Pluripotent Stem Cells: Current Understanding and Future Directions.
Pluripotent stem cells have the ability to undergo self-renewal and to give rise to all cells of the tissues of the body. However, this definition has been recently complicated by the existence of distinct cellular states that display these features. Here, we provide a detailed overview of the family of pluripotent cell lines derived from early mouse and human embryos and compare them with induced pluripotent stem cells. Shared and distinct features of these cells are reported as additional hallmark of pluripotency, offering a comprehensive scenario of pluripotent stem cells.


[Changes of EEG coherence in different stages of the formation of the psychoorganic syndrome].
The group of liquidators of Chernobyl Nuclear Power Plant accident (n=170) with nonpsychotic mental disorders of exogenic-organic origin was studied. Patients were stratified into five groups on the basis of dominating symptoms in different stages of disorders: group 1 included patients with the prevalence of asthenic symptoms (n=104); group 2 - with the prevalence of autonomous disorders (n=37); group 3 - with the marked neurotic-like symptom complex (n=10); group 4 - with depressive symptoms (n=10); group 5 - with disturbances of cognitive function. The control group included 150 healthy people. Recording and mapping of coherence (COH) of the brain electrical activity was conducted using the apparatus-software complex for topographic mapping of brain electrical activity NEURO-CM (Russia) with the bandwidth from 0 to 40 Hz and the time constant of 0.3 sec. The EEG record was carried out monopolar from symmetrical cortical zones (10-20% scheme). Changes of COH were characterized by staging in patients compared to the controls. In the initial stage of disease, the integrative links were decreased in the temporal cortical zones of the left hemisphere. The reduction of functional activity in temporal-central cortical zones was found that might be the consequence of mesodiencephalic dysfunction. In the later stages, temporal zones of the right hemisphere were mostly affected. The parallel reinforcement of functional activity of occipital zones, in particular, the increase of 'long links' with frontal areas, was noted in the overall formation of the psychoorganic syndrome. This phenomenon may be considered as a compensatory mechanism when the phylogenetically older cortical zones, which are more resistant to pathological changes, become leaders in the realization of integrative brain activity during the development of a pathological state.


[Efficacy on post-stroke depression treated with acupuncture at the acupoints based on ziwuliuzhu and prozac].
To observe the effects on post-stroke depression treated with acupuncture at the acu points based on ziwuliuzhu (the midnight-noon ebb-flow theory). Ninety-three patients were randomized into a comprehensive group, a ziwuliuzhu group and a prozac group, 31 cases in each group. In the ziwuliuzhu group, acupuncture was applied to the acupoints based on ziwuliuzhu, once a day, 5 times in a week. In the prozac group, fluoxertine hydrochloride (prozac) was prescribed for oral administration, once a day, 20 mg each time. In the comprehensive group, acupuncture based on ziwuliuzhu combined with the oral administration of prozac were adopted and the treatment frequency was the same as the ziwuliuzhu group and the prozac group. The 4-week treatment was taken as one session in the three groups and 6 sessions were required totally. The clinical efficacy and the Hamilton depression rating scale (HAMD) score and the adverse reaction were compared among the 3 groups. The total effective rate was 96.8% (30/31) in the comprehensive group, better than 83.9% (26/31) in the ziwuliuzhu group and 80. 6% (25/31) in the prozac group (both P<0.05). In 4, 12 and 24 weeks of treatment, HAMD score was lower significantly than that before the treatment in the three groups (all P<0.05), and the score in the comprehensive group at each time point after treatment was lower than the other two groups (all P<0.05). In 4 and 12 weeks of treatment, there were not different significantly between the ziwuliuzhu group and the prozac group (both P>0.05). In 24 weeks of treatment, HAMD score in the ziwuliuzhu group was lower than that in the prozac group (P<0.05). For the adverse reaction, there were 2 cases in the comprehensive group, 6 cases in the prozac group and 0 case in the ziwzuliuzhu group. The comprehensive therapy of acupuncture at the acupoints based on ziwuliuzhu and oral administration of prozac is superior to either the simple oral administration of prozac or the ziwuliuzhu acu-puncture in terms of clinical efficacy and the improvements in depressive state. Regarding the clinical efficacy, the impact of simple ziwuliuzhu acupuncture is not different significantly as compared with the simple oral administration of prozac, but it is better than the simple oral administration of prozac in terms of the long-term HAMD score and safety.


Osteopontin in the host response to Leishmania amazonensis.
Leishmania (L.) spp are intracellular eukaryotic parasites responsible for cutaneous or visceral leishmaniasis, replicating predominantly in macrophages (MF). In C57BL/6 mice virulence with L. amazonensis has been associated with inhibition of Th1 immune responses and an uncontrolled lesion development, whereas DBA/2 mice control any lesion. Parasitic clearance by the MFs requires the activation of proper immune responses. One of the immune related genes expressed in immune cells including MF, codes for osteopontin (OPN). OPN is a secreted glycoprotein, acting as an immune regulator. Its implication in promoting Th1 immunity in response to infectious microorganisms and its known protective effect against viral and bacterial infections via activation of the immune response, render OPN a molecule of interest in the study of the host response to L. amazonensis. We examined the host response to L. amazonensis of opn mutant and wild type C57BL/6 mice. Bone marrow derived MFs were infected with the parasites in vitro, and opn mutant and wild type mice were inoculated in vivo by intradermal injection in the ears. The DBA/2 strain known to control L. amazonensis infection was also used for comparison. Our data indicate that the parasites increased opn gene expression and OPN protein while parasitic proliferation was contained in the presence of OPN. In the presence of parasites the expression of inflammation-related transcripts was inhibited. Interleukin-1-beta (IL-1β), and transcripts of the NLR-family (NLRC4, NLRP3) were down regulated after L. amazonensis infection. In the absence of OPN, the inhibition by the parasites of IL-1β transcripts was less efficient and a pyroptosis-like cell phenotype was detected in vitro, suggesting a central role of OPN in the host-response to L. amazonensis. Similarly, in vivo, in the absence of OPN, while the clinical inflammatory phenotype is more severe, an increase of these transcripts was observed. L. amazonensis infection induces opn gene expression and protein, which in turn participates in shaping the host response to the parasites, seemingly by decreasing the activation of inflammation. OPN, further evaluated as a target for Leishmaniasis control represents an additional interest in improving vaccination strategies against the parasites.


