Protocol: inspiratory muscle training for promoting recovery and outcomes in ventilated patients (IMPROVe): a randomised controlled trial.
Inspiratory muscle weakness is a known consequence of mechanical ventilation and a potential contributor to difficulty in weaning from ventilatory support. Inspiratory muscle training (IMT) reduces the weaning period and increases the likelihood of successful weaning in some patients. However, it is not known how this training affects the residual inspiratory muscle fatigability following successful weaning nor patients' quality of life or functional outcomes. This dual centre study includes two concurrent randomised controlled trials of IMT in adult patients who are either currently ventilator-dependent (>7 days) (n=70) or have been recently weaned from mechanical ventilation (>7 days) in the past week (n=70). Subjects will be stable, alert and able to actively participate and provide consent. There will be concealed allocation to either treatment (IMT) or usual physiotherapy (including deep breathing exercises without a resistance device). Primary outcomes are inspiratory muscle fatigue resistance and maximum inspiratory pressures. Secondary outcomes are quality of life (Short Form-36v2, EQ-5D), functional status (Acute Care Index of Function), rate of perceived exertion (Borg Scale), intensive care length of stay (days), post intensive care length of stay (days), rate of reintubation (%) and duration of ventilation (days). Ethics approval has been obtained from relevant institutions, and results will be published with a view to influencing physiotherapy practice in the management of long-term ventilator-dependent patients to accelerate weaning and optimise rehabilitation outcomes. ACTRN12610001089022.


Rs4938723 Polymorphism Is Associated with Susceptibility to Hepatocellular Carcinoma Risk and Is a Protective Factor in Leukemia, Colorectal, and Esophageal Cancer.
BACKGROUND Growing evidence indicates that a non-coding RNA named miR-34b/c plays crucial roles in carcinogenesis, and its common polymorphism, pri-miR-34b/c rs4938723, also participates in this process and is associated with cancer susceptibility. However, this association was previously undefined and ambiguous. Therefore, we carried out an updated analysis to evaluate this relationship between rs4938723 polymorphism and cancer susceptibility. MATERIAL AND METHODS PubMed, EMbase, Web of Science and Chinese language (WanFang, CNKI and VIP) databases were searched for relevant studies until Sep 10, 2018. Odds ratios and 95% confidence interval were applied to assess this relationship. RESULTS Thirty case-control studies were retrieved. No positive association was found in either the overall study population or in the subgroups, based on ethnicity, source of group, sex, smoking, and drinking status. The main results were observed in the stratified analysis subgroups in cancer type subgroup: rs4938723 polymorphism may be a protective factor in leukemia, colorectal cancer, and esophageal cancer; however, C-allele was a risk factor in carriers for hepatocellular carcinoma. Last but not the least, poor positive results were discovered in the age subgroup. CONCLUSIONS Current meta-analysis suggested that rs4938723 polymorphism was potentially associated with hepatocellular carcinoma risk, but this polymorphism had a decreased association for susceptibility to esophageal cancer, leukemia, and colorectal cancer. Furthermore, studies with larger sample sizes and including gene-gene or gene-environment interactions should be carried out to elucidate the role of rs4938723 polymorphism in cancer risk.


A nonimprinted Prader-Willi Syndrome (PWS)-region gene regulates a different chromosomal domain in trans but the imprinted pws loci do not alter genome-wide mRNA levels.
Prader-Willi syndrome (PWS) is a complex neurobehavioral disorder that results from loss of function of 10 clustered, paternally expressed genes in a 1.5-Mb region of chromosome 15q11-q13. Many of the primary PWS region genes appear to have nuclear RNA regulatory functions, suggesting that multiple genetic pathways could be secondarily affected in PWS. Using a transgenic mouse model of PWS (TgPWS) with an approximately 4-Mb chromosome 7C deletion of paternal origin that models the neonatal phenotype of the human syndrome we compared by oligonucleotide microarrays expression levels of approximately 12,000 genes and ESTs in TgPWS and wild-type brain. Hybridization data were processed with two distinct statistical algorithms and revealed a dramatically reduced expression of 4 imprinted genes within the deletion region in TgPWS mice, with 2 nonimprinted, codeleted genes reduced twofold. However, only 3 genes outside the deletion were significantly altered in TgPWS mouse brain, with approximately 1.5-fold up-regulation of mRNA levels. Remarkably, these genes map to a single chromosome domain (18B3), and by quantitative RT-PCR we show that 8 genes in this domain are up-regulated in TgPWS brain. These 18B3 genes were up-regulated in an equivalent manner in Angelman syndrome mouse (TgAS) brain, which has the same deletion but of maternal origin. Therefore, the trans-regulation of the chromosome 18B3 domain is due to decreased expression of a nonimprinted gene within the TgPWS/AS mouse deletion in mouse chromosome 7C. Most surprisingly, since 48-60% of the genome was screened, it appears that the imprinted mouse PWS loci do not widely regulate mRNA levels of other genes and may regulate RNA structure.


Role of oxidative stress in the ammonia-induced mitochondrial permeability transition in cultured astrocytes.
Ammonia is a neurotoxin that has been strongly implicated in the pathogenesis of hepatic encephalopathy (HE) and other neurological disorders, and astrocytes are thought to be the principal target of ammonia toxicity. While the precise mechanisms of ammonia neurotoxicity remain to be more clearly defined, altered bioenergetics and oxidative stress appear to be critical factors in its pathogenesis. It has recently been demonstrated that pathophysiological concentrations of ammonia induce the mitochondrial permeability transition (MPT) in cultured astrocytes, a process associated with mitochondrial dysfunction, and frequently caused by oxidative stress. This study investigated the potential role of oxidative stress in the induction of the MPT by ammonia. Accordingly, the effect of various antioxidants on the induction of the MPT by ammonia in cultured astrocytes was examined. Astrocytes were subjected to NH4Cl (5 mM) treatment for 2 days with or without various antioxidants. The MPT was assessed by quantitative fluorescence imaging for the mitochondrial membrane potential (DeltaPsim), employing the potentiometric dye TMRE; by changes in mitochondrial calcein fluorescence and by 2-deoxyglucose-6-phosphate (2-DG-6-P) changes in mitochondrial permeability. Astrocytes treated with ammonia significantly dissipated the DeltaPsim, which was blocked by the MPT inhibitor, cyclosporin A, caused a decrease in mitochondrial calcein fluorescence and increased 2-DG-6-P permeability into mitochondria. All of these findings are consistent with induction of the MPT. Pretreatment with SOD, catalase, desferroxamine, Vitamin E, PBN and the nitric oxide synthase inhibitor, N(G)-nitro-L-arginine methyl ester (L-NAME), completely blocked the ammonia-induced MPT. These data provide strong evidence that oxidative stress is involved in the induction of the MPT by ammonia, and suggest that oxidative stress and the subsequent induction of the MPT contribute to the pathogenesis of HE and other hyperammonemic disorders.


Clinical effectiveness of care managers in collaborative care for patients with depression in Swedish primary health care: a pragmatic cluster randomized controlled trial.
Depression is one of the leading causes of disability and affects 10-15% of the population. The majority of people with depressive symptoms seek care and are treated in primary care. Evidence internationally for high quality care supports collaborative care with a care manager. Our aim was to study clinical effectiveness of a care manager intervention in management of primary care patients with depression in Sweden. In a pragmatic cluster randomized controlled trial 23 primary care centers (PCCs), urban and rural, included patients aged ≥ 18 years with a new (< 1 month) depression diagnosis. Intervention consisted of Care management including continuous contact between care manager and patient, a structured management plan, and behavioral activation, altogether around 6-7 contacts over 12 weeks. Control condition was care as usual (CAU). Depression symptoms (measured by Mongomery-Asberg depression score-self (MADRS-S) and BDI-II), quality of life (QoL) (EQ-5D), return to work and sick leave, service satisfaction, and antidepressant medication. Data were analyzed with the intention-to-treat principle. One hundred ninety two patients with depression at PCCs with care managers were allocated to the intervention group, and 184 patients at control PCCs were allocated to the control group. Mean depression score measured by MADRS-S was 2.17 lower in the intervention vs. the control group (95% CI [0.56; 3.79], p = 0.009) at 3 months and 2.27 lower (95% CI [0.59; 3.95], p = 0.008) at 6 months; corresponding BDI-II scores were 1.96 lower (95% CI [- 0.19; 4.11], p = 0.07) in the intervention vs. control group at 6 months. Remission was significantly higher in the intervention group at 6 months (61% vs. 47%, p = 0.006). QoL showed a steeper increase in the intervention group at 3 months (p = 0.01). During the first 3 months, return to work was significantly higher in the intervention vs. the control group. Patients in the intervention group were more consistently on antidepressant medication than patients in the control group. Care managers for depression treatment have positive effects on depression course, return to work, remission frequency, antidepressant frequency, and quality of life compared to usual care and is valued by the patients. Identifier: NCT02378272 . February 2, 2015. Retrospectively registered.


Digestive chitinolytic activity in marine fishes of Monterey Bay, California.
Chitinolytic activities, both chitinase (EC 188.8.131.52) and minimum chitobiase (beta-N-acetyl-D-glucosaminidase; EC 184.108.40.206), were measured in stomach and intestinal tissues and their contents, from 13 fish species. Higher activities were found in the tissues than in the gut contents, and higher activities were seen in the stomachs than in the intestines. Demersal species exhibited chitobiase activities very close to their chitinase activities, suggesting that these fishes can degrade chitin completely to its soluble, absorbable monomer, N-acetyl-glucosamine. This suggests that these species may catabolize chitin not just to penetrate prey exoskeletons but also to derive nutrients from the chitin itself. In contrast, three mesopelagic species exhibited low chitobiase but high chitinase activities. This chitobiase limitation correlated strongly with gastrointestinal tract morphology, with the myctophids having the greatest chitobiase limitation and the shortest alimentary tracts. The high chitinase activities measured in the myctophids reflect their ability to rapidly disrupt prey exoskeletons ingested during their nightly feeding in surface waters. Their chitobiase activities are greatly reduced because with rapid meal evacuation through a short gut there is little time for processing and limited energetic advantage in the complete degradation of chitin. These results suggest multiple roles for chitinolytic enzymes in marine fishes and that feeding habits and frequency may have a bearing on the evolution of their digestive enzymes systems.


