocytic gelation of deoxyhemoglobin S is the immediate cause of red cell deformation and rigidification in sickle cell disease. Hence the rheology of hemoglobin S gels, heretofore little studied, plays a central role in pathogenesis. I have shown previously [2] that unsheared gels are solid-like whereas sheared gels are viscous in character. In the present studies the delay (nucleation) time for gelation (after a temperature jump) was examined in the absence and presence of shear, employing a sharp rise in viscosity as the end point of the delay time. Shearing rates in the range from 1.92 to 384 s-1 progressively accelerate the delay time. In another series of experiments the temperature jump was carried out in the absence of shear, shear being instituted later in the delay period. There was a sparing effect of the time of incubation in the absence of shear on the subsequent time under shear needed to induce gelation. A linear relation was observed between these two parameters, indicating that shear operates with constant efficacy in accelerating gelation, independent of when in the delay time it is applied. This suggests that the mechanism of assembly is the same throughout the period. Since shear probably operates through the breakage of fibers with the creation of new growth centers, the results also suggest that long, breakable, fibers are present even relatively early in the delay period. Values were obtained for delay time under shear and (by extrapolation) delay time under no shear. The temperature dependence (and hence apparent activation energy) of the latter is larger than that of the former; i.e. the effect of shear in shortening delay time is more marked as temperatures are lowered. With respect to pathogenesis, these results suggest that intraerythrocytic shearing may be detrimental because it accelerates gelation. On the other hand shearing of gels converts them from solid-like to viscous, and hence more deformable, systems; this effect of shear might be expected to ameliorate pathogenesis. Consequently, the pathogenic effects of intraerythrocytic shearing may depend on when the shear is applied.


Glucose-induced insulin resistance of skeletal-muscle glucose transport and uptake.
The ability of glucose and insulin to modify insulin-stimulated glucose transport and uptake was investigated in perfused skeletal muscle. Here we report that perfusion of isolated rat hindlimbs for 5 h with 12 mM-glucose and 20,000 microunits of insulin/ml leads to marked, rapidly developing, impairment of insulin action on muscle glucose transport and uptake. Thus maximal insulin-stimulated glucose uptake at 12 mM-glucose decreased from 34.8 +/- 1.9 to 11.5 +/- 1.1 mumol/h per g (mean +/- S.E.M., n = 10) during 5 h perfusion. This decrease in glucose uptake was accompanied by a similar change in muscle glucose transport as measured by uptake of 3-O-[14C]-methylglucose. Simultaneously, muscle glycogen stores increased to 2-3.5 times initial values, depending on fibre type. Perfusion for 5 h in the presence of glucose but in the absence of insulin decreased subsequent insulin action on glucose uptake by 80% of the effect of glucose with insulin, but without an increase in muscle glycogen concentration. Perfusion for 5 h with insulin but without glucose, and with subsequent addition of glucose back to the perfusate, revealed glucose uptake and transport similar to initial values obtained in the presence of glucose and insulin. The data indicate that exposure to a moderately increased glucose concentration (12 mM) leads to rapidly developing resistance of skeletal-muscle glucose transport and uptake to maximal insulin stimulation. The effect of glucose is enhanced by simultaneous insulin exposure, whereas exposure for 5 h to insulin itself does not cause measurable resistance to maximal insulin stimulation.


Experimental evidence for naturally occurring nondiagonal depolarizers.
We report on two Stokes nondiagonalizable Mueller matrices experimentally observed in a biological and in an organic sample. These matrices are examples of naturally occurring nondiagonal depolarizers whose unique property is to preserve the degree of polarization of all but one totally polarized light state. The description of the experimental matrices within the theory of Bragg scattering on cholesteric liquid crystals, as well as their interpretation in physical and structural terms, are likewise addressed.


Simple, stable, and compact multiple-reflection optical cell for very long optical paths.
A new type of multiple-reflection optical cell is presented. One of the main advantages of this type of cell is that it can be made of standard mirrors without particular tolerance while allowing a great number of reflections and thus a large optical path, only limited by the reflection coefficient of the mirrors. The configuration is simple, compact, stable, and cheap. This cell consists of three mirrors as in a White cell but its principle is different. It behaves as a multiplier of a Herriott cell from which it inherits the opto-mechanical stability qualities. The Herriott cell and the White cell are two particular cases of this type of cell. As examples, a demonstrator and an absorption cell contained in a volume of 5 l are presented. The first device is usable with a laser in visible light. The second device is usable with an infrared laser diode for the detection of atmospheric trace species.


Filaggrin-2 variation is associated with more persistent atopic dermatitis in African American subjects.
Atopic dermatitis (AD) is a common skin disease characterized by recurrent episodes of itching. Genetic variation associated with the persistence of AD has not been described for African American subjects. We sought to evaluate genetic variation of filaggrin-2 (FLG2) in African American subjects with AD. We evaluated a multiyear prospective cohort study of African American children with AD with respect to FLG2 variation based on whole-exome sequencing, followed by a targeted analysis. We ultimately evaluated the association of rs12568784 and rs16833974 with respect to the persistence of AD symptoms over time. Whole-exome analysis was conducted on 60 subjects, revealing a premature stop codon in exon 3 at S2377X (rs12568784) and X2392S (rs150529054) and a large exon 3 deletion mutation, Q2053del224. On the basis of a priori criteria, we then studied rs12568784, rs16833974 (H1249R), and Q2053del224. We noted that patients with S2377X (odds ratio [OR], 0.44; 95% CI, 0.25-0.46) and H1249R (OR, 0.23; 05% CI, 0.12-0.46) were significantly less likely to be free of symptoms of AD, and Q2053del224 (OR, 0.54; 95% CI, 0.16-1.80) trended toward this outcome. S2377X and H1249R were in high linkage disequilibrium (D' = 0.95). In an African American cohort with AD, FLG2 mutations were associated with more persistent AD. This is the first finding of genetic variation of a skin barrier protein in subjects of African ancestry with AD.


New Generation Calcium Channel Blockers in Hypertensive Treatment.
During a couple of decades, a number of antihypertensive drugs have been developed, and the choice of hypertension treatment has been expanded. Among antihypertensive drugs, calcium channel blockers, which inhibit L-type voltage-gated calcium channels, are potent vasodilators, and have been used as a first- or second-line drug. Dihydropyridine-class calcium channel blockers are categorized into three generations according to the length of activity, and long-acting calcium channel blockers cause less activation of sympathetic nervous system, and are reported to offer beneficial action compared with short-action agents. Furthermore, novel types of calcium channel blockers have been developed that possess the blocking action on other calcium channel subtypes (T- and N-type), and exert agent-specific action apart from their class effects, such as the effects on heart rate and renin/aldosterone release. These additional benefits conferred by T/N-type calcium channel blockade are anticipated to provide organ protective actions in the treatment of hypertension, in addition to the blood pressure-lowering effect of L-type calcium channel blockade. In conclusion, novel calcium channel blockers with sustained activity and T/N-type calcium channel blocking action could provide more beneficial effects than classical blockers, and may expand the clinical utility of these agents.


Combination of Tanshinone IIA and Cisplatin Inhibits Esophageal Cancer by Downregulating NF-κB/COX-2/VEGF Pathway.
Cisplatin (DDP) represents one of the common drugs used for esophageal squamous cell carcinoma (ESCC), but side effects associated with DDP and drug resistance lead to the failure of treatment. This study aimed to understand whether tanshinone IIA (tan IIA) and DDP could generate a synergistic antitumor effect on ESCC cells. Tan IIA and DDP are demonstrated to restrain ESCC cell proliferation in a time- and dose-dependent mode. Tan IIA and DDP at a ratio of 2:1 present a synergistic effect on ESCC cells. The combination suppresses cell migration and invasion abilities, arrests the cell cycle, and causes apoptosis in HK and K180 cells. Molecular docking indicates that tan IIA and DDP could be docked into active sites with the tested proteins. In all treated groups, the expression levels of E-cadherin, β-catenin, Bax, cleaved caspase-9, P21, P27, and c-Fos were upregulated, and the expression levels of fibronectin, vimentin, Bcl-2, cyclin D1, p-Akt, p-ERK, p-JNK, P38, COX-2, VEGF, IL-6, NF-κB, and c-Jun proteins were downregulated. Among these, the combination induced the most significant difference. Our results suggest that tan IIA could be a novel treatment for combination therapy for ESCC.