Enforced expression of PPP1R13L increases tumorigenesis and invasion through p53-dependent and p53-independent mechanisms.
PPP1R13L was initially identified as a protein that binds to the NF-kappaB subunit p65/RelA and inhibits its transcriptional activity. It also binds p53 and inhibits its action. One set of experimental findings based on overexpression of PPP1R13L indicates that PPP1R13L blocks apoptosis. Another set of experiments, based on endogenous production of PPP1R13L, suggests that the protein may sometimes be pro-apoptotic. We have used primary mouse embryonic fibroblasts (MEFs), dually transformed by HRAS and adenovirus E1A and differing in their p53 status, to explore the effects of PPP1R13L overexpression, thus examining the ability of PPP1R13L to act as an oncoprotein. We found that overexpression of PPP1R13L strongly accelerated tumor formation by RAS/E1A. PPP1R13L overexpressing cells were depleted for both p53 and active p65/RelA and we found that both p53-dependent and -independent apoptosis pathways were modulated by PPP1R13L. Finally, studies with the proteasome inhibitor MG132 revealed that overexpression of PPP1R13L causes faster p53 degradation, a likely explanation for the depletion of p53. Taken together, our results show that increased levels of PPP1R13L can increase tumorigenesis and furthermore suggest that PPP1R13L can influence metastasis.


The evolution of alloimmunity and the genesis of adaptive immunity.
Infectious agents select for host immune responses that destroy infectious nonself yet maintain tolerance to self. Here we propose that retroviruses and other host-antigen associated pathogens (HAAPs) select for the genetic, biochemical, and cell biological properties of alloimmunity, also known as the histocompatibility or tissue rejection response. This hypothesis predicts the major observations regarding histocompatibility responses, including: (i) their existence in animals as diverse as sponges and humans; (ii) extreme polymorphism and balanced allele frequencies at histocompatibility loci, including the human MHC and blood group loci; (iii) the frequency dependent selection of histocompatibility alleles; (iv) the ancient age of many alloantigenic polymorphisms; (v) the high ratio of nonsynonymous mutations to synonymous mutations at histocompatibility loci; (vi) disassortative mating based on MHC alleles; (vii) the inability to explain the existence and continuing selection of histocompatibility alleles by other more conventional biochemical and genetic paradigms; and (viii) the susceptibility of HAAPs, particularly retroviruses such as HIV (human immunodeficiency virus), to histocompatibility reactions. In addition, the hypothesis that HAAPs select the forms and molecules of alloimmunity offers simple explanations for the evolution of histocompatibility systems over time, the initial selection of hypervariable immune mechanisms, and the genesis of adaptive immunity.


Objectively measured physical activity and sedentary time in youth: the International children's accelerometry database (ICAD).
Physical activity and sedentary behaviour in youth have been reported to vary by sex, age, weight status and country. However, supporting data are often self-reported and/or do not encompass a wide range of ages or geographical locations. This study aimed to describe objectively-measured physical activity and sedentary time patterns in youth. The International Children's Accelerometry Database (ICAD) consists of ActiGraph accelerometer data from 20 studies in ten countries, processed using common data reduction procedures. Analyses were conducted on 27,637 participants (2.8-18.4 years) who provided at least three days of valid accelerometer data. Linear regression was used to examine associations between age, sex, weight status, country and physical activity outcomes. Boys were less sedentary and more active than girls at all ages. After 5 years of age there was an average cross-sectional decrease of 4.2% in total physical activity with each additional year of age, due mainly to lower levels of light-intensity physical activity and greater time spent sedentary. Physical activity did not differ by weight status in the youngest children, but from age seven onwards, overweight/obese participants were less active than their normal weight counterparts. Physical activity varied between samples from different countries, with a 15-20% difference between the highest and lowest countries at age 9-10 and a 26-28% difference at age 12-13. Physical activity differed between samples from different countries, but the associations between demographic characteristics and physical activity were consistently observed. Further research is needed to explore environmental and sociocultural explanations for these differences.


Development of a cardiovascular risk score for use in low- and middle-income countries.
Summary measures of cardiovascular risk have long been used in public health, but few include nutritional predictors despite extensive evidence linking diet and heart disease. Study objectives were to develop and validate a novel risk score in a case-control study of myocardial infarction (MI) conducted in Costa Rica during 1994-2004. After restricting the data set to healthy participants (n = 1678), conditional logistic regression analyses modeled associations of lifestyle factors (unhealthy diet, decreased physical activity, smoking, waist:hip ratio, low or high alcohol intake, and low socioeconomic status) with risk for MI. Using the estimated coefficients as weights for each component, a regression model was fit to assess score performance. The score was subsequently validated in participants with a history of chronic disease. Higher risk score values were associated with a significantly increased risk of MI [OR = 2.72 (95% CI = 2.28-3.24)]. The findings were replicated in a model (n = 1392) that included the best covariate measures available in the study [OR = 2.71 (95% CI = 2.26-3.26)]. Performance of the score in different subsets of the study population showed c-statistics ranging from 0.63 to 0.67. The new score presents a quantitative summary of modifiable cardiovascular risk factors in the study population.


Efficient and stable MGMT-mediated selection of long-term repopulating stem cells in nonhuman primates.
HSC transplantation using genetically modified autologous cells is a promising therapeutic strategy for various genetic diseases, cancer, and HIV. However, for many of these conditions, the current efficiency of gene transfer to HSCs is not sufficient for clinical use. The ability to increase the percentage of gene-modified cells following transplantation is critical to overcoming this obstacle. In vivo selection with mutant methylguanine methyltransferase (MGMTP140K) has been proposed to overcome low gene transfer efficiency to HSCs. Previous studies have shown efficient in vivo selection in mice and dogs but only transient selection in primates. Here, we report efficient and stable MGMTP140K-mediated multilineage selection in both macaque and baboon nonhuman primate models. Treatment consisting of both O6-benzylguanine (O6BG) and N,N'-bis(2-chloroethyl)-N-nitroso-urea (BCNU) stably increased the percentage of transgene-expressing cells from a range of initial levels of engrafted genetically modified cells, with the longest follow-up after drug treatment occurring over 2.2 years. Drug treatment was well tolerated, and selection occurred in myeloid, lymphoid, and erythroid cells as well as platelets. Retrovirus integration site analysis before and after drug treatments confirmed the presence of multiple clones. These nonhuman primate studies closely model a clinical setting and should have broad applications for HSC gene therapy targeting human diseases of malignant, genetic, and infectious nature, including HIV.