Odor control during post-digestion processing of biosolids through bioaugmentation of anaerobic digestion.
The effects of bioaugmenting anaerobic biosolids digestion with a commercial product that contained selected strains of bacteria from genera Bacillus, Pseudomonas, and Actinomycetes, along with ancillary organic compounds containing various micronutrients were evaluated. The main objective of the study was to investigate the effects of bioaugmentation specifically on the performance of methanogenesis during anaerobic digestion, as well as on the generation and fate of odor-causing compounds during the storage of the digested biosolids. The bench-scale digester with 5 g/L bioaugment generated 29% more net CH4 than a control during the eight weeks of operation. In addition, the average residual propionic acid concentration in the bioaugmented digester was 46% lower than that in the control. The biosolids digested in the bioaugmented digester generated a negligible amount of methyl mercaptan (CH3SH) during 10 days of post-digestion storage, while CH3SH concentration in the control reached nearly 300 ppmv during the same period. Similarly peak dimethyl sulfide (CH3SCH3) generated by stored biosolids from the bioaugmented digester was only 37% of that from the control. Similar results were obtained in a subsequent short term study designed to confirm the repeatability of the findings.


ICTV Virus Taxonomy Profile: Hepeviridae.
The family Hepeviridae includes enterically transmitted small non-enveloped positive-sense RNA viruses. It includes the genera Piscihepevirus, whose members infect fish, and Orthohepevirus, whose members infect mammals and birds. Members of the genus Orthohepevirus include hepatitis E virus, which is responsible for self-limiting acute hepatitis in humans and several mammalian species; the infection may become chronic in immunocompromised individuals. Extrahepatic manifestations of Guillain-Barré syndrome, neuralgic amyotrophy, glomerulonephritis and pancreatitis have been described in humans. Avian hepatitis E virus causes hepatitis-splenomegaly syndrome in chickens. This is a summary of the International Committee on Taxonomy of Viruses (ICTV) Report on the taxonomy of the Hepeviridae, which is available at www.ictv.global/report/hepeviridae.


Fish oil feeding is associated with an increased accumulation of dietary lipids in enterocytes: results from an in vivo study in rats.
Chronic fish oil consumption is associated with reduced postprandial lipaemia, but the mechanism behind this effect is not fully understood. We studied whether lipid absorption might be altered in rats fed fish oil. Male Wistar rats were fed fish oil enriched chow (n = 6) or control oil enriched chow (n = 6). After 4 weeks, 61 mg 3H-triolein was instilled into duodenal tied-off loops. Intestinal segments were removed after 15, 30, 45, 60 and 90 min. Enterocytes were then isolated by calcium chelation and quantified by DNA determination. Non-absorbed 3H-lipid and 3H-lipid contents of enterocytes were determined by liquid scintillation counting. Two other groups of rats (2 x 6) fed the experimental diets were given an oral fat load and fasting and postprandial blood samples were taken. The accumulation of 3H-lipids in enterocytes was higher in rats fed fish oil than in controls (area under the 3H-lipid time curve: 1041.3 versus 670.3 nmol oleic acid x min/microg DNA, P < 0.05). Separation of lipids showed that an accumulation of triglycerides and free fatty acids occurred in rats fed fish oil. The amount of non-absorbed 3H-lipid tended to be higher in the fish oil fed rats (P > 0.1). It was confirmed that the fish oil enriched chow caused lower postprandial lipaemia (34% reduction in serum triglyceride concentrations, P < 0.05). Attenuated postprandial lipaemia following fish oil feeding is explained, at least partly, by a transient lipid accumulation in enterocytes which may result in a delayed triglyceride efflux from the enterocytes into the circulation.


Neurofilament light chain in serum for the diagnosis of amyotrophic lateral sclerosis.
To determine the diagnostic and prognostic performance of serum neurofilament light chain (NFL) in amyotrophic lateral sclerosis (ALS). This single-centre, prospective, longitudinal study included the following patients: 124 patients with ALS; 50 patients without neurodegenerative diseases; 44 patients with conditions included in the differential diagnosis of ALS (disease controls); 65 patients with other neurodegenerative diseases (20 with frontotemporal dementia, 20 with Alzheimer's disease, 19 with Parkinson's disease, 6 with Creutzfeldt-Jakob disease (CJD)). Serum NFL levels were measured using the ultrasensitive single molecule array (Simoa) technology. Serum NFL levels were higher in ALS in comparison to all other categories except for CJD. A cut-off level of 62 pg/mL discriminated between ALS and all other conditions with 85.5% sensitivity (95% CI 78% to 91.2%) and 81.8% specificity (95% CI 74.9% to 87.4%). Among patients with ALS, serum NFL correlated positively with disease progression rate (rs=0.336, 95% CI 0.14 to 0.506, p=0.0008), and higher levels were associated with shorter survival (p=0.0054). Serum NFL did not differ among patients in different ALS pathological stages as evaluated by diffusion-tensor imaging, and in single patients NFL levels were stable over time. Serum NFL is increased in ALS in comparison to other conditions and can serve as diagnostic and prognostic biomarker. We established a cut-off level for the diagnosis of ALS.


Nutritional and health benefits associted with kiwifruit consumption
Both the Green® kiwifruit (Actinidia deliciosa)and the Sungold® one (A. chinensis)stand out among other commonly consumed fruits for their nutritional composition. They are fruits exceptionally rich in vitamin C, since green kiwi fruit have twice and Sungold® have three times the same amount of the vitamin of strawberries or oranges. Kiwifruit is very rich in vitamins E, K, folates, carotenoids, potassium, fiber and other phytochemicals. Regular consumption of kiwifruit, in the context of a balanced diet, has proven to have beneficial effects on immune function and antioxidant defense; also in the gastrointestinal function, improving protein digestion and constipation; and in the upper respiratory tract, preventing infections and improving their symptoms. Finally, regular consumption of kiwifruit has been associated with improvements in mood. Most of these benefits may be due not only to the high content of vitamin C of the kiwifruit, but also to other nutrients and phytochemicals that work synergistically in the food matrix. The results of the studies suggest that the daily consumption of kiwifruit can be an effective strategy for health promotion and prevention of numerous diseases.


Long-term Audiometric Outcomes in Unilateral Sudden Sensorineural Hearing Loss without Recurrence.
The recurrence rate of sudden sensorineural hearing loss (SSNHL) varies from 0.8% to 40%. However, to the best of our knowledge, no data on long-term hearing variations are present in the literature. The aim of this observational study was to analyze long-term variations of the hearing threshold in unilateral SSNHL without recurrence. A total of 50 patients affected by unilateral SSNHL were evaluated. Patients underwent a treatment consisting of intravenous corticosteroids. Clinical and audiometric features were recorded. Patients underwent pure tone audiometry at a mean follow-up of 5.26±2.28 years. Differences between the affected and unaffected ear were analyzed. Comparing the post-treatment and follow-up audiograms, there was a worsening of hearing in the unaffected ear. On the contrary, no significant difference over time was found for the affected ear. 54% of patients showed no changes over time, 26% showed worsening, and 20% showed an improvement in hearing. The variation correlated with alcohol consumption and the presence of vasculopathies. An average improvement of hearing over time was observed at low frequencies. The time evolution in SSNHL is not predictable on the basis of the clinical and audiometric data. The majority the patients shows no changes in hearing loss in the affected ear. Patients who consume alcohol or have vasculopathies also have a higher risk of worsening of hearing. Further prospective studies are mandatory to better assess variations over time and their relationship with the effect of aging on hearing.


Cardiomyocyte apoptosis and cardiac angiotensin-converting enzyme in spontaneously hypertensive rats.
Increased apoptosis has been reported in the heart of rats with spontaneous hypertension and cardiac hypertrophy. This study was designed to investigate the relationship between apoptosis and hypertrophy in cardiomyocytes from the left ventricle of spontaneously hypertensive rats (SHR). In addition, we evaluated whether the development of cardiomyocyte apoptosis is related to blood pressure or to the activity of the local angiotensin-converting enzyme (ACE) in SHR. The study was performed in 16-week-old SHR, 30-week-old untreated SHR, and 30-week-old SHR treated with quinapril (10 mg x kg[-1] x d[-1]) during 14 weeks before they were killed. Cardiomyocyte apoptosis was assessed by direct immunoperoxidase detection of digoxigenin-labeled 3'-hydroxyl ends of DNA. Nuclear polyploidization measured by DNA flow cytometry was used to assess cardiomyocyte hypertrophy. Compared with 16-week-old normotensive Wistar-Kyoto rats, 16-week-old SHR exhibited increased blood pressure (P<.001), increased rate of tetraploidy (P<.05), and similar levels of ACE activity and apoptosis. Compared with 30-week-old Wistar-Kyoto rats, 30-week-old SHR showed increased blood pressure (P<.001), increased ACE activity (P<.05), increased rate of tetraploidy (P<.01), and increased apoptosis (P<.01). Untreated 30-week-old SHR exhibited similar values of blood pressure and tetraploidy and higher ACE activity (P<.05) and apoptosis (P<.001) than 16-week-old SHR. A direct correlation (P<.01) was found between ACE activity and the apoptotic index in untreated 30-week-old SHR. The long-term administration of quinapril was associated with the normalization of ACE activity and apoptosis in treated SHR. These results suggest that the timing and mechanisms responsible for apoptosis and hypertrophy of cardiomyocytes are different in SHR. Whereas hypertrophy seems to be an earlier alteration that develops in parallel with hypertension, apoptosis develops later in association with overactivity of the local ACE. Our data suggest that cell death dysregulation may be a novel target for antihypertensive agents that interfere with the renin-angiotensin system in hypertension.


The putative oncogene GASC1 demethylates tri- and dimethylated lysine 9 on histone H3.
Methylation of lysine and arginine residues on histone tails affects chromatin structure and gene transcription. Tri- and dimethylation of lysine 9 on histone H3 (H3K9me3/me2) is required for the binding of the repressive protein HP1 and is associated with heterochromatin formation and transcriptional repression in a variety of species. H3K9me3 has long been regarded as a 'permanent' epigenetic mark. In a search for proteins and complexes interacting with H3K9me3, we identified the protein GASC1 (gene amplified in squamous cell carcinoma 1), which belongs to the JMJD2 (jumonji domain containing 2) subfamily of the jumonji family, and is also known as JMJD2C. Here we show that three members of this subfamily of proteins demethylate H3K9me3/me2 in vitro through a hydroxylation reaction requiring iron and alpha-ketoglutarate as cofactors. Furthermore, we demonstrate that ectopic expression of GASC1 or other JMJD2 members markedly decreases H3K9me3/me2 levels, increases H3K9me1 levels, delocalizes HP1 and reduces heterochromatin in vivo. Previously, GASC1 was found to be amplified in several cell lines derived from oesophageal squamous carcinomas, and in agreement with a contribution of GASC1 to tumour development, inhibition of GASC1 expression decreases cell proliferation. Thus, in addition to identifying GASC1 as a histone trimethyl demethylase, we suggest a model for how this enzyme might be involved in cancer development, and propose it as a target for anti-cancer therapy.