Occurrence of Strongyloides stercoralis in Yunnan Province, China, and comparison of diagnostic methods.
Strongyloides stercoralis is a neglected soil-transmitted helminth species, and there is a lack of parasitologic and epidemiologic data pertaining to this parasite in China and elsewhere. We studied the local occurrence of S. stercoralis in a village in Yunnan province, China, and comparatively assessed the performance of different diagnostic methods. Multiple stool samples from a random population sample were subjected to the Kato-Katz method, an ether-concentration technique, the Koga agar plate method, and the Baermann technique. Among 180 participants who submitted at least 2 stool samples, we found a S. stercoralis prevalence of 11.7%. Males had a significantly higher prevalence than females (18.3% versus 6.1%, p = 0.011), and infections were absent in individuals <15 years of age. Infections were only detected by the Baermann (highest sensitivity) and the Koga agar plate method, but neither with the Kato-Katz nor an ether-concentration technique. The examination of 3 stool samples rather than a single one resulted in the detection of 62% and 100% more infections when employing the Koga agar plate and the Baermann technique, respectively. The use of a mathematical model revealed a 'true' S. stercoralis prevalence in the current setting of up to 16.3%. We conclude that S. stercoralis is endemic in the southern part of Yunnan province and that differential diagnosis and integrated control of intestinal helminth infections needs more pointed emphasis in rural China.


Young working women utilise the after hours service at Sydney Sexual Health Centre.
To analyse patterns of patient utilisation of the after hours service at Sydney Sexual Health Centre (SSHC). A retrospective cross sectional database study compared all new daytime and after hours patients who registered for a medical consultation at SSHC between August 1994 and February 1995. Daytime and after hours attenders were compared using demographic and behavioural factors and for prevalence of STDs and HIV using logistic regression analysis. Of the 1662 eligible patients, 1362 (81.9%) attended during daytime hours, and 300 (18.1%) attended after hours. There was no significant difference in after hours attendance between patients living in inner compared with outer metropolitan zones. Using logistic regression analysis, being female (p = 0.0008), being between 20 and 39 years of age (p = 0.008), being employed (p < 0.001), and having no previous STD/genitourinary condition (p = 0.034) were the factors significantly associated with after hours attendance. The evening service was disproportionately utilised by a patient group not defined as "high risk" in the objectives of the service. This study challenges the assumption that evening clinics are always the way to reach high risk groups.


Early death and causes of death of people with intellectual disabilities: A systematic review.
Death of people with intellectual disabilities is considered to be earlier than for the general population. Databases were searched for key words on intellectual disabilities and death. Strict inclusion/exclusion criteria were used. Information was extracted from selected papers, tabulated and synthesized. Prospero registration number: CRD42015020161. Of 19,111 retrieved articles, 27 met criteria. Death was earlier by 20 years. It has improved in recent decades; however, the same inequality gap with the general population remains. More severe intellectual disabilities, and/or additional comorbidities rendered it shortest. Standardized mortality rates showed a greater inequality for women than men. Respiratory disease and circulatory diseases (with greater congenital and lesser ischaemic disease compared with the general population) were the main causes of death. Cancer was less common, and cancer profile differed from the general population. Some deaths are potentially avoidable. All research is from high-income countries, and cause of death is surprisingly little investigated. Improved health care, including anticipatory care such as health checks, and initiatives addressing most relevant lifestyle behaviours and health risks are indicated.


Nuclear area is a prognostic determinant in advanced colorectal cancer.
The prognostic value of morphometric nuclear features in Dukes' Stages B/C and D colorectal cancer (CRC) was assessed. Primary tumours from 86 CRC patients were analysed, using an image overlay drawing system (Prodit Morphometry Program), for the following nuclear features: area, perimeter, diameter, form factor, roundness. The median nuclear area (NA) was 104.6 microm2 (range 57.2 - 237.2 microm2). The NA was larger in patients with lymph node metastasis (p < 0.02). Altogether, 43% of the patients showed clinical response to irinotecan-based chemotherapy. All six patients with complete response (CR) had a NA above the median (p < 0.03). The disease-specific survival of the patients with a NA above the median was significantly better than in patients with smaller NA (p < 0.02). Using the median NA as the cut-off value seems to effectively discriminate patients who are likely to respond to irinotecan-based chemotherapy (with improved prognosis) from those who are non-responsive and develop progressive disease.


Anchored protease-activatable polymersomes for molecular diagnostics of metastatic cancer cells.
Real-time quantitative and qualitative analyses of metastasis-associated proteases are critical for precise diagnosis and novel therapeutic treatment of advanced cancers. However, conventional methods based on DNA, peptides, and proteins require sophisticated chemistry and additional processes to expose detection moieties, and they lack elements of temporal control, which limit their applicability. We designed unique protease-activatable polymersomes (PeptiSomes) for high sensitivity, in situ quantitative analysis of activating membrane-type 1 matrix metalloproteinases (MT1-MMP, MMP14). To do this, we first synthesized an amphiphilic block polymer-peptide and a copolypeptide based on mPEG-b-pLeu and MT1-peptide-b-pLeu, respectively. Amphiphilic self-assembled PeptiSomes in water were capable of disassembling and releasing the encapsulated self-quenched fluorescence dye (calcein) via enzymatic activation by MT1-MMP. Our PeptiSome system may potentially prevent the initiation and progression of cancer metastasis. Furthermore, the PeptiSome approach described here is likely to facilitate the development of rapid protease assay techniques and further extend the role of proteases as metastasis indicators and therapeutic targets.


Blood-brain barrier penetration abolished by N-methyl quaternization of nicotine.
The present study determined the effect of organically quaternizing either of the two tertiary nitrogen sites of nicotine to assess the in vivo effects of the permanently ionized states of the synthesized N-[14C]methylnicotines on brain uptake in rat after intracarotid injection. Male Sprague-Dawley rats were used to measure the brain uptake index (BUI) by single-pass clearance in brain after rapid injection at pH 7.4 into the left common carotid artery (expressed as a percentage) relative to simultaneously injected 3HOH. The BUI of [14C]mannitol, a control for the method background, was measured to be 2.6 +/- 0.6. At physiological pH, in striking contrast to the [pyrrolidine-2-14C]nicotine BUI of 120 +/- 3, the N-[14C]-methylnicotines had a BUI of 3.0 +/- 0.6, which was not significantly different from the method background and which indicated abolition of blood-brain barrier penetration of nicotine with the sensitivity of the BUI method.


Identifying functional bases for multidimensional neural computations.
Current dimensionality-reduction methods can identify relevant subspaces for neural computations but do not favor one basis over the other within the relevant subspace. Finding the appropriate basis can simplify the description of the nonlinear computation with respect to the relevant variables, making it easier to elucidate the underlying neural computation and make hypotheses about the neural circuitry, giving rise to the observed responses. Part of the problem is that although some of the dimensionality reduction methods can identify many of the relevant dimensions, it is usually difficult to map out or interpret the nonlinear transformation with respect to more than a few relevant dimensions simultaneously without some simplifying assumptions. While recent approaches make it possible to create predictive models based on many relevant dimensions simultaneously, there still remains the need to relate such predictive models to the mechanistic descriptions of the operation of underlying neural circuitry. Here we demonstrate that transforming to a basis within the relevant subspace where the neural computation is best described by a given nonlinear function often makes it easier to interpret the computation and describe it with a small number of parameters. We refer to the corresponding basis as the functional basis, and illustrate the utility of such transformation in the context of logical OR and logical AND functions. We show that although dimensionality-reduction methods such as spike-triggered covariance are able to find a relevant subspace, they often produce dimensions that are difficult to interpret and do not correspond to a functional basis. The functional features can be found using a maximum likelihood approach. The results are illustrated using simulated neurons and recordings from retinal ganglion cells. The resulting features are uniquely defined and nonorthogonal, and they make it easier to relate computational and mechanistic models to each other.


Investigations on the biology, epidemiology, pathology, and control of Tunga penetrans in Brazil: VII. The importance of animal reservoirs for human infestation.
In Brazil tungiasis is endemic in many resource-poor communities, where various domestic and sylvatic animals act as reservoirs for this zoonosis. To determine the role of animal reservoirs in human tungiasis, a cross-sectional study was performed in a traditional fishing community in northeast Brazil. The human and the animal populations were examined for the presence of embedded sand fleas and the prevalence and the intensity of infestation were correlated. The overall prevalence of tungiasis in humans was 39% (95% CI 34-43%). Of six mammal species present in the village, only cats and dogs were found infested. The prevalence in these animals was 59% (95% CI 50-68%). In households, where infested pet animals were present, a higher percentage of household members had tungiasis (42% [95% CI 30-53%] versus 27% [20-33%], p=0.02), and the intensity of the infestation was higher (six lesions versus two lesions, p=0.01). The intensity of infestation in animals correlated with the intensity of infestation in humans (rho=0.3, p=0.02). Living in a household with an infested dog or cat led to a 1.6-fold (95% CI 1.1-2.3, p=0.015) increase in the odds for the presence of tungiasis in household members in the bivariate analysis and remained a significant risk factor in the multivariate regression analysis. The study shows that in this impoverished community tungiasis is highly prevalent in humans and domestic animals. In particular, it underlines the importance to include animals in control operation aiming at the reduction of disease occurrence in the human population.