Family relationships and adolescent well-being: are families equally protective for same-sex attracted youth?
Existing research suggests that sexual minority youth experience lower levels of well-being, in part because they perceive less social support than heterosexual youth. Sexual minority youth with strong family relationships may demonstrate resilience and increased well-being; however, it is also possible that the experience of sexual stigma may make these relationships less protective for sexual minority youth. Using two waves of data from the National Longitudinal Study of Adolescent Health, we explore the links between same-sex attraction, family relationships, and adolescent well-being in a sample of over 13,000 7th-12th grade adolescents (51 % female, 52 % non-Latino/a white, 17 % Latino, 21 % African American, and 7 % Asian). Specifically, we examine whether lower levels of parental closeness, parental involvement, and family support among same-sex attracted youth explain in part why these youth experience increased depressive symptoms and risk behaviors, including binge drinking, illegal drug use, and running away from home, relative to other-sex attracted youth. Second, we ask whether family relationships are equally protective against depressive symptoms and risk behaviors for same-sex attracted and other-sex attracted youth. We find that same-sex attracted youth, particularly girls, report higher levels of depressive symptoms, binge drinking, and drug use in part because they perceive less closeness with parents and less support from their families. Results also suggest that parental closeness and parental involvement may be less protective against risk behaviors for same-sex attracted boys than for their other-sex attracted peers. Findings thus suggest that interventions targeting the families of sexual minority youth should educate parents about the potentially negative effects of heteronormative assumptions and attitudes on positive adolescent development.


Food fortification with multiple micronutrients: impact on health outcomes in general population.
Vitamins and minerals are essential for growth and maintenance of a healthy body, and have a role in the functioning of almost every organ. Multiple interventions have been designed to improve micronutrient deficiency, and food fortification is one of them. To assess the impact of food fortification with multiple micronutrients on health outcomes in the general population, including men, women and children. We searched electronic databases up to 29 August 2018, including the Cochrane Central Register of Controlled Trial (CENTRAL), the Cochrane Effective Practice and Organisation of Care (EPOC) Group Specialised Register and Cochrane Public Health Specialised Register; MEDLINE; Embase, and 20 other databases, including clinical trial registries. There were no date or language restrictions. We checked reference lists of included studies and relevant systematic reviews for additional papers to be considered for inclusion. We included randomised controlled trials (RCTs), cluster-RCTs, quasi-randomised trials, controlled before-after (CBA) studies and interrupted time series (ITS) studies that assessed the impact of food fortification with multiple micronutrients (MMNs). Primary outcomes included anaemia, micronutrient deficiencies, anthropometric measures, morbidity, all-cause mortality and cause-specific mortality. Secondary outcomes included potential adverse outcomes, serum concentration of specific micronutrients, serum haemoglobin levels and neurodevelopmental and cognitive outcomes. We included food fortification studies from both high-income and low- and middle-income countries (LMICs). Two review authors independently screened, extracted and quality-appraised the data from eligible studies. We carried out statistical analysis using Review Manager 5 software. We used random-effects meta-analysis for combining data, as the characteristics of study participants and interventions differed significantly. We set out the main findings of the review in 'Summary of findings' tables, using the GRADE approach. We identified 127 studies as relevant through title/abstract screening, and included 43 studies (48 papers) with 19,585 participants (17,878 children) in the review. All the included studies except three compared MMN fortification with placebo/no intervention. Two studies compared MMN fortification versus iodised salt and one study compared MMN fortification versus calcium fortification alone. Thirty-six studies targeted children; 20 studies were conducted in LMICs. Food vehicles used included staple foods, such as rice and flour; dairy products, including milk and yogurt; non-dairy beverages; biscuits; spreads; and salt. Fourteen of the studies were fully commercially funded, 13 had partial-commercial funding, 14 had non-commercial funding and two studies did not specify the source of funding. We rated all the evidence as of low to very low quality due to study limitations, imprecision, high heterogeneity and small sample size. When compared with placebo/no intervention, MMN fortification may reduce anaemia by 32% (risk ratio (RR) 0.68, 95% confidence interval (CI) 0.56 to 0.84; 11 studies, 3746 participants; low-quality evidence), iron deficiency anaemia by 72% (RR 0.28, 95% CI 0.19 to 0.39; 6 studies, 2189 participants; low-quality evidence), iron deficiency by 56% (RR 0.44, 95% CI 0.32 to 0.60; 11 studies, 3289 participants; low-quality evidence); vitamin A deficiency by 58% (RR 0.42, 95% CI 0.28 to 0.62; 6 studies, 1482 participants; low-quality evidence), vitamin B2 deficiency by 64% (RR 0.36, 95% CI 0.19 to 0.68; 1 study, 296 participants; low-quality evidence), vitamin B6 deficiency by 91% (RR 0.09, 95% CI 0.02 to 0.38; 2 studies, 301 participants; low-quality evidence), vitamin B12 deficiency by 58% (RR 0.42, 95% CI 0.25 to 0.71; 3 studies, 728 participants; low-quality evidence), weight-for-age z-scores (WAZ) (mean difference (MD) 0.1, 95% CI 0.02 to 0.17; 8 studies, 2889 participants; low-quality evidence) and weight-for-height/length z-score (WHZ/WLZ) (MD 0.1, 95% CI 0.02 to 0.18; 6 studies, 1758 participants; low-quality evidence). We are uncertain about the effect of MMN fortification on zinc deficiency (RR 0.84, 95% CI 0.65 to 1.08; 5 studies, 1490 participants; low-quality evidence) and height/length-for-age z-score (HAZ/LAZ) (MD 0.09, 95% CI 0.01 to 0.18; 8 studies, 2889 participants; low-quality evidence). Most of the studies in this comparison were conducted in children. Subgroup analyses of funding sources (commercial versus non-commercial) and duration of intervention did not demonstrate any difference in effects, although this was a relatively small number of studies and the possible association between commercial funding and increased effect estimates has been demonstrated in the wider health literature. We could not conduct subgroup analysis by food vehicle and funding; since there were too few studies in each subgroup to draw any meaningful conclusions. When we compared MMNs versus iodised salt, we are uncertain about the effect of MMN fortification on anaemia (R 0.86, 95% CI 0.37 to 2.01; 1 study, 88 participants; very low-quality evidence), iron deficiency anaemia (RR 0.40, 95% CI 0.09 to 1.83; 2 studies, 245 participants; very low-quality evidence), iron deficiency (RR 0.98, 95% CI 0.82 to 1.17; 1 study, 88 participants; very low-quality evidence) and vitamin A deficiency (RR 0.19, 95% CI 0.07 to 0.55; 2 studies, 363 participants; very low-quality evidence). Both of the studies were conducted in children. Only one study conducted in children compared MMN fortification versus calcium fortification. None of the primary outcomes were reported in the study. None of the included studies reported on morbidity, adverse events, all-cause or cause-specific mortality. The evidence from this review suggests that MMN fortification when compared to placebo/no intervention may reduce anaemia, iron deficiency anaemia and micronutrient deficiencies (iron, vitamin A, vitamin B2 and vitamin B6). We are uncertain of the effect of MMN fortification on anthropometric measures (HAZ/LAZ, WAZ and WHZ/WLZ). There are no data to suggest possible adverse effects of MMN fortification, and we could not draw reliable conclusions from various subgroup analyses due to a limited number of studies in each subgroup. We remain cautious about the level of commercial funding in this field, and the possibility that this may be associated with higher effect estimates, although subgroup analysis in this review did not demonstrate any impact of commercial funding. These findings are subject to study limitations, imprecision, high heterogeneity and small sample sizes, and we rated most of the evidence low to very low quality. and hence no concrete conclusions could be drawn from the findings of this review.