Examination of brains of AIDS cases for human immunodeficiency virus and human cytomegalovirus nucleic acids.
The role of direct virus infection as a determining factor in acquired immunodeficiency syndrome (AIDS) dementia was investigated using in situ hybridisation for human immunodeficiency virus (HIV) and human cytomegalovirus (HCMV). Four of the five AIDS dementia patients in this series demonstrated HIV infected cells distributed in widely different parts of the brain, but only one case showed HCMV infected cells. The greater abundance of HIV was in subcortical white matter in nodular areas consisting of monocyte/macrophage infiltrates. The cells were occasionally arranged as a multinucleated syncitium. In two cases, a few large cells with the appearance of neurons were positive for HIV hybridisation. By appropriate treatment with ribonuclease, it was shown that hybridisation was primarily to HIV RNA. HCMV infected cells were observed in small numbers in only one of the positive cases, suggesting that HCMV is not a determining factor in AIDS dementia. HCMV positive cells were located in the grey matter, with an appearance suggestive of neurons. Cells expressing the MHC-class II antigen HLA-DR, a marker of reactive microglia and macrophages, were observed to be extensive in affected brain sections in the one case examined. These cells were present in greater number than HIV infected cells. In this case, extensive numbers of HIV infected cells were noticed along the peripheral margin of the substantia innominata. This could indicate infection in this case of a critical brain region from the cerebrospinal fluid.


Radiation dose at coronary CT angiography: second-generation dual-source CT versus single-source 64-MDCT and first-generation dual-source CT.
The purpose of this study was to assess the radiation doses of different coronary CTA (CTA) protocols: second-generation dual-source 128-MDCT, first-generation dual-source 64-MDCT, and single-source 64-MDCT. Thermoluminescent dosimetry was used to determine scanner-specific dose coefficients for standard coronary CTA of an anthropomorphic phantom. These coefficients were used to estimate the effective doses (EDs) of retrospectively gated, prospectively triggered, and prospectively triggered high pitch coronary CTA performed at 100 and 120 kV. The coronary CTA protocols used in imaging of 43 patients undergoing dual-source 128-MDCT were analyzed for ED, image quality, and signal-to-noise ratio. Regardless of coronary CTA protocol and CT system, imaging at 100 kV lowered the ED 40-50%. In retrospectively gated 120-kV coronary CTA, the ED ranged from 5.7 to 10.7 mSv and was approximately 50% lower with single-source 64-MDCT than with either DSCT protocol. In prospectively triggered 120-kV coronary CTA, the ED ranged from 3.8 to 4.0 mSv. The lowest ED of all protocols (1.3 mSv) was observed in prospectively triggered high-pitch 100-kV coronary CTA performed with dual-source 128-MDCT. Patient measurements showed similar dose reductions for prospective triggering and low voltage settings without an influence on signal-to-noise ratio or image quality. A combination of prospective triggering with low voltage settings is an effective measure for reducing the ED of coronary CTA to values of 2-4 mSv independent of scanner system. Further dose reduction to nearly 1 mSv can be achieved with high-pitch prospectively triggered coronary CTA.


Ca2+ microdomains in smooth muscle.
In smooth muscle, Ca(2+) controls diverse activities including cell division, contraction and cell death. Of particular significance in enabling Ca(2+) to perform these multiple functions is the cell's ability to localize Ca(2+) signals to certain regions by creating high local concentrations of Ca(2+) (microdomains), which differ from the cytoplasmic average. Microdomains arise from Ca(2+) influx across the plasma membrane or release from the sarcoplasmic reticulum (SR) Ca(2+) store. A single Ca(2+) channel can create a microdomain of several micromolar near (approximately 200 nm) the channel. This concentration declines quickly with peak rates of several thousand micromolar per second when influx ends. The high [Ca(2+)] and the rapid rates of decline target Ca(2+) signals to effectors in the microdomain with rapid kinetics and enable the selective activation of cellular processes. Several elements within the cell combine to enable microdomains to develop. These include the brief open time of ion channels, localization of Ca(2+) by buffering, the clustering of ion channels to certain regions of the cell and the presence of membrane barriers, which restrict the free diffusion of Ca(2+). In this review, the generation of microdomains arising from Ca(2+) influx across the plasma membrane and the release of the ion from the SR Ca(2+) store will be discussed and the contribution of mitochondria and the Golgi apparatus as well as endogenous modulators (e.g. cADPR and channel binding proteins) will be considered.


Solidarity and Care Coming of Age: New Reasons in the Politics of Social Welfare Policy.
Aging brings about the ordeal of coping. Younger people also cope, but for those in old age, the ordeal is so often elegiac, forced upon the self by changing functions within the body and by the outside social world, with its many impediments to the continuity of former roles, pursuits, and self-identities. Coping with change can be affirming, but when what is being forgone seems more valuable than what lies ahead, it is travail. For most, the coping is managed more moderately by a sense of resignation. This is especially true for those who survive into profound old age, when one is viewed as if being old is one's essential identity and nature. We must recognize and affirm difference and change without stigmatizing or losing sight of the specific capabilities and circumstances of the individual. This is what I think the often-used, but less often clearly defined, notion of a "person-centered" orientation should signify. Individuals age, but so do societies, not simply because they have a large population over age sixty-five, but in the sense that societies as a whole are also buffeted by significant disruption in orders of meaning. Aging has a public as well as a private manifestation, a social as well as a personal embodiment, and how it is paid attention to in culture, politics, and policy makes a great difference to how aging is concretely experienced in human lives. In this essay, I explore how the moral imagination nurtured by the practices of solidarity and care-and nurturing them in turn-can come of age-and how these practices can take their rightful place in an ethically mature political culture.


Parent-of-origin effects on seed development in Arabidopsis thaliana require DNA methylation.
Some genes in mammals and flowering plants are subject to parental imprinting, a process by which differential epigenetic marks are imposed on male and female gametes so that one set of alleles is silenced on chromosomes contributed by the mother while another is silenced on paternal chromosomes. Therefore, each genome contributes a different set of active alleles to the offspring, which develop abnormally if the parental genome balance is disturbed. In Arabidopsis, seeds inheriting extra maternal genomes show distinctive phenotypes such as low weight and inhibition of mitosis in the endosperm, while extra paternal genomes result in reciprocal phenotypes such as high weight and endosperm overproliferation. DNA methylation is known to be an essential component of the parental imprinting mechanism in mammals, but there is less evidence for this in plants. For the present study, seed development was examined in crosses using a transgenic Arabidopsis line with reduced DNA methylation. Crosses between hypomethylated and wild-type diploid plants produced similar seed phenotypes to crosses between plants with normal methylation but different ploidies. This is consistent with a model in which hypomethylation of one parental genome prevents silencing of alleles that would normally be active only when inherited from the other parent - thus phenocopying the effects of extra genomes. These results suggest an important role for methylation in parent-of-origin effects, and by inference parental imprinting, in plants. The phenotype of biparentally hypomethylated seeds is less extreme than the reciprocal phenotypes of uniparentally hypomethylated seeds. The observation that development is less severely affected if gametes of both sexes (rather than just one) are 'neutralized' with respect to parent-of-origin effects supports the hypothesis that parental imprinting is not necessary to regulate development.


Integrated programs for women with substance use issues and their children: a qualitative meta-synthesis of processes and outcomes.
There is a need for services that effectively and comprehensively address the complex needs of women with substance use issues and their children. A growing body of literature supports the relevance of integrated treatment programs that offer a wide range of services in centralized settings. Quantitative studies suggest that these programs are associated with positive outcomes. A qualitative meta-synthesis was conducted to provide insight into the processes that contribute to recovery in integrated programs and women's perceptions of benefits for themselves and their children. A comprehensive search of published and unpublished literature to August 2009 was carried out for narrative reports of women's experiences and perceptions of integrated treatment programs. Eligibility for inclusion in the meta-synthesis was determined using defined criteria. Quality assessment was then conducted. Qualitative data and interpretations were extracted from studies of adequate quality, and were synthesized using a systematic and iterative process to create themes and overarching concepts. A total of 15 documents were included in the meta-synthesis. Women experienced a number of psychosocial processes during treatment that played a role in their recovery and contributed to favourable outcomes. These included: development of a sense of self; development of personal agency; giving and receiving of social support; engagement with program staff; self-disclosure of challenges, feelings, and past experiences; recognizing patterns of destructive behaviour; and goal setting. A final process, the motivating presence of children, sustained women in their recovery journeys. Perceived outcomes included benefits for maternal and child well-being, and enhanced parenting capacity. A number of distinct but interconnected processes emerged as being important to women's addiction recovery. Women experienced individual growth and transformative learning that led to a higher quality of life and improved interactions with their children. The findings support the need for programs to adopt practices that focus on improving maternal health and social functioning in an environment characterized by empowerment, safety, and connections. Women's relationships with their children require particular attention as positive parenting practices and family relationships can alter predispositions toward substance use later in life, thereby impacting favourably on the cycle of addiction and dysfunctional parenting.