Differentiation of two bovine lentiviruses by a monoclonal antibody on the basis of epitope specificity.
Bovine immunodeficiency virus (BIV) and Jembrana disease virus (JDV) are bovine lentiviruses that are closely related genetically. A recombinant fusion protein containing the capsid protein of BIV expressed in Escherichia coli was used to immunize mice and produce monoclonal antibodies. Six hybridomas specific for BIV capsid protein were identified, and one antibody, designated 10H1, was characterized further. Competitive binding assays were performed to analyze the topography of antigenic determinants by enzyme-linked immunosorbent assay and demonstrated the existence of at least three distinct antigenic determinants on capsid protein. The monoclonal antibody reacted specifically with both BIV capsid and the recombinant fusion protein in Western immunoblot analyses. However, it did not react with the recombinant capsid fusion protein of JDV, indicating that BIV contains at least one unique epitope in the capsid protein that is absent in JDV. Further mapping of the epitope by chemical cleavage analysis identified that the epitope is located at the 6.4-kDa N terminus of the 29-kDa capsid protein. This monoclonal antibody assay will be valuable for distinguishing the two closely related lentiviruses by Western blotting.


WITHDRAWN: Dopamine agonists for cocaine dependence.
Cocaine dependence is a common and serious condition, which has become a substantial public health problem. There is a wide and well documented range of consequences associated to chronic use of cocaine, such as medical, psychological and social problems.. Therapeutic management of the cocaine addicts includes an initial period of abstinence from the drug. During this phase the subjects may experience, besides the intense craving for cocaine, symptoms such as depression, fatigue, irritability, anorexia, and sleep disturbances. It was demonstrated that the acute use of cocaine may enhance dopamine transmission and chronically it decreases dopamine concentrations in the brain. Pharmacological treatment that affects dopamine could theoretically reduce these symptoms and contribute to a more successful therapeutic approach. To evaluate the efficacy and acceptability of dopamine agonists for treating cocaine dependence. Electronic searches of Cochrane Library, EMBASE, MEDLINE, PsycLIT, Biological Abstracts and LILACS; reference searching; personal communication; conference abstracts; unpublished trials from pharmaceutical industry; book chapters on treatment of cocaine dependence, was performed for the primary version of this review in 2001. Another search of the electronic databases was done in December of 2002 for this update. The specialised register of trials of the Cochrane Group on Drugs and Alcohol was searched until February 2003. The inclusion criteria for all randomised controlled trials were that they should focus on the use of dopamine agonists on the treatment of cocaine dependence. The reviewers extracted the data independently and Relative Risks, weighted mean difference and number needed to treat were estimated. The reviewers assumed that people who died or dropped out had no improvement and tested the sensitivity of the final results to this assumption. Seventeen studies were included, with 1224 participants randomised. Amantadine, bromocriptine, and pergolide were the drugs evaluated. The main outcomes evaluated were positive urine sample for cocaine metabolites, for efficacy, and retention in treatment, as an acceptability measure. There were no significant differences between interventions, and in trials where participants had primary cocaine dependence or had additional diagnosis of opioid dependence and/or were in methadone maintenance treatment. Current evidence does not support the clinical use of dopamine agonists in the treatment of cocaine dependence. Given the high rate of dropouts in this population, clinicians may consider adding other supportive measures aiming to keep patients in treatment.


EMT- and stroma-related gene expression and resistance to PD-1 blockade in urothelial cancer.
Cancers infiltrated with T-cells are associated with a higher likelihood of response to PD-1/PD-L1 blockade. Counterintuitively, a correlation between epithelial-mesenchymal transition (EMT)-related gene expression and T-cell infiltration has been observed across tumor types. Here we demonstrate, using The Cancer Genome Atlas (TCGA) urothelial cancer dataset, that although a gene expression-based measure of infiltrating T-cell abundance and EMT-related gene expression are positively correlated, these signatures convey disparate prognostic information. We further demonstrate that non-hematopoietic stromal cells are a major source of EMT-related gene expression in bulk urothelial cancer transcriptomes. Finally, using a cohort of patients with metastatic urothelial cancer treated with a PD-1 inhibitor, nivolumab, we demonstrate that in patients with T-cell infiltrated tumors, higher EMT/stroma-related gene expression is associated with lower response rates and shorter progression-free and overall survival. Together, our findings suggest a stroma-mediated source of immune resistance in urothelial cancer and provide rationale for co-targeting PD-1 and stromal elements.


Brain area-specific effect of TGF-beta signaling on Wnt-dependent neural stem cell expansion.
Regulating the choice between neural stem cell maintenance versus differentiation determines growth and size of the developing brain. Here we identify TGF-beta signaling as a crucial factor controlling these processes. At early developmental stages, TGF-beta signal activity is localized close to the ventricular surface of the neuroepithelium. In the midbrain, but not in the forebrain, Tgfbr2 ablation results in ectopic expression of Wnt1/beta-catenin and FGF8, activation of Wnt target genes, and increased proliferation and horizontal expansion of neuroepithelial cells due to shortened cell-cycle length and decreased cell-cycle exit. Consistent with this phenotype, self-renewal of mutant neuroepithelial stem cells is enhanced in the presence of FGF and requires Wnt signaling. Moreover, TGF-beta signal activation counteracts Wnt-induced proliferation of midbrain neuroepithelial cells. Thus, TGF-beta signaling controls the size of a specific brain area, the dorsal midbrain, by antagonizing canonical Wnt signaling and negatively regulating self-renewal of neuroepithelial stem cells.


MCM-test: a fuzzy-set-theory-based approach to differential analysis of gene pathways.
Gene pathway can be defined as a group of genes that interact with each other to perform some biological processes. Along with the efforts to identify the individual genes that play vital roles in a particular disease, there is a growing interest in identifying the roles of gene pathways in such diseases. This paper proposes an innovative fuzzy-set-theory-based approach, Multi-dimensional Cluster Misclassification test (MCM-test), to measure the significance of gene pathways in a particular disease. Experiments have been conducted on both synthetic data and real world data. Results on published diabetes gene expression dataset and a list of predefined pathways from KEGG identified OXPHOS pathway involved in oxidative phosphorylation in mitochondria and other mitochondrial related pathways to be deregulated in diabetes patients. Our results support the previously supported notion that mitochondrial dysfunction is an important event in insulin resistance and type-2 diabetes. Our experiments results suggest that MCM-test can be successfully used in pathway level differential analysis of gene expression datasets. This approach also provides a new solution to the general problem of measuring the difference between two groups of data, which is one of the most essential problems in most areas of research.


Seroconversion, sexual activity, and condom use among 2915 HIV seronegative men followed for up to 2 years.
A cohort of 2915 HIV-1-seronegative men from the four centers of the Multicenter AIDS Cohort Study (MACS) was followed at 6 month intervals for 24 months to identify men who developed antibodies to HIV-1. Two hundred thirty-two men (8%) seroconverted. The highest attack rate was among men who reported practicing both receptive and insertive anal-genital intercourse. The attack rate among men who reported practicing receptive but not insertive intercourse was 3.6 times higher than among men practicing insertive intercourse although those practicing insertive only reported 38% more different partners. Only two men seroconverted who reported not practicing analgenital intercourse in the 12 month prior to the first antibody-positive visit. Because men were followed every 6 months, one of these men could have been infected within 6 months of the actual development of HIV-1 antibodies. The seroconversion rate was significantly lower among men who reported using condoms with all their partners. The results of this study (a) reaffirm that receptive anal-genital intercourse is the major route of infection among homosexual men of HIV-1, (b) suggest that there is a low risk of HIV-1 infection to the insertive partner in anal-genital intercourse, (c) suggest that infection may rarely occur through sexual activities other than anal-genital intercourse, (d) provide evidence that condoms as currently used by men in the MACS provide significant but not complete protection against HIV-1 infection, and (e) suggest that the number of men in the homosexual community engaging in high-risk behavior is declining.


The effects of a single or double GnRH dose on pregnancy survival in high producing dairy cows carrying singletons or twins.
Pregnancy loss during the late embryonic and early fetal periods influences dairy herd economy. The objectives of this study were to (1) investigate the effects of a single or double GnRH dose administered at the time of pregnancy diagnosis (28-34 days post-AI) on the pregnancy survival of cows in their third lactation or further carrying live singletons or unilateral twins, and (2) examine the impacts of GnRH treatment on subsequent twin reduction in twin pregnancies. Cows carrying singletons (n = 1,054) or unilateral twins (n = 379) were assigned at the time of pregnancy diagnosis to the following groups: control (no treatment), GnRH (100 μg GnRH), and 2GnRH (200 μg GnRH). Pregnancy loss was recorded in 180 of the 1,433 cows (12.6%) at 58-64 days post-AI. Based on the odds ratios, there was a significant (P < 0.0001) interaction between the treatment group and twin pregnancy. This interaction implies that control cows carrying twins were 3.2 times more likely to suffer pregnancy loss than the other cows, whereas the GnRH and 2GnRH treatment groups cows carrying singletons or twins had pregnancy loss rates similar to the control cows carrying singletons. Twin reduction was observed in 35 twin pregnancies (9.2%). Cows in the GnRH and 2 GnRH groups were seven times more likely to show twin reduction than control cows. Our results indicate that GnRH administered at the time of pregnancy diagnosis had no beneficial effects in cows carrying singletons. In contrast, for twin pregnancies, the treatment increased the rate of pregnancy survival and was accompanied by an increase in the twin reduction rate.