The influence of additives and drying methods on quality attributes of fish protein powder made from saithe (Pollachius virens).
Fish protein powder (FPP) is used in the food industry for developing formulated food products. This study investigates the feasibility of increasing the value of saithe (Pollachius virens) by producing a functional FPP. Quality attributes of spray and freeze-dried saithe surimi containing lyoprotectants were studied. A freeze-dried saithe surimi without lyoprotectants was also prepared as a control sample. The amount of protein, moisture, fat and carbohydrate in the FPPs were 745-928, 39-58, 21-32 and 10-151 g kg(-1). Quality attributes of FPPs were influenced by the two drying methods and lyoprotectants. The highest level of lipid oxidation was found in the control and the second highest in the spray-dried FPP. The spray-dried fish protein had the lowest viscosity among all FPPs. Gel-forming ability of samples with lyoprotectants was higher than that of the control. Water-binding capacity, emulsion properties and solubility of the freeze-dried fish protein containing lyoprotectants were significantly higher than spray-dried and control samples. However, functional properties of spray-dried FPP were higher than the control sample. It is feasible to develop value-added FPP from saithe surimi using spray- and freeze-drying processes, but freeze-dried FPP containing lyoprotectant had superior functional properties and stability compared with spray-dried sample. Both products might be used as functional protein ingredients in various food systems.


Spondyloarthropathies.
The spondyloarthropathies include ankylosing spondylitis, reactive arthritis (including Reiter's syndrome), psoriatic arthritis, inflammatory bowel disease-associated spondyloarthropathy, and undifferentiated spondyloarthropathy. These diseases are linked by their association with the HLA-B27 gene and by the presence of enthesitis as the basic pathologic lesion. Additional clinical features include inflammatory back pain, dactylitis, and extra-articular manifestations such as uveitis and skin rash. The history and physical examination are the major diagnostic tools, although radiographic evidence of sacroiliitis is helpful. Therapeutic options include nonsteroidal anti-inflammatory drugs, sulfasalazine, methotrexate, and tumor necrosis factor-alpha inhibitors. Early recognition and appropriate treatment can help to limit disability.


Protective effects of germinated and fermented soybean extract against tert-butyl hydroperoxide-induced hepatotoxicity in HepG2 cells and in rats.
The aim of the current study is to investigate the antioxidant and hepatoprotective effects of germinated and fermented soybean extract (GFSE) on tert-butyl hydroperoxide (t-BHP)-induced oxidative stress in HepG2 cells and in the rat liver. High performance liquid chromatography (HPLC) analysis showed that genistin (3.40 ± 0.14 μg mg(-1)) was the most abundant isoflavone in the GFSE. Coumestrol (1.00 ± 0.04 μg mg(-1)), daidzin (0.78 ± 0.14 μg mg(-1)), genistein (0.68 ± 0.05 μg mg(-1)), glycitin (0.54 ± 0.02 μg mg(-1)), glycitein (0.41 ± 0.02 μg mg(-1)), and daidzein (0.02 ± 0.0 g mg(-1)) are also contained in decreasing order of content. GFSE significantly inhibited t-BHP-induced reactive oxygen species (ROS) production in HepG2 cells. This GFSE-induced ROS reduction was associated with the down-regulation of nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4), a pro-oxidant enzyme, and the up-regulation of the mRNA levels of antioxidant enzymes, including catalase, superoxide dismutase (SOD), glutathione reductase (GR), and glutathione peroxidase (Gpx) in the rat liver. In addition, increased levels of antioxidant enzyme mRNAs correlated with the enhanced enzymatic activities of SOD, catalase, and glutathione-S-transferase (GST). The antioxidant effect of GFSE was supported by the reduction in the levels of malondialdehyde (MDA), a hydroperoxide, and the serum levels of lactate dehydrogenase (LDH), a biomarker of cell damage, were also lowered by GFSE. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST), which are clinical biomarkers of liver function, were shown to be improved with GFSE administration. The effects of GFSE were attributable to an improvement in liver tissue morphology. Taken together, GFSE protected the liver from t-BHP-induced oxidative stress by regulating ROS-related enzymes. Our results suggest that GFSE might be a hepatoprotective source against oxidative stress.


[A case report of childhood acute lymphoblastic leukemia with leukoencephalopathy that responded to oxygenation under hyperbaric pressure therapy].
In this report, we described a case of acute lymphoblastic leukemia with leukoencephalopathy that responded to oxygenation under hyperbaric pressure (OHP) therapy. The patient was 6 year-old female who was diagnosed as acute lymphoblastic leukemia (ALL) one year and 9 months earlier. After the first relapse of the central nervous system (CNS) leukemia, intrathecal administration of methotrexate (MTX) and skull irradiation induced CNS remission. The patient was readmitted because of second CNS relapse. After the third administration of weekly intrathecal MTX injection, apathy and finger tremor were observed. Her conscious disturbance continued for two weeks and magnetic resonance imaging (MRI) revealed abnormal findings in the white matter of her brain. Subsequently OHP therapy was commenced, and the conscious disturbance was improved gradually. One month later, neuro-disturbance resolved completely and the findings of MRI were improved. We could not find any case of leukoencephalopathy which was treated with OHP in the literature. But our case suggested that OHP therapy is valuable in patient with leukoencephalopathy in the early stage.