Convergent evolution of heat-inducibility during subfunctionalization of the Hsp70 gene family.
Heat-shock proteins of the 70 kDa family (Hsp70s) are essential chaperones required for key cellular functions. In eukaryotes, four subfamilies can be distinguished according to their function and localisation in different cellular compartments: cytosol, endoplasmic reticulum, mitochondria and chloroplasts. Generally, multiple cytosol-type Hsp70s can be found in metazoans that show either constitutive expression and/or stress-inducibility, arguing for the evolution of different tasks and functions. Information about the hsp70 copy number and diversity in microbial eukaryotes is, however, scarce, and detailed knowledge about the differential gene expression in most protists is lacking. Therefore, we have characterised the Hsp70 gene family of Paramecium caudatum to gain insight into the evolution and differential heat stress response of the distinct family members in protists and to investigate the diversification of eukaryotic hsp70s focusing on the evolution of heat-inducibility. Eleven putative hsp70 genes could be detected in P. caudatum comprising homologs of three major Hsp70-subfamilies. Phylogenetic analyses revealed five evolutionarily distinct Hsp70-groups, each with a closer relationship to orthologous sequences of Paramecium tetraurelia than to another P. caudatum Hsp70-group. These highly diverse, paralogous groups resulted from duplications preceding Paramecium speciation, underwent divergent evolution and were subject to purifying selection. Heat-shock treatments were performed to test for differential expression patterns among the five Hsp70-groups as well as for a functional conservation within Paramecium. These treatments induced exceptionally high mRNA up-regulations in one cytosolic group with a low basal expression, indicative for the major heat inducible hsp70s. All other groups showed comparatively high basal expression levels and moderate heat-inducibility, signifying constitutively expressed genes. Comparative EST analyses for P. tetraurelia hsp70s unveiled a corresponding expression pattern, which supports a functionally conserved evolution of the Hsp70 gene family in Paramecium. Our analyses suggest an independent evolution of the heat-inducible cytosol-type hsp70s in Paramecium and in its close relative Tetrahymena, as well as within higher eukaryotes. This result indicates convergent evolution during hsp70 subfunctionalization and implies that heat-inducibility evolved several times during the course of eukaryotic evolution.


Abundant kif21b is associated with accelerated progression in neurodegenerative diseases.
Kinesin family member 21b (kif21b) is one of the few multiple sclerosis (MS) risk genes with a presumed central nervous system function. Kif21b belongs to the kinesin family, proteins involved in intracellular transport of proteins and organelles. We hypothesised that kif21b is involved in the neurodegenerative component of MS and Alzheimer's (AD) disease. Post-mortem kinesin expression was assessed in 50 MS, 58 age and gender matched non-demented controls (NDC) and 50 AD. Kif21b expression was five-fold increased in AD compared to MS and NDC aged below 62 years (p = 8*10(-5)), three-fold between 62-72 years (p = 0.005) and not different above 72 years. No significant differences were observed between MS and NDC. In AD, kif21b expression was two-fold increased in Braak stage 6 (scoring for density of neurofibrillary tangles) compared with stage 5 (p = 0.003). In MS patients, kif21b correlated with the extent of grey matter demyelination (Spearman's rho = 0.31, p = 0.03). Abundant kif21b, defined as expression above the median, was associated with a two-fold accelerated development of the Kurtzke Expanded Disability Status Scale (EDSS) 6.0 (median time in low kif21b group 16 years vs. high kif21b 7.5 years, log-rank test p = 0.04) in MS. Given the genetic association of kif21b with MS, the results were stratified according to rs12122721[A] single nucleotide polymorphism (SNP). No association was found between kif21b expression or the time to EDSS 6 in kif21b risk SNP carriers compared to non-risk carriers. Kif21b was expressed in astrocytes in addition to neurons. Upon astrocyte activation, kif21b increased nine-fold. Abundant kif21b expression is associated with severe MS and AD pathology and with accelerated neurodegeneration independent of the kif21b risk SNP.


TAZ interacts with TTF-1 and regulates expression of surfactant protein-C.
Thyroid transcription factor-1 (TTF-1/Nkx-2.1) is required for formation of the lung and differentiation of peripheral respiratory epithelial cells. TTF-1 activates transcription of target genes, including the surfactant proteins critical for lung function. A recently identified protein TAZ (transcriptional co-activator with PDZ-binding motif) contains a WW domain and a COOH-terminal PDZ-binding motif that are proposed to mediate its interactions with various transcriptional proteins. To determine the role of TAZ in the regulation of gene expression in the lung, the sites of TAZ expression and the role of TAZ in the regulation of respiratory epithelial gene expression were assessed. TAZ mRNA was detected in immortalized mouse lung epithelial cells, primary isolates of mouse alveolar type II epithelial cells, and epithelial cells of fetal lung. Sites of TAZ mRNA and protein overlapped with those of TTF-1 and surfactant protein C (SP-C) in the respiratory epithelial cells of the mouse lung. In the presence of TTF-1, TAZ synergistically activated the expression of mouse SP-C-luciferase reporter constructs. Mammalian two-hybrid assays and pull-down experiments demonstrated that the TAZ directly interacted with TTF-1. Further, deletion analysis demonstrated that TAZ binds to the NH(2)-terminal domain of TTF-1. TAZ binds to TTF-1, increasing the transcriptional activity of TTF-1 on the SP-C promoter. Developmental and cell-selective regulation of TAZ provides a mechanism by which the activity of TTF-1 on target genes is modulated.


Persistent Muscle Inhibition after Anterior Cruciate Ligament Reconstruction: Role of Reflex Excitability.
Persistent voluntary quadriceps activation deficits are common after anterior cruciate ligament reconstruction (ACLR), but the direct causes are unclear. The primary purpose of this study was to determine whether spinal reflex excitability deficits are present in individuals with a history of ACLR, and secondarily to determine whether spinal reflex excitability predicts which individuals possess full voluntary quadriceps activation. One hundred and forty-seven individuals (74 healthy and 73 ACLR) participated in this cross-sectional case-control study. Quadriceps spinal reflex excitability was quantified using the Hoffmann reflex normalized to the maximal muscle response (H:M ratio). Voluntary quadriceps activation was evaluated with the burst superimposition technique and calculated via the central activation ratio (CAR). Separate 2 × 2 ANCOVA tests were used to compare between-limb and between-group differences for H:M ratio and CAR. A receiver operating characteristic curve was used to determine the accuracy of H:M ratio to predict if ACLR participants present with full voluntary activation (CAR ≥ 0.95). The ACLR H:M ratio was not different between limbs or compared with the healthy group (P > 0.05). Although ACLR CAR was lower bilaterally compared with the healthy group (P < 0.001), it did not differ between limbs. The H:M ratio has poor accuracy for predicting which individuals exhibit full voluntary activation (receiver operating characteristic area under the curve = 0.52, 95% CI = 0.37,0.66; odds ratio = 2.2, 95% CI = 0.8, 5.9). Spinal reflex excitability did not differ between limbs in individuals with ACLR or compared with healthy participants. The level of quadriceps spinal reflex excitability has poor accuracy at predicting which ACLR individuals would demonstrate full voluntary quadriceps activation.


Water permeability of C-terminally truncated aquaporin 0 (AQP0 1-243) observed in the aging human lens.
To first assess the distribution of posttranslationally truncated products of aquaporin 0 (AQP0) in dissected sections of a normal human lens and to determine the effect of backbone cleavage on the water permeability of AQP0. A 27-year-old lens was concentrically dissected into six sections. Membrane protein was isolated from each section and cleaved with cyanogen bromide, and the peptides were separated and analyzed by reverse-phase (RP)-HPLC-mass spectrometry (MS). The sites of posttranslational AQP0 C-terminal truncation were determined by mass spectrometry. Truncated forms of AQP0 were expressed in a Xenopus laevis oocyte system, and the effect of truncation on AQP0 water permeability was assessed in an oocyte osmotic swelling assay. The extent of truncation at many sites within the C terminus increased with fiber cell age, and the effects of truncations after residues 234, 238, and 243 on AQP0 water permeability were examined. Truncation after residue 243 resulted in an approximate 15% decrease in permeability compared with the full-length protein, AQP0 1-263. However, rather than a direct effect on water transport, analysis of surface protein expression indicated that the decrease in permeability was a result of less efficient protein trafficking to the oocyte surface and that the permeabilities of full-length and 1-243 AQP0 were indistinguishable. Further, C-terminal truncation of AQP0 to 1-234 and 1-238, completely impaired trafficking into the plasma membrane, precluding the measurement of permeability. These data provide evidence that loss of 20 amino acids from the C terminus may not directly affect the ability of AQP0 to transport water.


Head-up tilt in the nonhuman primate. Effects of renal denervation.
Experiments were performed to determine the role of the renal nerves in mediating the antinatriuresis of head-up tilt in the nonhuman primate. Male Macaca fascicularis monkeys underwent chronic bilateral renal denervation or sham surgery and were allowed a 1- to 2-week recovery period. After that time, each animal was anesthetized with sodium pentobarbital and subjected to 40 min of 35 degrees head-up tilt. Renal perfusion pressure was maintained constant throughout the experiment. Tilt caused significant decreases in urine flow, sodium excretion and osmolar clearance and increases in urine osmolality in both groups. Creatinine and para-aminohippurate clearances decreased in the sham-operated animals but were unchanged in the denervated animals. Although the pattern of the renal excretory responses showed some group differences in that a significant antidiuresis and antinatriuresis occurred after 10 min of tilt in the sham-operated group but not until 20 min in the denervated group, the magnitudes of these excretory responses were similar in both groups throughout the entire tilt procedure. These results suggest that, in this species, the renal nerves are not necessary for eliciting the overall antinatriuretic response to orthostasis but may have some minor involvement in the onset of the response.


Long-Term Follow-Up of Tamoxifen Treatment and the Use of Imaging in Psammocarcinoma: A Case Report, Review of the Literature and Discussion of Diagnostic and Therapeutic Challenges.
Psammocarcinoma (PsC) represents a rare form of low-grade serous tumor of the ovary or peritoneum. Although ovarian cancer generally has a poor prognosis in its late stages, PsC seems to have a more indolent course. We present a patient with a history of unspecific abdominal pain for more than a year, with sudden acute onset of severe inguinal pain. On admission to the hospital, a computed tomography (CT) revealed a pelvic mass of suspected ovarian origin. Radical surgery was attempted but not achieved due to widespread tumor growth. Histopathological evaluation revealed estrogen receptor-positive stage III PsC. Tamoxifen treatment was thus initiated, still maintaining stable disease 10 years later. The patient has undergone extensive radiological work-up, including CT, chest X-ray, 18F-fluoro-deoxy-glucose positron emission tomography (PET)/CT, 99mTc- hydroxymethylene diphosphonate (HDP) bone scintigraphy, 18F-fluoro-thymidine (FLT) PET/CT, Tc-99m depreotide scintigraphy and magnetic resonance imaging. In conclusion, we demonstrate that PsC has characteristic radiological features and different imaging modalities can be suitable in different clinical situations. In contrast to most other ovarian cancers, PsC does not always warrant adjuvant chemotherapy, even in advanced stages. This emphasizes the need for a deeper knowledge of the biological behavior of this rare tumor, to select the optimal treatment strategy.