Effectiveness of physiotherapy interventions for improving erectile function and climacturia in men after prostatectomy: a systematic review and meta-analysis of randomized controlled trials.
To determine the effectiveness of physiotherapy interventions for postprostatectomy erectile dysfunction and climacturia. Multiple databases were searched from database inception to February 2019. Randomized controlled trials comparing physiotherapy interventions to control were included. The search yielded 127 potentially relevant articles; seven met the inclusion criteria and were included in the review. Meta-analysis of two studies revealed a statistically significant effect of pelvic floor muscle training (PFMT) plus biofeedback compared to the no treatment control group for erectile function at the12-month follow-up period (risk ratio (RR) = 3.65, 95% confidence interval (CI) = 1.02-13.05; P = 0.05). Data from one small study (n = 31) identified a greater number of men reporting improved climacturia in the PFMT plus electrical stimulation group compared to the no treatment control group, and the overall effect was significant (RR = 15.60, 95% CI = 0.95-254.91; P = 0.05). Meta-analyses of two studies found no statistically significant differences between groups receiving PFMT and no treatment control for erectile function or climacturia at long-term follow-up. PFMT augmented with biofeedback improves erectile function after prostatectomy. Data from a single study found PFMT combined with electrical stimulation to be beneficial for postprostatectomy climacturia. However, electrical stimulation is recommended for terminally ill people only. The effect of PFMT alone on postprostatectomy erectile dysfunction and climacturia remains inconclusive. However, this is likely to be affected by the participant adherence and physiotherapy supervision. High-quality trials providing intensive supervision and due consideration of adherence factors are recommended.


Role of dehydroepiandrosterone and cortisol in nociceptive sensitivity to thermal pain in anorexia nervosa and healthy women.
Anorexia nervosa (AN) patients represent a natural model of relationship between changed hormonal level and pain perception due to lower level of sex hormones and consistently described increased pain threshold. As the adrenal stress steroid hormones (cortisol and DHEA) are known to be also changed in AN (and share a common precursor), our study was aimed to analyze the association between these hormones and pain perception in AN patients and control healthy women. The pain threshold latencies to radiant heat stimuli were measured in 20 DSM-IV diagnosed patients with AN and in 21 healthy women. Blood samples were collected in the morning hours and analyses of the plasma levels of dehydroepiandrosterone (DHEA), its conjugated sulfate ester (DHEA-S) and cortisol were implemented. Thermal pain threshold was higher in AN than in healthy women and correlated negatively with the level of DHEA and positively with cortisol/DHEA(S) ratio. No significant correlation between thermal pain and hormones was found in healthy women. If both groups were pooled together, the rest pain threshold correlated negatively with DHEA-S (r=-0.42, p=0.008). We showed for the first time that sensitivity to thermal pain in women is dependent on DHEA-S and on cortisol/DHEA(S) ratio in patients with AN.


Diagnostic yield and clinical impact of exome sequencing in early-onset scoliosis (EOS).
Early-onset scoliosis (EOS), defined by an onset age of scoliosis less than 10 years, conveys significant health risk to affected children. Identification of the molecular aetiology underlying patients with EOS could provide valuable information for both clinical management and prenatal screening. In this study, we consecutively recruited a cohort of 447 Chinese patients with operative EOS. We performed exome sequencing (ES) screening on these individuals and their available family members (totaling 670 subjects). Another cohort of 13 patients with idiopathic early-onset scoliosis (IEOS) from the USA who underwent ES was also recruited. After ES data processing and variant interpretation, we detected molecular diagnostic variants in 92 out of 447 (20.6%) Chinese patients with EOS, including 8 patients with molecular confirmation of their clinical diagnosis and 84 patients with molecular diagnoses of previously unrecognised diseases underlying scoliosis. One out of 13 patients with IEOS from the US cohort was molecularly diagnosed. The age at presentation, the number of organ systems involved and the Cobb angle were the three top features predictive of a molecular diagnosis. ES enabled the molecular diagnosis/classification of patients with EOS. Specific clinical features/feature pairs are able to indicate the likelihood of gaining a molecular diagnosis through ES.


Epifaunal and infaunal responses to submarine mine tailings in a Norwegian fjord.
Disposal of mine tailings in marine shallow water ecosystems represents an environmental challenge, and the present paper reports results from a field study in Frænfjorden, Norway, which is subject to such disposal. Structural and functional responses of benthic infauna and epifauna were investigated along a gradient from heavy tailings deposition to reference conditions. The tailings clearly impacted the faunal composition, with lowered species number close to the outfall. Total abundance of infauna increased in the most impacted area due to dominance of opportunistic species, whereas the epifauna was reduced and represented by a few scattered specimens only. In the most impacted area functional responses included an increase in mobile carnivores/omnivores and species utilizing symbionts. Sessile and tube-living taxa, and deposit and suspension feeders decreased, probably due to smothering in combination with tailings-associated changes of the substrate. Functional diversity decreased for both infauna and epifauna, but less than the structural diversity.


Transcranial Direct Current Stimulation Enhances Motor Skill Learning but Not Generalization in Chronic Stroke.
Motor training alone or combined with transcranial direct current stimulation (tDCS) positioned over the motor cortex (M1) improves motor function in chronic stroke. Currently, understanding of how tDCS influences the process of motor skill learning after stroke is lacking. To assess the effects of tDCS on the stages of motor skill learning and on generalization to untrained motor function. In this randomized, sham-controlled, blinded study of 56 mildly impaired chronic stroke patients, tDCS (anode over the ipsilesional M1 and cathode on the contralesional forehead) was applied during 5 days of training on an unfamiliar, challenging fine motor skill task (sequential visual isometric pinch force task). We assessed online and offline learning during the training period and retention over the following 4 months. We additionally assessed the generalization to untrained tasks. With training alone (sham tDCS group), patients acquired a novel motor skill. This skill improved online, remained stable during the offline periods and was largely retained at follow-up. When tDCS was added to training (real tDCS group), motor skill significantly increased relative to sham, mostly in the online stage. Long-term retention was not affected by tDCS. Training effects generalized to untrained tasks, but those performance gains were not enhanced further by tDCS. Training of an unfamiliar skill task represents a strategy to improve fine motor function in chronic stroke. tDCS augments motor skill learning, but its additive effect is restricted to the trained skill.


Early response to preventive strategies in the Diabetes Prevention Program.
Recommendations for diabetes prevention in patients with prediabetes include lifestyle modification and metformin. However, the significance of early weight loss and glucose measurements when monitoring response to these proven interventions is unknown. To quantify the relationship between early measures of weight and glucose and subsequent diabetes in patients undergoing diabetes prevention interventions. Analysis of results from a randomized controlled trial in 27 academic medical centers in the United States. 3,041 adults with hyperglycemia randomized to lifestyle (n = 1,018), metformin (n = 1,036), or placebo (n = 987) with complete follow-up in The Diabetes Prevention Program. Independent variables were weight loss at 6 and 12 months; fasting glucose (FG) at 6 months; hemoglobin A1c (HbA1c) at 6 months; and post-load glucose at 12 months. The main outcome was time to diabetes diagnosis. After 6 months, 604 participants developed diabetes in the lifestyle (n = 140), metformin (n = 206), and placebo (n = 258) arms over 2.7 years. In the lifestyle arm, 6-month weight loss predicted decreased diabetes risk in a graded fashion: adjusted HR (95 % CI) 0.65 (0.35-1.22), 0.62 (0.33-1.18), 0.46 (0.24-0.87), 0.34 (0.18-0.64), and 0.15 (0.07-0.30) for 0-<3 %, 3-<5 %, 5-<7 %, 7-<10 %, and ≥10 % weight loss, respectively (reference: weight gain). Attainment of optimal 6-month FG and HbA1c and 12-month post-load glucose predicted >60 % lower diabetes risk across arms. We found a significant interaction between 6-month weight loss and FG in the lifestyle arm (P = 0.038). Weight and glucose at 6 and 12 months strongly predict lower subsequent diabetes risk with a lifestyle intervention; lower FG predicts lower risk even with substantial weight loss. Early reduction in glycemia is a stronger predictor of future diabetes risk than weight loss for metformin. We offer the first evidence to guide clinicians in making interval management decisions for high-risk patients undertaking measures to prevent diabetes.