Asymptomatic filariasis and leprosy co-morbidity in a patient with suspected Guillain-Barrè syndrome: the first case report of an incidental finding in a slit-skin smear.
Lymphatic filariasis (LF) and leprosy are both endemic in India. These diseases are on the World Health Organization (WHO) list of neglected tropical diseases (NTDs), as they affect the most marginalized communities in the world, resulting in deformities and functional limitation. We report the first case of asymptomatic filariasis and leprosy co-morbidity in a patient with suspected Guillain-Barré syndrome. A 55-year-old male who was a farmer by occupation presented to the Neurology Outpatient Department (OPD) of our institute with complaints of weakness in all four limbs for the last 15 days. After admission, a detailed history revealed that the patient had been taking multi-drug therapy (MDT) for leprosy for the previous 6 months. After symptomatic management of the presenting complaints, the patient was sent to the Department of Microbiology for a consultation and six-site slit-skin sampling. The initial screening of Ziehl-Neelsen (ZN)-stained smears under a 10× objective led to the incidental finding of sheathed structures resembling microfilaria (Mf) on the smear made from ear lobules. In addition, short acid-fast bacilli (AFB) were also observed under the oil-immersion objective. We emphasize that a high index of suspicion and thorough screening of smears by a microbiologist is essential in specimens obtained from any body site.


Mitochondria-Targeted and Ultrasound-Activated Nanodroplets for Enhanced Deep-Penetration Sonodynamic Cancer Therapy.
Sonodynamic therapy (SDT), a promising alternative for cancer therapy, utilizes a sonosensitizer combined with ultrasound (US) irradiation to damage tumor cells/tissues for therapeutic purposes. The ability of sonosensitizers to specifically accumulate in tumor cells/tissues could greatly influence their therapeutic efficiency. In this work, we report the use of US-activated sonosensitizer (IR780)-based nanodroplets (IR780-NDs) for SDT, which provide numerous benefits for killing cancer cells compared with traditional methods. For instance, IR780-NDs showed effective surface-to-core diffusion both in vitro and in vivo. In the presence of US, the acoustic droplet vaporization (ADV) effect significantly assisted the conveyance of IR780-NDs from the circulatory system to tumor regions, and the acoustic wave force also increased the penetration depth within tumor tissues. Furthermore, IR780-NDs possesses mitochondrial targeting capabilities, which improves the precision and accuracy of SDT delivery. During the in vitro assessment, the overproduction of reactive oxygen species (ROS) was observed following mitochondrial targeting, which rendered cancer cells more susceptible to ROS-induced apoptosis. Additionally, IR780-ND is a suitable candidate for photoacoustic and fluorescence imaging and can also enhance US imaging because of the ADV-generated bubbles, which provides the potential for SDT guidance and monitoring. Therefore, with combined modalities, IR780-NDs can be a promising theranostics nanoplatform for cancer therapy.


Evidence for nucleosynthetic enrichment of the protosolar molecular cloud core by multiple supernova events.
The presence of isotope heterogeneity of nucleosynthetic origin amongst meteorites and their components provides a record of the diverse stars that contributed matter to the protosolar molecular cloud core. Understanding how and when the solar system's nucleosynthetic heterogeneity was established and preserved within the solar protoplanetary disk is critical for unraveling the earliest formative stages of the solar system. Here, we report calcium and magnesium isotope measurements of primitive and differentiated meteorites as well as various types of refractory inclusions, including refractory inclusions (CAIs) formed with the canonical 26Al/27Al of ~5 × 10-5 (26Al decays to 26Mg with a half-life of ~0.73 Ma) and CAIs that show fractionated and unidentified nuclear effects (FUN-CAIs) to understand the origin of the solar system's nucleosynthetic heterogeneity. Bulk analyses of primitive and differentiated meteorites along with canonical and FUN-CAIs define correlated, mass-independent variations in 43Ca, 46Ca and 48Ca. Moreover, sequential dissolution experiments of the Ivuna carbonaceous chondrite aimed at identifying the nature and number of presolar carriers of isotope anomalies within primitive meteorites have detected the presence of multiple carriers of the short-lived 26Al nuclide as well as carriers of anomalous and uncorrelated 43Ca, 46Ca and 48Ca compositions, which requires input from multiple and recent supernovae sources. We infer that the solar system's correlated nucleosynthetic variability reflects unmixing of old, galactically-inherited homogeneous dust from a new, supernovae-derived dust component formed shortly prior to or during the evolution of the giant molecular cloud parental to the protosolar molecular cloud core. This implies that similarly to 43Ca, 46Ca and 48Ca, the short-lived 26Al nuclide was heterogeneously distributed in the inner solar system at the time of CAI formation.


Thin dendrites of cerebellar interneurons confer sublinear synaptic integration and a gradient of short-term plasticity.
Interneurons are critical for neuronal circuit function, but how their dendritic morphologies and membrane properties influence information flow within neuronal circuits is largely unknown. We studied the spatiotemporal profile of synaptic integration and short-term plasticity in dendrites of mature cerebellar stellate cells by combining two-photon guided electrical stimulation, glutamate uncaging, electron microscopy, and modeling. Synaptic activation within thin (0.4 μm) dendrites produced somatic responses that became smaller and slower with increasing distance from the soma, sublinear subthreshold input-output relationships, and a somatodendritic gradient of short-term plasticity. Unlike most studies showing that neurons employ active dendritic mechanisms, we found that passive cable properties of thin dendrites determine the sublinear integration and plasticity gradient, which both result from large dendritic depolarizations that reduce synaptic driving force. These integrative properties allow stellate cells to act as spatiotemporal filters of synaptic input patterns, thereby biasing their output in favor of sparse presynaptic activity.


Real-time image deblurring by optoelectronic hybrid processing.
An efficient approach is presented to restore a motion-blurred image in real time by optoelectronic hybrid processing, by which an image motion vector can be effectively detected and an accurate point spread function is constructed rapidly. A simple Wiener filter algorithm is employed to restore the blurred image. It greatly alleviates the complexity of the restoration algorithm. The proposed approach can apply to arbitrary motion-blurred image restoration. An optoelectronic hybrid joint transform correlation is constructed to verify the efficiency. The experimental results show that the proposed method has distinct advantages of preferable effect and good real time.


Psychosurgery: stereotactic subcaudate tractomy. An indispensable treatment.
Stereotactic subcaudate tractotomy (SST) is the only type of psychosurgery performed at the Geoffrey Knight Unit, London, where nearly 1300 operations have been done since 1961. Statistically reliable data are not available to prove the effectiveness of SST. A detailed statement about contemporary psychosurgery is given. Relevant publications from the Unit and via Medline are discussed. The outcome figures are reviewed. The outcome is assessed at the Unit in global and clinical terms, associated with results of self-completed questionnaires. SST allows 40-60% of patients to live normal or near-normal lives, perhaps with continuation of medication. A reduction in suicide rate to 1% post-operatively, from 15% in cases of uncontrolled affective disorders is seen. As a treatment of last resort, no controlled trial against a comparable treatment is possible. It appears reasonable to offer SST to patients with suicidal and deluded depression or with frequently swinging moods, not responding to other treatments.