Mitochondrial fusion is essential for organelle function and cardiac homeostasis.
Mitochondria constitute 30% of myocardial mass. Mitochondrial fusion and fission appear essential for health of most tissues. Mitochondrial fission occurs in neonatal cardiomycyte and is implicated in cardiomyocyte death. Mitochondrial fusion has not been observed in postmitotic myocytes of adult hearts, and its occurrence and function in this context are controversial. Determine the consequences on organelle and organ function of disrupting cardiomyocyte mitochondrial fusion in vivo. The murine mfn1 and mfn2 genes, encoding mitofusins (Mfn) 1 and 2 that mediate mitochondrial tethering and outer mitochondrial membrane fusion, were interrupted by Cre-mediated excision of essential exons in neonatal (Nkx2.5-Cre) and adult (MYH6 modified estrogen receptor-Cre-modified estrogen receptor plus tamoxifen or Raloxifene) hearts. Embryonic combined Mfn1/Mfn2 ablation was lethal after e9.5. Conditional combined Mfn1/Mfn2 ablation in adult hearts induced mitochondrial fragmentation, cardiomyocyte and mitochondrial respiratory dysfunction, and rapidly progressive and lethal dilated cardiomyopathy. Before heart failure developed, cardiomyocyte shortening and calcium cycling were unaffected by absence of Mfn1 and Mfn2. Based on the time course over which fusion-defective mitochondrial size decreases, a mitochondrial fusion/fission cycle in adult mouse hearts occurs approximately every 16 days. Mitochondrial fusion in adult cardiac myocytes is necessary to maintain normal mitochondrial morphology and is essential for normal cardiac respiratory and contractile function. Interruption of mitochondrial fusion causes lethal cardiac failure at a time corresponding to 3 or 4 cycles of unopposed mitochondrial fission.


Localization of Rac2 via the C terminus and aspartic acid 150 specifies superoxide generation, actin polarity and chemotaxis in neutrophils.
Despite having a high degree of sequence similarity, the Rho guanosine triphosphatases Rac1 and Rac2 regulate distinct functions in neutrophils. Here we demonstrate that the unique Rac2 localization and functions in neutrophils are regulated by two separate C-terminal motifs, the hypervariable domain and aspartic acid 150, one of which has not previously been linked to the function of Rho GTPases. In addition, we show an unexpected dependence of Rac1 localization on Rac2 activity in these same cells, demonstrating a degree of crosstalk between two closely related Rho GTPases. Thus, we have defined specific sequences in Rac that specify subcellular localization and determine the specificity of Rac2 in neutrophil chemotaxis and superoxide generation.


Fear of recurrence and possible cases of anxiety and depression in orofacial cancer patients.
Recurrence risk in orofacial cancer patients is relatively high in comparison to other cancers. Little information exists on whether patients are unduly concerned over the possibility of recurrence and the association of this concern with psychological morbidity. Aim of study was to assess fear of recurrence and psychological morbidity in orofacial cancer patients. Two samples of patients with orofacial cancer were followed prospectively. First sample (n = 87) were consecutively drawn 3 months and 7 months following initial treatment. Second sample (n = 100) were cross-sectionally drawn from out-patient list and followed 2 years later. A single question item was employed to assess fear of recurrence used in previous work. Hospital Anxiety and Depression Scale was adopted as the measure of psychological morbidity. A prospective survey design was employed. Over 80% of patients expressed concern over the possibility of recurrence at 3 months post treatment. This level reduced to 72% at 7 months (P=0.06). Approximately two-thirds of patients sampled cross-sectionally were concerned at both assessment occasions. Psychological morbidity was greatest at 3 months post treatment (possible cases: anxiety 37% and depression 28%). Women were more likely to report anxiety (at possible case level) than men 3 months following treatment (P<0.05). Patients aged 65 or more years were less concerned about recurrence. This effect was significant on both occasions that sample two patients were assessed (P's<0.002). Very few patients who expressed no concern about recurrence, at 3 months, were found to report anxiety or depression sufficient to be recognized as a possible case (3 and 0% respectively). The positive association between psychological morbidity and fears of recurrence was significant at the majority of data collection points, with the exception that depression was more independent of these concerns.


In Silico HCT116 Human Colon Cancer Cell-Based Models En Route to the Discovery of Lead-Like Anticancer Drugs.
To discover new inhibitors against the human colon carcinoma HCT116 cell line, two quantitative structure⁻activity relationship (QSAR) studies using molecular and nuclear magnetic resonance (NMR) descriptors were developed through exploration of machine learning techniques and using the value of half maximal inhibitory concentration (IC50). In the first approach, A, regression models were developed using a total of 7339 molecules that were extracted from the ChEMBL and ZINC databases and recent literature. The performance of the regression models was successfully evaluated by internal and external validations, the best model achieved R² of 0.75 and 0.73 and root mean square error (RMSE) of 0.66 and 0.69 for the training and test sets, respectively. With the inherent time-consuming efforts of working with natural products (NPs), we conceived a new NP drug hit discovery strategy that consists in frontloading samples with 1D NMR descriptors to predict compounds with anticancer activity prior to bioactivity screening for NPs discovery, approach B. The NMR QSAR classification models were built using 1D NMR data (¹H and 13C) as descriptors, from 50 crude extracts, 55 fractions and five pure compounds obtained from actinobacteria isolated from marine sediments collected off the Madeira Archipelago. The overall predictability accuracies of the best model exceeded 63% for both training and test sets.


A cross-sectional study of the prevalence and associated risk factors for bursitis in weaner, grower and finisher pigs from 93 commercial farms in England.
A cross-sectional study of 93 farms in England was carried out to estimate the prevalence and associated risk factors for bursitis. A total of 6250 pigs aged 6-22 weeks were examined for presence and severity of bursitis. Details of pen construction, pen quality and farm management were recorded including floor type, presence of bedding, condition of the floor and floor materials. The prevalence of bursitis was 41.2% and increased with each week of age (OR 1.1). Two-level logistic regression models were developed with the outcome as the proportion of pigs affected with bursitis in a pen. Pigs kept on soil floors with straw bedding were used as the reference level. In comparison with these soil floors, bursitis increased on concrete floors where the bedding was deep throughout (OR 4.6), deep in part (OR 3.7), and sparse throughout (OR 9.0), part slatted floors (OR 8.0), and fully slatted floors (OR 18.8). Slip or skid marks in the dunging area (OR 1.5), pigs observed slipping during the examination of the pen (OR 1.3) and wet floors (OR 3.6) were also associated with an increased risk of bursitis. The results indicate that bursitis is a common condition of growing pigs and that the associated risk factors for bursitis were a lack of bedding in the lying area, presence of voids and pen conditions which increased the likelihood of injury.


Size specific emission in peptide capped gold quantum clusters with tunable photoswitching behavior.
Three different types of fluorescent gold clusters (namely blue, green and red emitting) have been prepared from a gold precursor (chloroauric acid) under moderate conditions in aqueous medium. A cysteine containing dipeptide has been used for the formation of these quantum clusters as this peptide molecule contains a thiol group in the side chain to cap these nascently formed clusters and the free amino and carboxylic moieties assist in water solubility. Thus, the clusters are also environmentally friendly as the capped peptide is made up of only naturally occurring protein amino acids. These clusters have been well characterized by using UV-visible, fluorescence, X-ray photoelectron spectroscopy (XPS)spectroscopy, matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS) and ultrahigh resolution field emission gun-transmission electron microscopy (UHR-FEG-TEM). Arrangements of gold atoms and their interaction with the corresponding ligands in three different fluorescent clusters have been predicted computationally. The excited state behavior of three different clusters has also been studied using time dependent density functional theory (TD-DFT). Time correlated single photon counting (TCSPC) and computational studies suggest intersystem crossing (S1 → T1) in the case of red-emitting Au23 clusters. Interestingly, these gold clusters exhibit semiconducting and photoswitching properties (Ion/Ioff), which are shown to be controlled by varying the size of these clusters. This holds future promise of using these gold cluster based nanomaterials for optoelectronic applications.


The guardian's little helper: microRNAs in the p53 tumor suppressor network.
Several microRNAs (miRNAs) have been implicated in tumor development based on both changes in their expression patterns and gene structural alterations in human tumors. However, we are only now beginning to see how miRNAs interact with classic oncogene and tumor suppressor mechanisms. Several recent studies have implicated the miR-34 family of miRNAs in the p53 tumor suppressor network. The expression of miR-34a, miR-34b, and miR-34c is robustly induced by DNA damage and oncogenic stress in a p53-dependent manner. When overexpressed, miR-34 leads to apoptosis or cellular senescence, whereas reduction of miR-34 function attenuates p53-mediated cell death. These findings, together with the fact that miR-34 is down-regulated in several types of human cancer, show that miRNAs can affect tumorigenesis by working within the confines of well-known tumor suppressor pathways.


Silent circulation of St. Louis encephalitis virus prior to an encephalitis outbreak in Cordoba, Argentina (2005).
St. Louis encephalitis virus is a complex zoonoses. In 2005, 47 laboratory-confirmed and probable clinical cases of SLEV infection were reported in Córdoba, Argentina. Although the causes of 2005 outbreak remain unknown, they might be related not only to virological factors, but also to ecological and environmental conditions. We hypothesized that one of the factors for SLE reemergence in Córdoba, Argentina, was the introduction of a new SLEV genotype (SLEV genotype III), with no previous activity in the area. In order to evaluate this hypothesis we carried out a molecular characterization of SLEV detections from mosquitoes collected between 2001 and 2004 in Córdoba city. A total of 315 mosquito pools (11,002 individuals) including 12 mosquitoes species were analyzed. Overall, 20 pools (8 mosquitoes species) were positive for SLEV. During this study, genotypes II, V and VII were detected. No mosquito pool infected with genotype III was detected before the 2005 outbreak. Genotype V was found every year and in the 8 sampled sites. Genotypes II and VII showed limited temporal and spatial activities. We cannot dismiss the association of genotype II and V as etiological agents during the outbreak. However, the silent circulation of other SLEV strains in Córdoba city before the 2005 outbreak suggests that the introduction of genotype III was an important factor associated to this event. Not mutually exclusive, other factors such as changes in avian hosts and mosquitoes vectors communities, driven by climatic and environmental modifications, should also be taken into consideration in further studies.