Percutaneous transluminal angioplasty and stent placement in acute vessel occlusion: evaluation of new methods for interventional stroke treatment.
The major goal of acute ischemic stroke treatment is fast and sufficient recanalization. Percutaneous transluminal balloon angioplasty (PTA) and/or placement of a stent might achieve both by compressing the thrombus at the occlusion site. This study assesses the feasibility, recanalization rate, and complications of the 2 techniques in an animal model. Thirty cranial vessels of 7 swine were occluded by injection of radiopaque thrombi. Fifteen vessel occlusions were treated by PTA alone and 15, by placement of a stent and postdilation. Recanalization was documented immediately after treatment and after 1, 2, and 3 hours. Thromboembolic events and dissections were documented. PTA was significantly faster to perform (mean, 16.6 minutes versus 33.0 minutes for stent placement; P < .001), but the mean recanalization rate after 1 hour was significantly better after stent placement compared with PTA alone (67.5% versus 14.6%, P < .001). Due to the self-expanding force of the stent, vessel diameter further increased with time, whereas the recanalization result after PTA was prone to reocclusion. Besides thromboembolic events related to the passing maneuvers at the occlusion site, no thrombus fragmentation and embolization occurred during balloon inflation or stent deployment. Flow to side branches could also be restored at the occlusion site because it was possible to direct thrombus compression. Stent placement and postdilation proved to be much more efficient in terms of acute and short-term vessel recanalization compared with PTA alone.


[Alternative models for the epidemiological analysis of obesity as a public health problem].
Public health problems have been analyzed over time using different approaches involving a variety of methodological and theoretical models. The classical epidemiological model and the social epidemiological model are two examples of models used in public health research. Although each of these models covers a whole range of public research approaches, it is possible to identify the different theoretical and methodological criteria and the different ideological assumptions on which they are based. The objective of this article is to make a comparison of the criteria used by the classical and social epidemiological models in the study of public health problems, with special emphasis on the study of obesity. This comparison shows that the knowledge generated by studies carried out under each of these models is rather different, as an effect of the different theoretical, methodological and ideological criteria used by each model. However, far from being contradictory, the knowledge generated by each model can complement that generated by the other. Finally, the inclusion of social sciences as a tool for the analysis of public health problems, specifically the problem of obesity, is discussed.


Validity Evidence From Ratings of Pediatric Interns and Subinterns on a Subset of Pediatric Milestones.
To investigate evidence for validity of faculty members' pediatric milestone (PM) ratings of interns (first-year residents) and subinterns (fourth-year medical students) on nine subcompetencies related to readiness to serve as a pediatric intern in the inpatient setting. The Association of Pediatric Program Directors Longitudinal Educational Assessment Research Network (APPD LEARN) and the National Board of Medical Examiners collaborated to investigate the utility of assessments of the PMs for trainees' performance. Data from 32 subinterns and 179 interns at 17 programs were collected from July 2012 through April 2013. Observers used several tools to assess learners. At each site, a faculty member used these data to make judgments about the learner's current developmental milestone in each subcompetency. Linear mixed models were fitted to milestone judgments to examine their relationship with learner's rank and subcompetency. On a 5-point developmental scale, mean milestone levels for interns ranged from 3.20 (for the subcompetency Work effectively as a member of a team) to 3.72 (Humanism) and for subinterns from 2.89 (Organize and prioritize care) to 3.61 (Professionalization). Mean milestone ratings were significantly higher for the Professionalism competency (3.59-3.72) for all trainees compared with Patient Care (2.89-3.24) and Personal and Professional Development (3.33-3.51). Mean intern ratings were significantly higher than mean subintern ratings for all nine subcompetencies except Professionalization, Humanism, and Trustworthiness. The PMs had a coherent internal structure and could distinguish between differing levels of trainees, which supports their validation for documenting developmental progression of pediatric trainees.


Post-exercise whey protein hydrolysate supplementation induces a greater increase in muscle protein synthesis than its constituent amino acid content.
It is well known that ingestion of a protein source is effective in stimulating muscle protein synthesis after exercise. In addition, there are numerous reports on the impact of leucine and leucine-rich whey protein on muscle protein synthesis and mammalian target of rapamycin (mTOR) signalling. However, there is only limited information on the effects of whey protein hydrolysates (WPH) on muscle protein synthesis and mTOR signalling. The aim of the present study was to compare the effects of WPH and amino acids on muscle protein synthesis and the initiation of translation in skeletal muscle during the post-exercise phase. Male Sprague–Dawley rats swam for 2 h to depress muscle protein synthesis. Immediately after exercise, the animals were administered either carbohydrate (CHO), CHO plus an amino acid mixture (AA) or CHO plus WPH. At 1 h after exercise, the supplements containing whey-based protein (AA and WPH) caused a significant increase in the fractional rate of protein synthesis (FSR) compared with CHO. WPH also caused a significant increase in FSR compared with AA. Post-exercise ingestion of WPH caused a significant increase in the phosphorylation of mTOR levels compared with AA or CHO. In addition, WPH caused greater phosphorylation of ribosomal protein S6 kinase and eukaryotic initiation factor 4E-binding protein 1 than AA and CHO. In contrast, there was no difference in plasma amino acid levels following supplementation with either AA or WPH. These results indicate that WPH may include active components that are superior to amino acids for stimulating muscle protein synthesis and initiating translation.


An Investigation to Identify Potential Risk Factors Associated with Common Chronic Diseases Among the Older Population in India.
In India, chronic diseases are the leading cause of death and their prevalence has constantly increased over the last decade. This study aimed to identify risk factors associated with common chronic diseases among people aged 50 years and over in India. Data from Wave 1 of the 2007/2008 Indian Study on Global Ageing and Adult Health (SAGE) was used to investigate the association between lifestyle choices and chronic diseases using logistic regression. The fully adjusted model showed that significant independent risk factors for angina included area of residence, being diagnosed with diabetes, chronic lung disease (CLD) [highest odds ratio (OR) 4.77, 95% confidence interval (CI): 2.95-7.70] and arthritis. For arthritis, risk factors included having underlying diabetes, CLD diagnosis, or angina (highest OR 2.32, 95% CI: 1.63-3.31). Risk factors associated with CLD included arthritis, angina (highest OR 4.76, 95% CI: 2.94-7.72), alcohol use, and tobacco use. Risk factors associated with diabetes included level of education, area of residence, socioeconomic status, angina (highest OR 3.59, 95% CI: 2.44-5.29), CLD, arthritis, stroke, and vegetable consumption. Finally, risk factors associated with stroke included diabetes and angina (highest OR 3.34, 95% CI: 1.72-6.50). The presence of any other comorbidity was significantly associated with all five chronic diseases studied. The results show that within the older population, the contribution of lifestyle risk factors to the common chronic diseases investigated in this study was limited. Our findings showed that the major health issue within the study population was multimorbidity.


Haemostatic dysfunction and acute renal failure following envenoming by Merrem's hump-nosed viper (Hypnale hypnale) in Sri Lanka: first authenticated case.
A five years old boy was bitten by a Merrem's hump-nosed viper (Hypnale hypnale) in Central Province, Sri Lanka. He developed local swelling, incoagulable blood, thrombocytopenia, bleeding into the gastrointestinal tract, and acute renal failure. Treatment with Serum Institute of Indian polyspecific antivenom (specific for venoms of cobra, common krait, Russell's viper and saw-scaled viper) had no effect on the coagulopathy, which persisted for more than a week. The boy recovered after 27 d in hospital, during which he was treated with peritoneal dialysis for renal failure. Laboratory studies demonstrated that the venom of H. hypnale was procoagulant, fibrinolytic and aggregated platelets. This first authenticated case of life-threatening acute renal failure and haemostatic disturbances caused by H. hypnale, a species responsible for 27% of snake bites in Sri Lanka, demonstrates the need for a new antivenom with specific activity against the venom of this species.


Age-related changes in GABA and benzodiazepine receptor binding in rat brain are influenced by sampling time.
1. This study examined the saturation binding of tritiated gamma-aminobutyric acid [( 3H]GABA) and [3H]diazepam in brain membranes from young (3 month-old) and aged (21-23 month-old) Long Evans male rats killed at two time points in the 24-hour cycle. 2. The daytime density of low-affinity GABA binding sites was significantly (p less than 0.05) lower in cortical membranes from aged animals. There were no differences between young and old rats in low-affinity GABA binding at night, or in high-affinity GABA binding at either time point. 3. Diazepam binding was significantly lower in the brains of aged animals killed during the daytime. There was no differences at night, when diazepam binding in young animals declined to match that of aged animals. 4. There were no differences in the affinities of either GABA or diazepam binding sites. 5. These findings indicate that sampling time significantly influences age-associated changes in the densities of low-affinity GABA and diazepam binding sites. Therefore, the effects of age on brain receptor binding parameters should be measured at several points in the 24-hour light/dark cycle in order to control for possible age-related changes in binding rhythmicity.


Nonreciprocal Bloch oscillations in magneto-optic waveguide arrays.
We show that nonreciprocal optical Bloch-like oscillations can emerge in transversely magnetized waveguide arrays in the presence of an effective index step between the waveguides. Normal modes of the system are shown to acquire different wavenumbers in opposite propagation directions. Significant differences in phase coherence and decoherence between these normal modes are presented and discussed. Nonreciprocity is established by imposing unequal vertical refractive index gradients at the substrate/core and core/cover interfaces in the presence of transverse magnetization.