Particle Count Statistics Applied to the Penetration of a Filter Challenged with Nanoparticles.
Statistical confidence in a single measure of filter penetration (P) is dependent on the low number of particle counts made downstream of the filter. This paper discusses methods for determining an upper confidence limit (UCL) for a single measure of penetration. The magnitude of the UCL was then compared to the P value, UCL ≤ 2P, as a penetration acceptance criterion (PAC). This statistical method was applied to penetration trials involving an N95 filtering facepiece respirator challenged with sodium chloride and four engineered nanoparticles: titanium dioxide, iron oxide, silicon dioxide and single-walled carbon nanotubes. Ten trials were performed for each particle type with the aim of determining the most penetrating particle size (MPPS) and the maximum penetration, Pmax. The PAC was applied to the size channel containing the MPPS. With those P values that met the PAC for a given set of trials, an average Pmax and MPPS was computed together with corresponding standard deviations. Because the size distribution of the silicon dioxide aerosol was shifted towards larger particles relative to the MPPS, none of the ten trials satisfied the PAC for that aerosol. The remaining four particle types resulted in at least 4 trials meeting the criterion. MPPS values ranged from 35 - 53 nm with average Pmax values varying from 4.0% for titanium dioxide to 7.0% for iron oxide. The use of the penetration acceptance criterion is suggested for determining the reliability of penetration measurements obtained to determine filter Pmax and MPPS.


Metronomic cyclophosphamide and capecitabine combined with bevacizumab in advanced breast cancer.
Metronomic chemotherapy has shown efficacy in patients with metastatic breast cancer. When used in association with targeted antiangiogenic drugs, it was more active than metronomic therapy alone in preclinical and clinical studies. Patients with advanced breast cancer were candidates to receive metronomic oral capecitabine (500 mg thrice daily) and cyclophosphamide (50 mg daily) plus bevacizumab (10 mg/kg every 2 weeks). In 46 assessable patients, we observed one complete response (CR; 2%), 21 partial responses (PR; 46%), 19 patients (41%) with stable disease (SD), and five patients (11%) with progressive disease, for an overall response rate of 48% (95% CI, 33% to 63%). Additional long-term disease stabilization (SD > or = 24 weeks) occurred in eight patients, for an overall clinical benefit (CR + PR + SD > or = 24 weeks) of 68% (95% CI, 51% to 81%). Median time to progression was 42 weeks (95% CI, 26 to 72 weeks). Toxicity was generally mild. Grade 3 or 4 nonhematologic adverse effects included hypertension (n = 8), transaminitis (n = 2), and nausea/vomiting (n = 2). Higher baseline circulating endothelial cells (CECs) were correlated with overall response (P = .02), clinical benefit (P = .01), and improved progression-free survival (P = .04). Treatment with metronomic capecitabine and cyclophosphamide in combination with bevacizumab was effective in advanced breast cancer and was minimally toxic. The number of baseline CECs significantly correlated with response and outcome, therefore supporting further studies on this surrogate marker for the selection of patients to be candidates for antiangiogenic treatments.


Sudden Vegetation Dieback in Atlantic and Gulf Coast Salt Marshes.
Salt marshes rank as the most productive ecosystems on the planet. Biomass production can be greater than 3 kg dry matter/m2/year, which is 40% more biomass than tropical rainforests produce. Salt marshes provide multiple benefits to mankind. For example, coastal communities receive protection from storm surges and wave erosion. Salt marshes absorb excess nitrogen and phosphorus from sewage and fertilizer run-off into rivers, which, in turn, prevents algal blooms and hypoxia in coastal waters. In addition, these unique ecosystems provide habitat and shelter for many hundreds of species of shellfish, finfish, migratory and sedentary birds, and other marine animals. Despite the richness in animal species, the intertidal marshes of the salt marsh ecosystem are dominated by only a few plant species. Of these, the most prevalent plant species in a marsh are the tall and short forms of smooth cordgrass (Spartina alterniflora). The first recorded account of a dieback in a U.S. salt marsh was in the early 1990s in the Florida panhandle where patches of Sp. alterniflora as large as 1 ha died. This article explores possible causes of Sudden Vegetation Dieback.


Facial expressions and the evolution of the speech rhythm.
In primates, different vocalizations are produced, at least in part, by making different facial expressions. Not surprisingly, humans, apes, and monkeys all recognize the correspondence between vocalizations and the facial postures associated with them. However, one major dissimilarity between monkey vocalizations and human speech is that, in the latter, the acoustic output and associated movements of the mouth are both rhythmic (in the 3- to 8-Hz range) and tightly correlated, whereas monkey vocalizations have a similar acoustic rhythmicity but lack the concommitant rhythmic facial motion. This raises the question of how we evolved from a presumptive ancestral acoustic-only vocal rhythm to the one that is audiovisual with improved perceptual sensitivity. According to one hypothesis, this bisensory speech rhythm evolved through the rhythmic facial expressions of ancestral primates. If this hypothesis has any validity, we expect that the extant nonhuman primates produce at least some facial expressions with a speech-like rhythm in the 3- to 8-Hz frequency range. Lip smacking, an affiliative signal observed in many genera of primates, satisfies this criterion. We review a series of studies using developmental, x-ray cineradiographic, EMG, and perceptual approaches with macaque monkeys producing lip smacks to further investigate this hypothesis. We then explore its putative neural basis and remark on important differences between lip smacking and speech production. Overall, the data support the hypothesis that lip smacking may have been an ancestral expression that was linked to vocal output to produce the original rhythmic audiovisual speech-like utterances in the human lineage.


Cell of origin of transformed follicular lymphoma.
Follicular lymphoma (FL) is an indolent disease but transforms in 2% to 3% of patients per year into aggressive, large cell lymphoma, a critical event in the course of the disease associated with increased lymphoma-related mortality. Early transformation cannot be accurately predicted at the time of FL diagnosis and the biology of transformed FL (TFL) is poorly understood. Here, we assembled a cohort of 126 diagnostic FL specimens including 40 patients experiencing transformation (<5 years) and 86 patients not experiencing transformation for at least 5 years. In addition, we assembled an overlapping cohort of 155 TFL patients, including 114 cases for which paired samples were available, and assessed temporal changes of routinely available biomarkers, outcome after transformation, as well as molecular subtypes of TFL. We report that the expression of IRF4 is an independent predictor of early transformation (Hazard ratio, 13.3; P < .001). We also show that composite histology at the time of transformation predicts favorable prognosis. Moreover, applying the Lymph2Cx digital gene expression assay for diffuse large B-cell lymphoma (DLBCL) cell-of-origin determination to 110 patients with DLBCL-like TFL, we demonstrate that TFL is of the germinal-center B-cell-like subtype in the majority of cases (80%) but that a significant proportion of cases is of the activated B-cell-like (ABC) subtype (16%). These latter cases are commonly negative for BCL2 translocation and arise preferentially from BCL2 translocation-negative and/or IRF4-expressing FLs. Our study demonstrates the existence of molecular heterogeneity in TFL as well as its relationship to the antecedent FL.