Cost-effectiveness of tubal patency tests.
Guidelines are not in agreement on the most effective diagnostic scenario for tubal patency testing; therefore, we evaluated the cost-effectiveness of invasive tubal testing in subfertile couples compared with no testing and treatment. Cost-effectiveness analysis. Decision analytic framework. Computer-simulated cohort of subfertile women. We evaluated six scenarios: (1) no tests and no treatment; (2) immediate treatment without tubal testing; (3) delayed treatment without tubal testing; (4) hysterosalpingogram (HSG), followed by immediate or delayed treatment, according to diagnosis (tailored treatment); (5) HSG and a diagnostic laparoscopy (DL) in case HSG does not prove tubal patency, followed by tailored treatment; and (6) DL followed by tailored treatment. Expected cumulative live births after 3 years. Secondary outcomes were cost per couple and the incremental cost-effectiveness ratio. For a 30-year-old woman with otherwise unexplained subfertility for 12 months, 3-year cumulative live birth rates were 51.8, 78.1, 78.4, 78.4, 78.6 and 78.4%, and costs per couple were €0, €6968, €5063, €5410, €5405 and €6163 for scenarios 1, 2, 3, 4, 5 and 6, respectively. The incremental cost-effectiveness ratios compared with scenario 1 (reference strategy), were €26,541, €19,046, €20,372, €20,150 and €23,184 for scenarios 2, 3, 4, 5 and 6, respectively. Sensitivity analysis showed the model to be robust over a wide range of values for the variables. The most cost-effective scenario is to perform no diagnostic tubal tests and to delay in vitro fertilisation (IVF) treatment for at least 12 months for women younger than 38 years old, and to perform no tubal tests and start immediate IVF treatment from the age of 39 years. If an invasive diagnostic test is planned, HSG followed by tailored treatment, or a DL if HSG shows no tubal patency, is more cost-effective than DL.


DIETARY DIVERSITY AND ITS RELATIONSHIP WITH NUTRITIONAL STATUS AMONG ADOLESCENTS AND ADULTS IN RURAL INDIA.
Dietary diversity is associated with household or individual food availability and intake of nutrients from different food groups and is an important component of nutritional outcome. This study examined the Nutrient Adequacy Ratio (NAR) and the Mean Adequacy Ratio (MAR) of three dietary diversity indices and their relationship with the nutritional status of adolescents and adults in rural regions of two states in India, Wardha district in Maharashtra and Koraput district in Odisha, in 2014. Individual dietary diversity was calculated using 24-hour diet recall (FS24hr) data and household dietary diversity was measured with food frequency data using Berry's index (DDI) and food scores (FSFFQ). The nutritional status of individuals was assessed using anthropometric indices. The diets in both locations were cereal dominated. It was observed that 51% of adolescent boys and 27% of adolescent girls had 'thinness' and stunting. The prevalence of undernutrition was higher among adult women (48%) than adult men (36%). The mean diversity indices were FS24hr of 8, DDI of 89-90 and FSFFQ of 64-66 in the two locations. The FS24hr was found to be positively correlated with the NAR of all nutrients while DDI and FSFFQ were correlated with seven and six nutrients, respectively. The DDI and FS24hr showed an association with MAR if the two locations were combined together. Sensitivity and specificity analysis showed that FS24hr gave more true positives than false positives and the area under the Receiver Operating Characteristic curve was 0.68, implying that this measure truly differentiates individuals having low dietary diversity with low MAR from those with low dietary diversity and a high MAR. All three measures of dietary diversity showed a linear association with the nutritional outcomes of adults, while in the adolescent group only DDI showed a relationship. It is concluded that 24-hour diet recall is a good measure for studying the relationship between dietary diversity and nutritional status in adults.


Interleukin-3 supports expansion of long-term multilineage repopulating activity after multiple stem cell divisions in vitro.
Although long-term repopulating hematopoietic stem cells (HSC) can self-renew and expand extensively in vivo, most efforts at expanding HSC in vitro have proved unsuccessful and have frequently resulted in compromised rather than improved HSC grafts. This has triggered the search for the optimal combination of cytokines for HSC expansion. Through such studies, c-kit ligand (KL), flt3 ligand (FL), thrombopoietin, and IL-11 have emerged as likely positive regulators of HSC self-renewal. In contrast, numerous studies have implicated a unique and potent negative regulatory role of IL-3, suggesting perhaps distinct regulation of HSC fate by different cytokines. However, the interpretations of these findings are complicated by the fact that different cytokines might target distinct subpopulations within the HSC compartment and by the lack of evidence for HSC undergoing self-renewal. Here, in the presence of KL+FL+megakaryocyte growth and development factor (MGDF), which recruits virtually all Lin(-)Sca-1(+)kit(+) bone marrow cells into proliferation and promotes their self-renewal under serum-free conditions, IL-3 and IL-11 revealed an indistinguishable ability to further enhance proliferation. Surprisingly, and similar to IL-11, IL-3 supported KL+FL+MGDF-induced expansion of multilineage, long-term reconstituting activity in primary and secondary recipients. Furthermore, high-resolution cell division tracking demonstrated that all HSC underwent a minimum of 5 cell divisions, suggesting that long-term repopulating HSC are not compromised by IL-3 stimulation after multiple cell divisions. In striking contrast, the ex vivo expansion of murine HSC in fetal calf serum-containing medium resulted in extensive loss of reconstituting activity, an effect further facilitated by the presence of IL-3. (Blood. 2000;96:1748-1755)


Incidence of cerebral concussions associated with type of mouthguard used in college football.
Controversy exists among sports dentists as to whether or not a 'custom made' mouthguard is more effective in reducing the incidence of cerebral concussion than the boil-and-bite 'non-custom made' mouthguard. While members on each side remain steadfast in their opinion, not a single epidemiological study has been conducted to investigate the effect of type of mouthguard worn on the incidence of cerebral concussion. The aim of this study was to determine if there was a difference between the type of mouthguard worn and the incidence of cerebral concussions among National Collegiate Athletic Association (NCAA) Division I-A football players. During the 15-week 2001 college football season, trainers entered, via an interactive web site, weekly data for each game and practice sessions for the preceding week. Eighty-seven (76%) out of a possible 114 Division I teams participated. A total of 506 297 athletic exposures were recorded; 369 brain concussions were reported. The incidence of cerebral concussions per 1000 exposures was 0.73. Utilizing a risk ratio with a 95% confidence interval, no statistical difference occurred in the incidence of cerebral concussions between football players wearing custom made versus non-custom made mouthguards (0.990,1.750). In this study, there was no advantage of wearing a custom made mouthguard over a boil-and-bite mouthguard to reduce the risk of cerebral concussion in football players.


Predictive Value of Preoperative Periocular Skin Cancer Measurements for Final Mohs Defect Size.
To evaluate the relationship between pre-Mohs skin cancer lesion measurements with the post-Mohs defect size in order to most accurately estimate post-Mohs defect size. This is a retrospective analysis of patients who underwent Mohs excision by one of 3 Mohs surgeons followed by reconstruction for basal cell carcinoma or squamous cell carcinoma of the eyelid. The study included all patients from January 2011 to May 2018 operated on by a single oculoplastic surgeon (R.M.) at the University of Texas Southwestern Medical Center. Maximum horizontal and vertical (H/V) dimensions were determined clinically by Mohs surgeons at the time of excision and photographs of the lesion and defect size were analyzed in order to determine the total area of the lesion preoperatively and the defect postoperatively with Image J using H/V dimensions and the area tracing function. Forty-two patients with periocular skin cancers underwent Mohs resection followed by reconstruction. The Mohs defect was overall 4.88 times the size of the preoperative skin cancer measurement using maximum H/V dimensions by Mohs surgeons (p < 0.0001). When using Image J, the area of the Mohs defect was 6.5 times the size of the preoperative lesion (p < 0.0001) using both the maximum H/V dimensions and the area tracing function. There was a statistically significant difference between the Image J area tracing and area determined with H/V dimensions by both the Mohs surgeon and Image J. Postoperative Mohs defect size can be estimated based on maximum H/V dimensions clinically or with Image J technology. Image J digital photograph analysis using the area tracing function more accurately determines the pre-Mohs lesion size and the post-Mohs defect area when compared with standard maximum H/V measurements and digital photographic analysis of maximum H/V measurements with Image J.The preoperative periocular skin cancer measurements can assist in determining the post-Mohs defect size.


Prevention of chronic kidney disease and subsequent effect on mortality: a systematic review and meta-analysis.
To perform a systematic review of randomized controlled trials to determine whether prevention or slowing of progression of chronic kidney disease would translate into improved mortality, and if so, the attributable risk due to CKD itself on mortality. CKD is associated with increased mortality. This association is largely based on evidence from the observational studies and evidence from randomized controlled trials is lacking. We searched Ovid, Medline and Embase for RCTs in which an intervention was given to prevent or slow the progression of CKD and mortality was reported as primary, secondary or adverse outcomes were eligible and selected. For the first phase, pooled relative risks for renal endpoints were assessed. For the second phase, we assessed the effect on mortality in trials of interventions that definitively reduced CKD endpoints. Among 52 studies selected in first phase, only renin-angiotensin-aldosterone-system blockade vs. placebo (n = 18 trials, 32,557 participants) met the efficacy criteria for further analysis in the second phase by reducing renal endpoints 15 to 27% compared to placebo. There was no difference in all-cause mortality (RR 0.99, 95% CI 0.92 to 1.08) or CV death (RR 0.97, 95% CI 0.78 to 1.21) between the treatment and control groups in these trials. There was sufficient statistical power to detect a 9% relative risk reduction in all-cause mortality and a 14% relative risk reduction in cardiovascular mortality. Firm evidence is lacking that prevention of CKD translates into reductions in mortality. Larger trials with longer follow-up time are needed to determine the benefit of CKD prevention on survival.


Stretch-mediated release of angiotensin II induces myocyte apoptosis by activating p53 that enhances the local renin-angiotensin system and decreases the Bcl-2-to-Bax protein ratio in the cell.
Physical forces activate apoptosis and gene expression, but the mechanism is unknown. For this purpose, adult myocytes were stretched in an equibiaxial stretch apparatus and the magnitude of cell death was examined 4 and 24 h later. The possibility of stretch-mediated activation of p53 and p53-dependent genes was evaluated at 30 min, 2, 4, 8, and 24 h. Myocyte apoptosis increased by 4.4- and 7.6-fold at 4 and 24 h after stretch. p53 binding to the promoter of angiotensinogen, AT1 receptor, and Bax also increased. Expression of angiotensinogen, AT1 receptor, p53, and Bax increased and Bcl-2 decreased in stretched myocytes. The changes in AT1 receptor, p53, Bax, and Bcl-2 became more apparent with the duration of stretch. Angiotensin II concentration in the medium increased at 10 min, reaching maximal levels at 1 and 20 h. The AT1 blocker, losartan, abolished apoptosis in stretched myocytes. Myocyte volume was not influenced by stretch. In conclusion, stretch-mediated release of angiotensin II is coupled with apoptosis and the activation of p53 which may be responsible for the prolonged upregulation of the local renin-angiotensin system and the increased susceptibility of myocytes to undergo apoptosis.