Depression and self-focused language in structured interviews with older men.
The association between depression and self-focused language has been found to varying extents across studies. The presence or absence of the association may depend on the communicative context. Based on Beck's depression model, a broad, evaluative self-focused question was predicted more likely to elicit a stronger association than a full interview containing a more heterogeneous question set of items. The spontaneous speech obtained during structured interviews of 26 depressed and nondepressed older men, an as-yet little studied population, was analyzed. Results were consistent with the hypothesis that association between self-focused language and depression was demonstrated in the target question but not across the entire interview. The results may explain some of the aforementioned discrepancies in prior studies.


Volatile anaesthetic depression of the carotid body chemoreflex-mediated ventilatory response to hypoxia: directions for future research.
In assessing whether volatile anaesthetics directly depress the carotid body response to hypoxia it is necessary to combine in meta-analysis studies of when it is "functionally isolated" (e.g., recordings are made from its afferent nerve). Key articles were retrieved (full papers in English) and subjected to quantitative analysis to yield an aggregate estimate of effect. Results from articles that did not use such methodology were assessed separately from this quantitative approach, to see what could be learned also from a nonquantitative overview. Just 7 articles met the inclusion criteria for hypoxia and just 6 articles for hypercapnia. Within these articles, the anaesthetic (mean dose 0.75, standard deviation (SD) 0.40 minimum alveolar concentration, MAC) statistically significantly depressed carotid body hypoxic response by 24% (P = 0.041), but a similar dose (mean 0.81 (0.42) MAC) did not affect the hypercapnic response. The articles not included in the quantitative analysis (31 articles), assessed qualitatively, also indicated that anaesthetics depress carotid body function. This conclusion helps direct future research on the anaesthetic effects on putative cellular/molecular processes that underlie the transduction of hypoxia in the carotid body.


A soluble tau fragment generated by caspase-2 is associated with dementia in Lewy body disease.
Lewy body diseases are neurodegenerative disorders characterized by Lewy bodies in the brain. Lewy body dementia (LBD) refers to two forms of Lewy body disease: Parkinson's disease with dementia (PDD) and dementia with Lewy bodies (DLB). Tau is a cytoskeletal protein found in neurofibrillary tangles, but not Lewy bodies. The gene encoding tau, MAPT, is a well-established genetic risk factor for LBD; odds ratios of the H1:H2 MAPT haplotypes have been reported in the range of 2 to 4. Despite this genetic association, the mechanism by which tau contributes to dementia is unclear. Recently, a soluble form of tau, Δtau314, which is generated when caspase-2 (Casp2) cleaves tau at Asp314, was reported to be associated with impaired cognition in mice modeling frontotemporal dementia, and with mild cognitive impairment and Alzheimer's disease (AD) in humans. To investigate whether Δtau314 is associated with dementia in Lewy body disease, we compared Δtau314 levels in aqueous extracts from the superior temporal gyrus of pathologically confirmed LBD (n = 21) and non-dementia Parkinson's disease (PD) (n = 12). We excluded subjects with AD or microvascular pathology, which could mask potential associations of Δtau314 with LBD.Using a Δtau314-specific ELISA, we found ~ 2-fold higher levels of Δtau314 in LBD relative to PD (p = 0.009). Additionally, we found ~40% lower levels of soluble total tau and the neuronal marker β-III-tubulin in LBD. These results suggest that in LBD, there is substantial neuron loss or axonal degeneration in the neocortex but disproportionately high levels of Δtau314 in the surviving neurons.Our results indicate an association between Δtau314 and dementia in Lewy body disease. Cleavage of tau by Casp2 promotes the mislocalization of tau to dendritic spines leading to a reduction in postsynaptic AMPA receptors and excitatory neurotransmission, which suggests a mechanism of the synaptic dysfunction underlying cognitive impairment in LBD. These findings support the potential of Casp2 as a novel drug target for treating LBD.


Alcohol use and misuse within the military: a review.
Traditionally alcohol has been used by the military to cope with the intense stress of battle but also as a way of mediating the transition from the heightened experience of combat to routine safety. The use of alcohol has divided medical opinion. Some doctors viewed it as wholly harmful to both social and occupational function and to health, while others argued that alcohol had a specific role in lifting morale, aiding unit cohesion and protecting soldiers from adjustment disorders. Although alcoholism has always been identified as incompatible with military service, the effects of habitual heavy drinking among military personnel are less well understood. Recent studies have suggested that young single males and those who have undergone particularly stressful experiences are at greatest risk of misusing alcohol. These associations, observed in the aftermath of recent conflicts in Iraq and Afghanistan, have again raised questions about the place of alcohol in military culture.


Downregulation of the Deiminase PADI2 Is an Early Event in Colorectal Carcinogenesis and Indicates Poor Prognosis.
Peptidyl arginine deiminases (PADI) are a family of enzymes that catalyze the poorly understood posttranslational modification converting arginine residues into citrullines. In this study, the role of PADIs in the pathogenesis of colorectal cancer was investigated. Specifically, RNA expression was analyzed and its association with survival in a cohort of 98 colorectal cancer patient specimens with matched adjacent mucosa and 50 controls from donors without cancer. Key results were validated in an independent collection of tumors with matched adjacent mucosa and by mining of a publicly available expression data set. Protein expression was analyzed by immunoblotting for cell lines or IHC for patient specimens that further included 24 cases of adenocarcinoma with adjacent dysplasia and 11 cases of active ulcerative colitis. The data indicate that PADI2 is the dominantly expressed PADI enzyme in colon mucosa and is upregulated during differentiation. PADI2 expression is low or absent in colorectal cancer. Frequently, this occurs already at the stage of low-grade dysplasia. Mucosal PADI2 expression is also low in ulcerative colitis. The expression level of PADI2 in tumor and adjacent mucosa correlates with differential survival: low levels associate with poor prognosis. Downregulation of PADI2 is an early event in the pathogenesis of colorectal cancer associated with poor prognosis and points toward a possible role of citrullination in modulating tumor cells and their microenvironment. Mol Cancer Res; 14(9); 841-8. ©2016 AACR.


Evidence that multiple genetic variants of MC4R play a functional role in the regulation of energy expenditure and appetite in Hispanic children.
Melanocortin-4-receptor (MC4R) haploinsufficiency is the most common form of monogenic obesity; however, the frequency of MC4R variants and their functional effects in general populations remain uncertain. The aim was to identify and characterize the effects of MC4R variants in Hispanic children. MC4R was resequenced in 376 parents, and the identified single nucleotide polymorphisms (SNPs) were genotyped in 613 parents and 1016 children from the Viva la Familia cohort. Measured genotype analysis (MGA) tested associations between SNPs and phenotypes. Bayesian quantitative trait nucleotide (BQTN) analysis was used to infer the most likely functional polymorphisms influencing obesity-related traits. Seven rare SNPs in coding and 18 SNPs in flanking regions of MC4R were identified. MGA showed suggestive associations between MC4R variants and body size, adiposity, glucose, insulin, leptin, ghrelin, energy expenditure, physical activity, and food intake. BQTN analysis identified SNP 1704 in a predicted micro-RNA target sequence in the downstream flanking region of MC4R as a strong, probable functional variant influencing total, sedentary, and moderate activities with posterior probabilities of 1.0. SNP 2132 was identified as a variant with a high probability (1.0) of exerting a functional effect on total energy expenditure and sleeping metabolic rate. SNP rs34114122 was selected as having likely functional effects on the appetite hormone ghrelin, with a posterior probability of 0.81. This comprehensive investigation provides strong evidence that MC4R genetic variants are likely to play a functional role in the regulation of weight, not only through energy intake but through energy expenditure.


Differential Angiogenic Gene Expression in TP53 Wild-Type and Mutant Ovarian Cancer Cell Lines.
Underlying mechanisms regulating angiogenesis in ovarian cancer have not been completely elucidated. Evidence suggests that the TP53 tumor suppressor pathway and tumor microenvironment play integral roles. We utilized microarray technology to study the interaction between TP53 mutational status and hypoxia on angiogenic gene expression. Affymetrix U133A arrays were analyzed for angiogenic gene expression in 19 ovarian cancer cell lines stratified both by TP53 mutation status and A2780 wild-type (wt) TP53 vs. mutated (m) TP53 cell lines after treatment under hypoxic conditions or with ionizing radiation. Twenty-eight differentially expressed angiogenic genes were identified in the mTP53 cell lines compared to wtTP53 lines. Five genes were upregulated in mTP53 cells: 40% involved in extracellular matrix (ECM) degradation [matrix metalloproteinase 10 (MMP10)/15] and 60% in angiogenesis (fibroblast growth factor receptor 3/VEGFA/ephrin receptor-B4). Twenty-three genes were upregulated in wtTP53: nearly 22% were ECM constituents or involved in ECM degradation; over 40% were growth factors or mediators of angiogenesis. Five genes were upregulated in the A2780mTP53 cells: 40% involved in ECM remodeling (MMP10, ADAMTS1), 40% with pro-angiogenic activity (EFNB2, factor 2 receptor), and 20% with anti-angiogenic properties (ADAMTS1). Three genes were upregulated in hypoxia treated cells compared to controls: one with anti-angiogenic activity (angiopoietin-like 4) and two with pro-angiogenic activity (VEGFA, EFNA3). No significant gene fold changes were noted after exposure to radiation. Four genes continued to demonstrate significant differential expression (p ≤ 0.05) after adjusting for multiple comparisons. These genes included endoglin upregulation in wt lines (pro-angiogenesis) and upregulation of FGF20 (growth factor), ADAMTS1 (anti-angiogenesis) and MMP10 (ECM degradation) in mTP53 cell lines. Our exploratory findings indicate that non-overlapping angiogenic pathways may be altered by TP53 mutations and hypoxic conditions in the tumor microenvironment. Further evaluation is needed for confirmation.