WE-G-211-03: Development of Ultrasound Imaging Equipment.
One of the earliest man-made ultrasound images of the human body was produced by Dussik in 1941, when he attempted to image the brain using a through transmission technique. These early images were later judged to be artifacts related to sound wave transmission through skull bone. Pulse-echo examination of the body started in the late 1940's following developments of sonar, radar, and ultrasound flaw detectors. Ludwig and colleagues measured speeds of sound in tissues, publishing the value 1540 m/s for many tissue paths, a figure still used today. Among the pioneering pulse- echo imaging teams in the USA were Wild and Reid who developed real time imaging of the breast in the early 1950's, and Howry and Bliss, who were able to generate detailed anatomical pictures of the neck by employing water bath scanners. Many other groups, including from Japan, Australia, and Europe were pursuing both A-scope and B-scope applications of ultrasound around this time. Notable achievements include work by Ian Donald in the UK, who in 1955 described a contact scanner and published B-scope images depicting a variety of anatomical regions. The systems of Donald and of Wild are said to have inspired engineers from Howry's water bath team in Colorado to develop their own contact scanner, and in 1963 a new company, Physionics produced the first commercial, single element transducer "articulated arm" scanner. It provided bi-stable B-mode images on a storage oscilloscope, marking the beginning of widespread acceptance of this modality. Gradual instrument improvements include analog then digital scan converters for gray scale in the 70's, and both auxiliary and stand alone mechanical scanning real time probes. Phased array technology also emerged for cardiac imaging, as did linear arrays for obstetrics and abdominal imaging. Perhaps the most revolutionary instrument ever was produced in the early 1980's, the Acuson 128, introducing high image quality linear and phased array beamformed images for radiology applications and helping to conclude the brief era of manual scanners. As beamformers became digital devices in the 1990's, unprecedented image quality, diagnostic features, two dimensional arrays, and even system miniaturization evolved, bringing ultrasound imaging to its present state. The ultrasound field is still characterized by novel instruments emerging from the laboratories of clever scientists, addressing diagnostic and therapeutic needs not provided by present day technology. 1. Describe features of the first commercially available ultrasound scanners. 2. Identify the relationship between technological developments in radar and emergence of ultrasound as a modality 3. Explain the significance of a high large channel count in beamforming 4. Contrast echo acquisition and processing in a modern scanner with first generation devices.


Use of patient-controlled psychiatric hospital admissions: patients' perspective.
By patient-controlled admission (PCA), psychiatric patients with a PCA contract can initiate a brief admission without a health professional gatekeeper. However, research regarding use of PCA is scarce. In this Danish multi-centre study, motives for and satisfaction with PCA were explored. During a 1-year period, patients from 11 Danish mental health units evaluated PCA using a questionnaire developed for the purpose. In total, 190 patients evaluated 462 admissions. The majority had concluded a PCA contract to receive early help. PCA was mostly initiated because of mental health conditions, but also because of social and everyday problems. The purpose was mainly to be at peace and prevent symptom increase. Patients from units with a quarantine period felt more ready for discharge than the others. Patients were in general satisfied with PCA (61.7%), but patients who hoped for improved medication or wished to obtain more care were less satisfied. Patients can use PCA as a means to receive timely help. Motives for patients seeking help are not limited to mental conditions. Expectations that cannot be met within the organizational structure of the PCA programme are associated with less satisfaction. However, regional differences in structures were associated with satisfaction. Patients who had access to shorter PCAs were more satisfied, and a quarantine period may even help patients become more ready for discharge. A brief admission period does not cause dissatisfaction at discharge and can be used in the clinical setting.


Analysis of input-grating couplers having finite lengths.
Planar waveguide-grating couplers are analyzed to determine the effects of grating length, the incident beam size, and the coupling length of the grating on the input-coupling efficiency. The emphasis is to examine the effects of these finite lengths on the range of angles over which input coupling occurs and the shape of the efficiency curve. A general formula for normalized input-coupling efficiency is given to relate these lengths. When any one of these characteristic lengths is much smaller than the other two, both the angular width and angular dependence of the coupling efficiency for a scan of the incident beam angle will be mainly determined by that characteristic length. This is demonstrated experimentally for two cases: one has a relatively short grating length, and the other has a short coupling length.


The effect of visual and sensory performance on head impact biomechanics in college football players.
The development of prevention strategies is critical to address the rising prevalence of sport-related concussions. Visual and sensory performance may influence an individual's ability to interpret environmental cues, anticipate opponents' actions, and create appropriate motor responses limiting the severity of an impending head impact. The purpose of this study was to determine the relationship between traditional and visual sensory reaction time measures, and the association between visual and sensory performance and head impact severity in college football players. Thirty-eight collegiate football players participated in the study. We used real-time data collection instrumentation to record head impact biomechanics during games and practices. Our findings reveal no significant correlations between reaction time on traditional and visual sensory measures. We found a significant association between head impact severity and level of visual and sensory performance for multiple assessments, with low visual and sensory performers sustaining a higher number of severe head impacts. Our findings reveal a link between level of visual and sensory performance and head impact biomechanics. Future research will allow clinicians to have the most appropriate testing batteries to identify at-risk athletes and create interventions to decrease their risk of injurious head impacts.


Broadband continuum generation in mode-locked lasers with phase-matched output couplers.
The concept of intracavity phase matching is proposed and demonstrated both theoretically and experimentally with a broadband phase-matched dielectric output coupler for linear-cavity few-cycle Ti:sapphire oscillators. The spectrum in the matched wavelength range is enhanced by >10 dB while maintaining good beam quality via resonantly enhanced continuum generation. The enhanced spectral components can be continuously tuned by varying the intracavity dispersion. Because dielectric coatings offer flexible design capabilities, this approach is applicable to various lasers with different gain media to obtain custom-tailored spectra, which have the potential to benefit several applications, such as shorter pulse generation, seeding of ytterbium lasers for pumping optical parametric amplifiers, and direct f-2f detection of the carrier-envelope phase.