Randomized Trial of a Hypofractionated Radiation Regimen for the Treatment of Localized Prostate Cancer.
Purpose Men with localized prostate cancer often are treated with external radiotherapy (RT) over 8 to 9 weeks. Hypofractionated RT is given over a shorter time with larger doses per treatment than standard RT. We hypothesized that hypofractionation versus conventional fractionation is similar in efficacy without increased toxicity. Patients and Methods We conducted a multicenter randomized noninferiority trial in intermediate-risk prostate cancer (T1 to 2a, Gleason score ≤ 6, and prostate-specific antigen [PSA] 10.1 to 20 ng/mL; T2b to 2c, Gleason ≤ 6, and PSA ≤ 20 ng/mL; or T1 to 2, Gleason = 7, and PSA ≤ 20 ng/mL). Patients were allocated to conventional RT of 78 Gy in 39 fractions over 8 weeks or to hypofractionated RT of 60 Gy in 20 fractions over 4 weeks. Androgen deprivation was not permitted with therapy. The primary outcome was biochemical-clinical failure (BCF) defined by any of the following: PSA failure (nadir + 2), hormonal intervention, clinical local or distant failure, or death as a result of prostate cancer. The noninferiority margin was 7.5% (hazard ratio, < 1.32). Results Median follow-up was 6.0 years. One hundred nine of 608 patients in the hypofractionated arm versus 117 of 598 in the standard arm experienced BCF. Most of the events were PSA failures. The 5-year BCF disease-free survival was 85% in both arms (hazard ratio [short v standard], 0.96; 90% CI, 0.77 to 1.2). Ten deaths as a result of prostate cancer occurred in the short arm and 12 in the standard arm. No significant differences were detected between arms for grade ≥ 3 late genitourinary and GI toxicity. Conclusion The hypofractionated RT regimen used in this trial was not inferior to conventional RT and was not associated with increased late toxicity. Hypofractionated RT is more convenient for patients and should be considered for intermediate-risk prostate cancer.


Distribution of knock-down resistance mutations in Anopheles gambiae molecular forms in west and west-central Africa.
Knock-down resistance (kdr) to DDT and pyrethroids in the major Afrotropical vector species, Anopheles gambiae sensu stricto, is associated with two alternative point mutations at amino acid position 1014 of the voltage-gated sodium channel gene, resulting in either a leucine-phenylalanine (L1014F), or a leucine-serine (L1014S) substitution. In An. gambiae S-form populations, the former mutation appears to be widespread in west Africa and has been recently reported from Uganda, while the latter, originally recorded in Kenya, has been recently found in Gabon, Cameroon and Equatorial Guinea. In M-form populations surveyed to date, only the L1014F mutation has been found, although less widespread and at lower frequencies than in sympatric S-form populations. Anopheles gambiae M- and S-form specimens from 19 sites from 11 west and west-central African countries were identified to molecular form and genotyped at the kdr locus either by Hot Oligonucleotide Ligation Assay (HOLA) or allele-specific PCR (AS-PCR). The kdr genotype was determined for about 1,000 An. gambiae specimens. The L1014F allele was found at frequencies ranging from 6% to 100% in all S-form samples (N = 628), with the exception of two samples from Angola, where it was absent, and coexisted with the L1014S allele in samples from Cameroon, Gabon and north-western Angola. The L1014F allele was present in M-form samples (N = 354) from Benin, Nigeria, and Cameroon, where both M- and S-forms were sympatric. The results represent the most comprehensive effort to analyse the overall distribution of the L1014F and L1014S mutations in An. gambiae molecular forms, and will serve as baseline data for resistance monitoring. The overall picture shows that the emergence and spread of kdr alleles in An. gambiae is a dynamic process and that there is marked intra- and inter-form heterogeneity in resistance allele frequencies. Further studies are needed to determine: i) the importance of selection pressure exerted by both agricultural and public health use of pyrethroid insecticides, ii) the phenotypic effects, particularly when the two mutations co-occur; and iii) the epidemiological importance of kdr for both pyrethroid- and DDT-based malaria control operations, particularly if/when the two insecticides are to be used in concert.


Migration as a determinant of childhood obesity in the United States and Latin America.
International migration has economic and health implications. The acculturation process to the host country may be linked to childhood obesity. We use the Community Energy Balance (CEB) framework to analyze the relationship between migration and childhood obesity in Mexican households with international migrants. Using longitudinal data from the Mexican Family Life Survey (MxFLS), we examine how migrant networks affect childhood obesity in origin communities. We also review binational health programs that could be effective at tackling childhood obesity in migrant households from Mexico. Children embedded in migrant networks are at greater risk of developing overweight or obesity, suggesting a significant relationship between childhood obesity and international migration in Mexican households. Based on our search criteria, our analysis of health outreach programs shows that Ventanillas de Salud (VDS)/Health Windows has great promise to prevent childhood obesity in a culturally sensitive and trustful environment. The CEB framework is useful to understand how migration contributes to the risk of childhood overweight and obesity in migrant households. VDS is a feasible and replicable strategy with great potential to address childhood obesity among migrant families accounting for the dynamic and binational determinants of childhood obesity.


Real-time discriminative background subtraction.
The authors examine the problem of segmenting foreground objects in live video when background scene textures change over time. In particular, we formulate background subtraction as minimizing a penalized instantaneous risk functional--yielding a local online discriminative algorithm that can quickly adapt to temporal changes. We analyze the algorithm's convergence, discuss its robustness to nonstationarity, and provide an efficient nonlinear extension via sparse kernels. To accommodate interactions among neighboring pixels, a global algorithm is then derived that explicitly distinguishes objects versus background using maximum a posteriori inference in a Markov random field (implemented via graph-cuts). By exploiting the parallel nature of the proposed algorithms, we develop an implementation that can run efficiently on the highly parallel graphics processing unit (GPU). Empirical studies on a wide variety of datasets demonstrate that the proposed approach achieves quality that is comparable to state-of-the-art offline methods, while still being suitable for real-time video analysis ( ≥ 75 fps on a mid-range GPU).


Pelvic Floor Disorders After Obstetric Avulsion of the Levator Ani Muscle.
With vaginal childbirth, 10% to 30% of women sustain levator ani muscle avulsion. The objective of this study was to estimate the cumulative incidence of prolapse and other pelvic floor disorders (PFDs), comparing vaginally parous women with and without levator avulsion. Parous women enrolled in a longitudinal study were assessed annually for PFDs with the Pelvic Organ Prolapse Quantification Examination (for prolapse) and the Epidemiology of Prolapse and Incontinence Questionnaire (for stress incontinence, overactive bladder, and anal incontinence). Three-dimensional transperineal ultrasound was used to identify levator avulsion. Women with and without levator avulsion after vaginal delivery were compared for the cumulative incidence of PFDs. Further analysis also stratified by forceps delivery. At the time of assessment, 453 participants were 6 to 17 years from first delivery (median, 11 years). Levator avulsion was identified in 15% (66/453) and was more common among those who had undergone forceps-assisted delivery (P < 0.001). Levator avulsion was strongly associated with prolapse beyond the hymen (odds ratio, 2.7; 95% confidence interval, 1.3-5.7) and with symptoms of prolapse (odds ratio, 3.0; 95% confidence interval-1.2, 7.3). These associations persisted after controlling for forceps-assisted delivery. In contrast, the odds of stress incontinence, overactive bladder, and anal incontinence were marginally (but not significantly) increased among women with levator avulsion in this cohort. Obstetric levator avulsion is strongly associated with pelvic organ prolapse. The relationship between levator avulsion and other PFDs may not be significant.


LADDERS: A dynamic paradigm for planning, implementing, and evaluating sustainable change in learning health systems.
The science of learning health systems borrows and adapts models from many fields. One in particular is implementation science which has been experiencing a flourishing of new theories, models, and frameworks, some of which are generating sufficient evidence as to their effectiveness and applicability to emerge as candidates for wide adoption as useful tools for the field. In reviewing these, a common paradigm can be described which is a synthesis of those elements regularly cited by health systems implementing successful transformational change activities. As a paradigm, it offers a practical bridge to these models, concepts, and frameworks that are often hard to operationalize and are used with varying degrees of completeness. These elements can be arranged in a memorable acronym-LADDERS-Leadership, Alignment, Data, Demonstration, Evaluation, Replication, and Sustainability. LADDERS identifies the multiple elements and dimensions recognized by persons involved in leading health system change activities. It provides a simple, useful way to assess progress by health systems in planning, implementing, evaluating, and sustaining change. There is ample organizational and systems change literature to fully describe the actual LADDERS elements individually; therefore, this article describes characteristics and functions of each element and the dynamics represented in a DNA image to reflect that in learning health systems change is recursive, constant, and happens in complex environments that are always readjusting to new stimuli and directions, and this is often not accounted for in a framework, model, or theory. It concludes with several examples of application of the LADDERS paradigm and suggests how it is a complementary approach to accomplishing Institute of Medicine Learning Health Systems goals.


Single Component Lanthanide Hybrids Based on Metal-Organic Framework for Near-Ultraviolet White Light LED.
Near-UV single-phase white-light phosphor (Eu0.045Tb0.955CPOMBA/La0.6Eu0.1Tb0.3CPOMBA) based on metal-organic framework was prepared by in situ doping isostructural lanthanide MOF with Eu(3+) and Tb(3+), and it is found that the energy can effectively transfer from organic ligand to lanthanides, which can overcome weak absorption under direct excitation of lanthanide ions due to the forbidden f-f transitions. The photoluminescence and thermostability of the new MOF phosphor are investigated, and effective white-light emission is achieved under 365 and 380 nm excitations. By employing Eu0.045Tb0.955CPOMBA as phosphor, we fabricated a near-ultraviolet white-light-emitting diode (n-UV WLED) (365 nm) with low CCT (5733 K), high CRI (Ra = 73.4), and CIE chromaticity coordinate (0.3264, 0.3427). This approach may open new perspectives for developing single-phase UV phosphors.