Attitudes of patients with anorexia nervosa to compulsory treatment and coercion.
The compulsory treatment of anorexia nervosa is a contentious issue. Research suggests that patients are often subject to compulsion and coercion even without formal compulsory treatment orders. Research also suggests that patients suffering from anorexia nervosa can change their minds in retrospect about compulsion. Qualitative interviewing methods were used to explore the views of 29 young women concerning compulsion and coercion in the treatment of anorexia nervosa. The participants were aged between 15 to 26years old, and were suffering or had recently suffered from anorexia nervosa at the time of interview. Compulsion and formal compulsory treatment of anorexia nervosa were considered appropriate where the condition was life-threatening. The perception of coercion was moderated by relationships. What mattered most to participants was not whether they had experienced restriction of freedom or choice, but the nature of their relationships with parents and mental health professionals. People with anorexia nervosa appear to agree with the necessity of compulsory treatment in order to save life. The perception of coercion is complex and not necessarily related to the degree of restriction of freedom.


Candidate Soluble Immune Mediators in Young Women with High-Risk Human Papillomavirus Infection: High Expression of Chemokines Promoting Angiogenesis and Cell Proliferation.
The causal interpretation of cervical immune response to Human Papillomavirus (HPV) infection is complex and poorly characterized mainly due to the delicate balance that exists between viral infection, increase of inflammatory cytokines and host risk factors. This study aims to explore the significance of cervical immune mediators associated to cell survival, angiogenesis and interaction with immune response, in predicting the risk to develop HPV-related intraepithelial lesions. A panel of 48 cytokines and growth factors were explored in a selected cohort of 168 immunocompetent women including 88 diagnosed with low (LSIL) or high (HSIL) squamous intraepithelial lesions of the cervix and 80 with normal cervical cytology (NIL). HPV genotyping was performed by Linear Array HPV test and the soluble concentration of 48 immune molecules was analyzed using the Bio-Plex platform. The prevalence of single HR-HPV infection was 30% in NIL and 100% in LSIL and HSIL women. The expression of 13 cytokines, including interleukins IL-6, IL-3, IL-12p40, IL-12p70, IL-16, IL-18, LIF, of chemokines CCL7 (MCP-3), CXCL9 (MIG), CXCL12 (SDF-1α) and of the tropic factors VEGF, G-CSF, M-CSF were significantly associated with the presence of infection, with levels being higher in women with precancerous lesions compared to NIL HPV negative women. Only the growth factor GM-CSF was positively associated with the cytological abnormalities. The ability of HR-HPV to escape from innate immune recognition and to orchestrate the production of specific inflammatory and growth factors, involved in early inflammatory response and in the cell-proliferating phase of intraepithelial damage, was documented in women before the development of cervical lesions.


Predictors of preventable nursing home hospitalizations: the role of mental disorders and dementia.
Nursing home (NH) hospitalizations place an enormous economic burden on an already overtaxed American healthcare system. Hospitalizations for "ambulatory care-sensitive" (ACS) conditions are considered preventable, as these are physical health conditions that can potentially be treated safely in a NH. The authors examined risk factors, including mental disorders and dementia, for hospitalization of Medicaid-enrolled NH residents with ACS conditions during fiscal year 2003-2006. The authors merged Medicaid claims and enrollment data and Online Survey Certification and Reporting information for 72,251 Medicaid-enrolled NH residents in 647 NHs in Florida. The authors identified at least one ACS hospitalization in 8,382 residents for a total of 10,091 hospital admissions (18.5% of all hospitalizations). The authors used Cox proportional hazard regression to assess time to the first ACS hospitalization. In a fully adjusted model, younger age, non-white race, dementia, and serious mental disorder were associated with greater risk of ACS hospitalization. In addition, residents with a diagnosed mental disorder and no dementia incurred relatively high expenditures for ACS hospitalizations. Among facility characteristics, participants from for-profit facilities, facilities that were not a member of a chain, had more Medicaid recipients, and fewer than 120 beds had greater risk of ACS hospitalizations. Attention to the identified predictors of hospitalization for ACS conditions, which are potentially preventable, could reduce the risk and cost of these hospitalizations among Medicaid-enrolled NH residents. The need to reduce unnecessary hospitalization will become only more urgent as the population ages and healthcare expenses continue to escalate.


Essential gene identification and drug target prioritization in Aspergillus fumigatus.
Aspergillus fumigatus is the most prevalent airborne filamentous fungal pathogen in humans, causing severe and often fatal invasive infections in immunocompromised patients. Currently available antifungal drugs to treat invasive aspergillosis have limited modes of action, and few are safe and effective. To identify and prioritize antifungal drug targets, we have developed a conditional promoter replacement (CPR) strategy using the nitrogen-regulated A. fumigatus NiiA promoter (pNiiA). The gene essentiality for 35 A. fumigatus genes was directly demonstrated by this pNiiA-CPR strategy from a set of 54 genes representing broad biological functions whose orthologs are confirmed to be essential for growth in Candida albicans and Saccharomyces cerevisiae. Extending this approach, we show that the ERG11 gene family (ERG11A and ERG11B) is essential in A. fumigatus despite neither member being essential individually. In addition, we demonstrate the pNiiA-CPR strategy is suitable for in vivo phenotypic analyses, as a number of conditional mutants, including an ERG11 double mutant (erg11BDelta, pNiiA-ERG11A), failed to establish a terminal infection in an immunocompromised mouse model of systemic aspergillosis. Collectively, the pNiiA-CPR strategy enables a rapid and reliable means to directly identify, phenotypically characterize, and facilitate target-based whole cell assays to screen A. fumigatus essential genes for cognate antifungal inhibitors.


Hormonal induction of thumb pads and the evolution of secondary sexual characteristics of the Southeast Asian fanged frog, Rana blythii.
The fanged frogs of Southeast Asia do not express most of the hormone-dependent secondary sexual characteristics such as thumb pads that are common to other ranid frogs. At the same point in the evolutionary history of the group that these androgen-mediated characteristics are lost, male parental care first evolves. This behavior is often correlated with low androgen levels. Prior work indicates that in one of the fanged frogs, Rana blythii, adult males have low androgen levels compared to North Temperate species of Rana. This leads to the question of whether these low androgen levels are related to the unusual male parental care and the lack of expression of the thumb pad and other hormone-dependent secondary sexual characteristics in this species. We tested that hypothesis by examining the effects of exogenous dihydrotestosterone supplements on the expression of thumb pads in Rana blythii. Dihydrotestosterone injections appear to stimulate the expression of the thumb pad in R. blythii. These results support the hypothesis that low androgen levels are involved in the loss of the thumb pad in R. blythii. This work provides an example of how mapping characters on phylogenies can be a powerful approach for gaining insights into proximate physiological mechanisms of selection at the evolutionary level.


Teaching children about bicycle safety: an evaluation of the New Jersey Bike School program.
There are multiple health and environmental benefits associated with increasing bicycling among children. However, the use of bicycles is also associated with severe injuries and fatalities. In order to reduce bicycle crashes, a bicycling education program was implemented in selected New Jersey schools and summer camps as part of the New Jersey Safe Routes to School Program. Using a convenience sample of participants to the program, an opportunistic study was designed to evaluate the effectiveness of two bicycle education programs, the first a more-structured program delivered in a school setting, with no on-road component, and the other a less structured program delivered in a summer camp setting that included an on-road component. Tests administered before and after training were designed to assess knowledge acquired during the training. Questions assessed children's existing knowledge of helmet use and other equipment, bicycle safety, as well as their ability to discriminate hazards and understand rules of the road. Participating children (n=699) also completed a travel survey that assessed their bicycling behavior and their perception of safety issues. Response to individual questions, overall pre- and post-training test scores, and changes in test scores were compared using comparison of proportion, t-tests, and ordinary least-squares (OLS) regression. Improvements between the pre-training and post-training test are apparent from the frequency distribution of test results and from t-tests. Both summer camps and school-based programs recorded similar improvements in test results. Children who bicycled with their parents scored higher on the pre-training test but did not improve as much on the post-training test. Without evaluating long-term changes in behavior, it is difficult to ascertain how successful the program is on eventual behavioral and safety outcomes.