Taste Acuity of the Morbidly Obese before and after Gastric Bypass Surgery.
Obese individuals have an increased preference for high caloric foods, such as sweets and fats. However, following gastric bypass (GBP) surgery, morbidly obese patients tend to avoid these foods. We hypothesize that this aversion may occur, in part, from permutations in taste acuity. To test this hypothesis, taste detection and recognition thresholds for the four basic tastes (salt, sweet, sour, and bitter) were assessed using a modification of the Henkin forced choice three stimulus technique. Taste acuity measurements were obtained at baseline and at 30, 60, and 90 days post-operative for six morbidly obese GBP women and ten non-surgical, lean female controls. We found nonsignificant differences in taste detection and recognition thresholds between morbidly obese and lean control study subjects at baseline, and no significant correlation between taste acuity and body size. Furthermore, in our study population of lean and obese women, ages 26 to 52, there were no significant interrelationships between baseline taste thresholds and known effectors of taste acuity, i.e., zinc levels, glycemic status, liver and kidney function, or age. Following GBP surgery, a significant up-regulation in taste acuity for bitter and sour was observed along with a trend toward a reduction in salt and sweet detection and recognition thresholds. These findings would suggest the following: (1) taste acuity does not influence taste preferences of the obese individual who has not had bariatric surgery; (2) taste effectors such as zinc, when within the range of normal values, do not alter thresholds of the 4 basic tastes; and (3) weight loss following gastric bypass surgery is associated with an up-regulation in taste acuity in the morbidly obese. Studies are currently under investigation at our center to identify the specific etiology of taste acuity upregulation in the morbidly obese following GBP surgery.


'Restoring the person's life': a qualitative study to inform development of care for people with severe mental disorders in rural Ethiopia.
In low-income countries, care for people with severe mental disorders (SMDs) who manage to access treatment is usually emergency-based, intermittent or narrowly biomedical. The aim of this study was to inform development of a scalable district-level mental health care plan to meet the long-term care needs of people with SMD in rural Ethiopia. The present study was carried out as formative work for the Programme for Improving Mental health CarE which seeks to develop, implement and evaluate a district level model of integrating mental health care into primary care. Six focus group discussions and 25 in-depth interviews were conducted with service planners, primary care providers, traditional and religious healers, mental health service users, caregivers and community representatives. Framework analysis was used, with findings mapped onto the domains of the Innovative Care for Chronic Conditions (ICCC) framework. Three main themes were identified. (1) Focused on 'Restoring the person's life', including the need for interventions to address basic needs for food, shelter and livelihoods, as well as spiritual recovery and reintegration into society. All respondents considered this to be important, but service users gave particular emphasis to this aspect of care. (2) Engaging with families, addressed the essential role of families, their need for practical and emotional support, and the importance of equipping families to provide a therapeutic environment. (3) Delivering collaborative, long-term care, focused on enhancing accessibility to biomedical mental health care, utilising community-based health workers and volunteers as an untapped resource to support adherence and engagement with services, learning from experience of service models for chronic communicable diseases (HIV and tuberculosis) and integrating the role of traditional and religious healers alongside biomedical care. Biomedical approaches were more strongly endorsed by health workers, with traditional healers, religious leaders and service users more inclined to see medication as but one component of care. The salience of poverty to service planning was cross-cutting. Stakeholders prioritised interventions to meet basic needs for survival and endorsed a multi-faceted approach to promoting recovery from SMD, including social recovery. However, sole reliance on this over-stretched community to mobilise the necessary resources may not be feasible. An adapted form of the ICCC framework appeared highly applicable to planning an acceptable, feasible and sustainable model of care.


Deep brain stimulation that abolishes Parkinsonian activity in basal ganglia improves thalamic relay fidelity in a computational circuit.
Deep brain stimulation (DBS) of the subthalamic nucleus reduces the severity of parkinsonian motor symptoms, but the therapeutic mechanisms are not understood. We hypothesize that clinically effective high frequency DBS suppresses disordered neuronal activity in the globus pallidus internus (GPi), a primary output structure of the basal ganglia. In a computational model of the basal ganglia thalamic circuit, periodic high frequency (>100 Hz) stimulation of the subthalamic nucleus reduced the incidence of thalamic cell errors, from the high error rates seen in the parkinsonian case back to the low error rates seen in the normal-healthy case. In contrast, both low frequency (<70 Hz) DBS and high frequency aperiodic DBS failed to alleviate thalamic errors. In high error rate conditions, disordered patterns of GPi activity lead to irregular synaptic inhibition of thalamus. In low error rate conditions, ordered patterns of GPi activity lead to regular synaptic inhibition of thalamus. Linear regression revealed that the variance of the GPi synaptic output accounted for 87-97% of the changes in thalamic error rate. In contrast, the average GPi synaptic output - a measure of total GPi activity--accounted for only 25-50% of the changes in thalamic error rate. Thus, while the firing rate of GPi cells may play some minor role, regularizing the pathological patterns of GPi activity is the mechanism by which DBS treats parkinsonian motor symptoms.


The adding-and-averaging effect in bundles of information: Preference reversals across joint and separate evaluation.
When does adding mildly favorable information (e.g., job experience at the Railway Credit Union) alongside highly favorable (e.g., job experience at Goldman Sachs) increase versus decrease evaluations of a bundle of information like a resume or product bundle? We posit that whether that package of information is evaluated by itself-in separate evaluation (SE)-or side by side with another package-in joint evaluation (JE)-matters. Across a variety of contexts, four studies show that people "average" in SE and "add" in JE. Consequently, mildly favorable information hurts evaluations in SE but helps in JE. Study 1 demonstrated this "adding-and-averaging effect" among persons with expertise: law professors judging law faculty candidates. Adding middle tier academic publications to a higher tier publication on a CV decreased evaluations of a candidate judged in SE but increased evaluations of the same candidate in JE. Study 3 examined a linear pattern prediction, showing that each piece of mildly favorable information linearly added to the overall impression of a package of information in JE but linearly detracted from evaluations of the identical target in SE. Finally, Study 4 traced these differences in evaluative judgments to a shift in reference points brought about by evaluation mode. Implications for the organization specifically and our understanding of judgment and decision making processes more generally are considered. (PsycINFO Database Record


Executive Function and Self-Regulation: Bi-Directional Longitudinal Associations and Prediction of Early Academic Skills.
Despite a tendency to study executive function (EF) and self-regulation (SR) separately, parallel lines of research suggest considerable overlap between the two abilities. Specifically, both show similar developmental trajectories (i.e., develop rapidly in the early years), predict a broad range of overlapping outcomes across the lifespan (e.g., academic success, mental and physical health, and social competence), and have overlapping neural substrates (e.g., prefrontal cortex). While theoretical frameworks diverge in how they reconcile EF and SR - ranging from treating the two as functionally synonymous, to viewing them as related yet distinct abilities - there is no consensus and limited empirical evidence on the nature of their relationship and how this extends developmentally. The current study examined bi-directional longitudinal associations between early EF and SR, and their longitudinal associations with subsequent early academic skills, in a sample of 199 3- to 5-year-old pre-school children. The adopted measures permitted EF and SR to be modelled as composite indices for these analyses, thereby decreasing task-specific components of these associations. Early academic skills were captured by a standardized direct assessment. Bi-directional associations between EF and SR were found, with both accounting for unique variance in early academic skills 7 and 19months later. The current results provide important evidence to distinguish between EF and SR abilities, yet also for their reciprocal influence in situ and across early development.


Mast cell proteases.
Mast cells (MCs) are traditionally thought of as a nuisance for its host, for example, by causing many of the symptoms associated with allergic reactions. In addition, recent research has put focus on MCs for displaying harmful effects during various autoimmune disorders. On the other hand, MCs can also be beneficial for its host, for example, by contributing to the defense against insults such as bacteria, parasites, and snake venom toxins. When the MC is challenged by an external stimulus, it may respond by degranulation. In this process, a number of powerful preformed inflammatory "mediators" are released, including cytokines, histamine, serglycin proteoglycans, and several MC-specific proteases: chymases, tryptases, and carboxypeptidase A. Although the exact effector mechanism(s) by which MCs carry out their either beneficial or harmful effects in vivo are in large parts unknown, it is reasonable to assume that these mediators may contribute in profound ways. Among the various MC mediators, the exact biological function of the MC proteases has for a long time been relatively obscure. However, recent progress involving successful genetic targeting of several MC protease genes has generated powerful tools, which will enable us to unravel the role of the MC proteases both in normal physiology as well as in pathological settings. This chapter summarizes the current knowledge of the biology of the MC proteases.


Attenuation of the neural response to sad faces in major depression by antidepressant treatment: a prospective, event-related functional magnetic resonance imaging study.
Depression is associated with interpersonal difficulties related to abnormalities in affective facial processing. To map brain systems activated by sad facial affect processing in patients with depression and to identify brain functional correlates of antidepressant treatment and symptomatic response. Two groups underwent scanning twice using functional magnetic resonance imaging (fMRI) during an 8-week period. The event-related fMRI paradigm entailed incidental affect recognition of facial stimuli morphed to express discriminable intensities of sadness. Participants were recruited by advertisement from the local population; depressed subjects were treated as outpatients. We matched 19 medication-free, acutely symptomatic patients satisfying DSM-IV criteria for unipolar major depressive disorder by age, sex, and IQ with 19 healthy volunteers. Intervention After the baseline assessment, patients received fluoxetine hydrochloride, 20 mg/d, for 8 weeks. Average activation (capacity) and differential response to variable affective intensity (dynamic range) were estimated in each fMRI time series. We used analysis of variance to identify brain regions that demonstrated a main effect of group (depressed vs healthy subjects) and a group x time interaction (attributable to antidepressant treatment). Change in brain activation associated with reduction of depressive symptoms in the patient group was identified by means of regression analysis. Permutation tests were used for inference. Over time, depressed subjects showed reduced capacity for activation in the left amygdala, ventral striatum, and frontoparietal cortex and a negatively correlated increase of dynamic range in the prefrontal cortex. Symptomatic improvement was associated with reduction of dynamic range in the pregenual cingulate cortex, ventral striatum, and cerebellum. Antidepressant treatment reduces left limbic, subcortical, and neocortical capacity for activation in depressed subjects and increases the dynamic range of the left prefrontal cortex. Changes in anterior cingulate function associated with symptomatic improvement indicate that fMRI may be a useful surrogate marker of antidepressant treatment response.