Preference classes in society for coastal marine protected areas.
Marine protected areas (MPAs) are increasingly being used as conservation tools in the marine environment. Success of MPAs depends upon sound scientific design and societal support. Studies that have assessed societal preferences for temperate MPAs have generally done it without considering the existence of discrete groups of opinion within society and have largely considered offshore and deep-sea areas. This study quantifies societal preferences and economic support for coastal MPAs in Wales (UK) and assesses the presence of distinct groups of preference for MPA management, through a latent class choice experiment approach. Results show a general support for the protection of the marine environment in the form of MPAs and that society is willing to bear the costs derived from conservation. Despite a general opposition toward MPAs where human activities are completely excluded, there is some indication that three classes of preferences within society can be established regarding the management of potentially sea-floor damaging activities. This type of approach allows for the distinction between those respondents with positive preferences for particular types of management from those who experience disutility. We conclude that insights from these types of analyses can be used by policy-makers to identify those MPA designs and management combinations most likely to be supported by particular sectors of society.


Strong Dipolar Effects on an Octupolar Luminiscent Chromophore: Implications on their Linear and Nonlinear Optical Properties.
Design parameters derived from structure-property relationships play a very important role in the development of efficient molecular-based functional materials with optical properties. Here, we report on the linear and nonlinear optical properties of a fluorene-derived dipolar system (DS) and its octupolar analogue (OS), in which donor and acceptor groups are connected by a phenylacetylene linkage, as a strategy to increase the number of delocalized electrons in the π-conjugated system. The optical nonlinear response was analyzed in detail by experimental and theoretical methods, showing that, in the octupolar system OS, the dipolar effects induced a strong two-photon absorption process whose magnitude is as large as 2210 GM at infrared wavelengths. Solvatochromism studies were implemented to obtain further insight on the charge transfer process. We found that the triple bond plays a fundamental role in the linear and nonlinear optical responses. The strong solvatochromism behavior in DS and OS was analyzed by using four empirical solvent scales, namely Lippert-Mataga, Kamlet-Taft, Catalán, and the recently proposed scale of Laurence et al., finding consistent results of strong solvent polarizability and viscosity dependence. Finally, the role of the acceptor groups was further studied by synthesizing the analogous compound 2DS, having no acceptor group.


Experimental evidence of signal-optical noise interferencelike effect in underwater amplitude-modulated laser optical radar systems.
We report experimental evidence that in an amplitude-modulated laser optical radar system for underwater 3D imaging the observed contrast oscillations as a function of the modulation frequency originate from an interference-like effect between target signal VT and water backscattered radiation VW. The demonstration relies on the ability to perform a direct measurement of VW in a 25 m long test tank. The proposed data processing method enables one to remove the contribution of water backscattering from the detected signal and drastically reduce signal fluctuations due to the medium. Experiments also confirm the possibility to improve the signal to optical noise ratio and contrast by increasing the modulation frequency.


Expressed emotion and the course of schizophrenia in Pakistan.
Aim of the study is to evaluate the predictive power of Expressed Emotion in Schizophrenia relapse in Pakistan. A longitudinal study was conducted comprising 53 in-patients' sample diagnosed with Schizophrenia and their 101 key carers. Participants fulfilled DSM-IV-TR criteria for Schizophrenia based on Structural Clinical Interview for the DSM-IV diagnosis. Symptomatic status was measured through Brief Psychiatric Rating Scales-Expanded (BPRS-E). Caregivers' level of EE was assessed through Camberwell Family Interview (CFI). Patients were followed up for 9 months after hospital discharge. Relapse rate for patients with high-EE household was 72% as compared with 36% in the low-EE household. Logistic Regression showed a positive relationship between high-EE and relapse (CI 0.06-0.80; p < 0.05). Both hostility and critical comments emerged as significant predictors of relapse. The odds ratio showed that a one unit increase in caregivers' score on the CCs and hostility scales were associated with a 1.29 (CI 1.06-1.56; p < 0.05) and 1.89 (CI 1.14-3.13; p < 0.05) times increased rate of relapse, respectively. Conversely, a non-significant relationship was observed between EOI and relapse. The findings from this study confirmed the validity of EE construct in predicting schizophrenia relapse in a Pakistani sample. However, medication compliance has not been experimentally controlled and that is one of the limitations of the study.


Regulation of a G protein-gated inwardly rectifying K+ channel by a Ca(2+)-independent protein kinase C.
1. Members of the Kir3.0 family of inwardly rectifying K(+) channels are expressed in neuronal, atrial and endocrine tissues and play key roles in generating late inhibitory postsynaptic potentials (IPSPs), slowing heart rate and modulating hormone release. They are activated directly by G(betagamma) subunits released in response to G(i/o)-coupled receptor stimulation. However, it is not clear to what extent this process can be dynamically regulated by other cellular signalling systems. In this study we have explored pathways activated by the G(q/11)-coupled M(1) and M(3) muscarinic receptors and their role in the regulation of Kir3.1+3.2A neuronal-type channels stably expressed in the human embryonic kidney cell line HEK293. 2. We describe a novel biphasic pattern of behaviour in which currents are initially stimulated but subsequently profoundly inhibited through activation of M(1) and M(3) receptors. This contrasts with the simple stimulation seen through activation of M(2) and M(4) receptors. 3. Channel stimulation via M(1) but not M(3) receptors was sensitive to pertussis toxin whereas channel inhibition through both M(1) and M(3) receptors was insensitive. In contrast over-expression of the C-terminus of phospholipase Cbeta1 or a G(q/11)-specific regulator of G protein signalling (RGS2) essentially abolished the inhibitory phase. 4. The inhibitory effects of M(1) and M(3) receptor stimulation were mimicked by phorbol esters and a synthetic analogue of diacylglycerol but not by the inactive phorbol ester 4alphaphorbol. Inhibition of the current by a synthetic analogue of diacylglycerol effectively occluded any further inhibition (but not activation) via the M(3) receptor. 5. The receptor-mediated inhibitory phenomena occur with essentially equal magnitude at all intracellular calcium concentrations examined (range, 0-669 nM). 6. The expression of endogenous protein kinase C (PKC) isoforms in HEK293 cells was examined by immunoblotting, and their translocation in response to phorbol ester treatment by cellular extraction. The results indicated the expression and translocation of the novel PKC isoforms PKCdelta and PKCepsilon. 7. We also demonstrate that activation of such a pathway via both receptor-mediated and receptor-independent means profoundly attenuated subsequent channel stimulation by G(i/o)-coupled receptors. 8. Our data support a role for a Ca(2+)-independent PKC isoform in dynamic channel regulation, such that channel activity can be profoundly reduced by M(1) and M(3) muscarinic receptor stimulation.


Notes on Human Trials of Transcranial Direct Current Stimulation between 1960 and 1998.
Background: Transcranial direct current stimulation (tDCS) is investigated to modulate neuronal function including cognitive neuroscience and neuropsychiatric therapies. While cases of human stimulation with rudimentary batteries date back more than 200 years, clinical trials with current controlled stimulation were published intermittently since the 1960s. The modern era of tDCS only started after 1998. Objectives: To review methods and outcomes of tDCS studies from old literature (between 1960 and 1998) with intention of providing new insight for ongoing tDCS trials and development of tDCS protocols especially for the purpose of treatment. Methods: Articles were identified through a search in PubMed and through the reference list from its selected articles. We included only non-invasive human studies that provided controlled direct current and were written in English, French, Spanish or Portuguese before the year of 1998, the date in which modern stimulation paradigms were implemented. Results: Fifteen articles met our criteria. The majority were small-randomized controlled clinical trials that enrolled a mean of approximately 26 subjects (Phase II studies). Most of the studies (around 83%) assessed the role of tDCS in the treatment of psychiatric conditions, in which the main outcomes were measured by means of behavioral scales and clinical observation, but the diagnostic precision and the quality of outcome monitoring, including adverse events, were deficient by modern standards. Compared to modern tDCS dose, the stimulation intensities used (0.1-1 mA) were lower, however as the electrodes were typically smaller (e.g., 1.26 cm2), the average electrode current density (0.2 mA/cm2) was approximately 4× higher. The number of sessions ranged from one to 120 (median 14). Notably, the stimulation session durations of several minutes to 11 h (median 4.5 h) could markedly exceed modern tDCS protocols. Twelve studies out of 15 showed positive results. Only mild side effects were reported, with headache and skin alterations the most common. Conclusion: Most of the studies identified were for psychiatric indications, especially in patients with depression and/or schizophrenia and majority indicated some positive results. Variability in outcome is noted across trials and within trials across subjects, but overall results were reported as encouraging, and consistent with modern efforts, given some responders and mild side effects. The significant difference with modern dose, low current with smaller electrode size and interestingly much longer stimulation duration may worth considering.