Secondary Salivary Gland Malignancy in Thyroid Cancer: A United States Population Based Study.
There is an increased risk of second primary malignancies with thyroid cancer. However, the risk and characters of secondary salivary gland malignancy (sSGM) in patients with thyroid cancer have not been evaluated before. We used the Surveillance Epidemiology and End Results (SEER) 18 registry to identify thyroid cancer patients from 1973 to 2014. We then calculated the risk of sSGM using standardized incidence ratio and excess risk. Separately, all cases of primary salivary gland malignancy (pSGM) diagnosed between 1973 - 2014 were extracted from the SEER 18 registry, and their characteristics compared with sSGM using independent samples t-test for continuous variables and Chi-square tests for categorical variables. There were a total of 68,339 cases of primary thyroid cancer. Of these, 18 patients developed sSGM with the observed to expected ratio being 3.58 (95% CI: 2.12 to 5.65; P < 0.05) and excess risk being 0.48 per 10,000 population. The incidence of sSGM remained higher between 6 months to 10 years from the time of diagnosis of thyroid carcinoma. The risk of developing sSGM was significantly higher if they were below 60 years of age (O/E: 4.51; 95% CI: 2.33 - 7.88; P < 0.05), were females (O/E: 4.91; 95% CI: 2.80 - 7.97; P < 0.05), were whites (O/E: 3.04; 95% CI: 1.62 - 5.1 9; P < 0.05), had well-differentiated thyroid carcinoma (O/E: 9.70; 95% CI: 3.90 - 19.98; P < 0.05) or were treated with radioactive iodine (O/E: 5.26; 95% CI: 2.72 - 9.19; P < 0.05). While the proportion of females developing sSGM was significantly greater than those developing pSGM (88.9% vs. 44%; P < 0.05), there was no statistical difference between pSGM and sSGM in terms of the age at diagnosis, the proportion of patients diagnosed before 60 years of age, anatomic site of origin or the histological grade of tumor. Patients with thyroid cancers are at an increased risk of developing sSGM than the general population. This risk is greater if the person is below 60 years of age, female, white, with well-differentiated thyroid carcinoma or is treated with radioactive iodine.


Transcranial magnetic stimulation and motor plasticity in human lateral cerebellum: dual effect on saccadic adaptation.
The cerebellum is a key area for movement control and sensory-motor plasticity. Its medial part is considered as the exclusive cerebellar center controlling the accuracy and adaptive calibration of saccadic eye movements. However, the contribution of other zones situated in its lateral part is unknown. We addressed this question in healthy adult volunteers by using magnetic resonance imaging (MRI)-guided transcranial magnetic stimulation (TMS). The double-step target paradigm was used to adaptively lengthen or shorten saccades. TMS pulses over the right hemisphere of the cerebellum were delivered at 0, 30, or 60 ms after saccade detection in separate recording sessions. The effects on saccadic adaptation were assessed relative to a fourth session where TMS was applied to Vertex as a control site. First, TMS applied upon saccade detection before the adaptation phase reduced saccade accuracy. Second, TMS applied during the adaptation phase had a dual effect on saccadic plasticity: adaptation after-effects revealed a potentiation of the adaptive lengthening and a depression of the adaptive shortening of saccades. For the first time, we demonstrate that TMS on lateral cerebellum can influence plasticity mechanisms underlying motor performance. These findings also provide the first evidence that the human cerebellar hemispheres are involved in the control of saccade accuracy and in saccadic adaptation, with possibly different neuronal populations concerned in adaptive lengthening and shortening. Overall, these results require a reappraisal of current models of cerebellar contribution to oculomotor plasticity.


Observing Maternal Restriction of Food with 3⁻5-Year-Old Children: Relationships with Temperament and Later Body Mass Index (BMI).
Overt parental restriction of food has previously been associated with child weight; however, most research has relied on self-reported feeding behaviour, or observations which give little opportunity to observe restriction of food. Using a novel lab-based observational technique to increase the opportunity to observe maternal feeding restriction, we explored the relationships between maternal restriction, child responses to restriction and child temperament with child body mass index (BMI) Z-scores over time. Sixty-two mother child dyads were recruited to the study when their children were aged 3⁻5 years and were followed up 2 years later (N = 39 dyads). Families were observed during a feeding interaction in the laboratory where cookies were offered with the main meal to increase the opportunity for maternal restriction of food. Feeding observations were coded and child temperament and BMI were measured. Controlling for current child BMI Z-scores, greater maternal verbal and physical restriction of food at 3⁻5 years was related to higher child BMI Z-scores at 5⁻7 years. More emotional children were less likely to experience restriction and less likely to accept attempts to restrict their food intake. Further research should consider children's reactions to parental feeding behaviours in greater depth and explore how feeding practices interact with child temperament in the prediction of changes in child weight.


Balancing hypoxia and hypothermia in cold-submerged frogs.
Many animals respond to hypoxic stress by selecting cooler environments, the so-called 'behavioural hypothermia' response. Amphibians overwintering in ice-covered ponds and lakes offer an ecologically relevant test of this response since they must choose between the confounding metabolic effects of profound hypothermia or hypoxia; thermal and chemical conditions can vary from 0 degrees C and normoxic at the ice-water interface to 4 degrees C and markedly hypoxic at depths of 2-4 m. To mimic such environmental conditions, we constructed an experimental chamber that enabled continuous electronic surveillance of an animal's movement along a thermal gradient. When Rana temporaria pre-acclimated to 3.5 degrees C were placed in a normoxic thermal gradient ranging from 0.8 to 8 degrees C, they invariably favoured the warmer end of the chamber. Upon exposure to hypoxia, however, their preferred temperature shifted from a median of 6.8 degrees C (P02 = 158 mmHg; 1 mmHg = 0.133 kPa) to 1.9 degrees C (P02 = 25 mmHg). Metabolic rate measurements from animals exposed simultaneously to acute changes in water temperature and PO2 suggest that movement to colder conditions in hypoxia effects the greatest metabolic savings and prolongs the onset of a plasma lactacidosis.


Prevalence and Clinical Significance of Herpesvirus Infection in Populations of Australian Marsupials.
Herpesviruses have been reported in several marsupial species, but molecular classification has been limited to four herpesviruses in macropodids, a gammaherpesvirus in two antechinus species (Antechinus flavipes and Antechinus agilis), a gammaherpesvirus in a potoroid, the eastern bettong (Bettongia gaimardi) and two gammaherpesviruses in koalas (Phascolarctos cinereus). In this study we examined a range of Australian marsupials for the presence of herpesviruses using molecular and serological techniques, and also assessed risk factors associated with herpesvirus infection. Our study population included 99 koalas (Phascolarctos cinereus), 96 eastern grey kangaroos (Macropus giganteus), 50 Tasmanian devils (Sarcophilus harrisii) and 33 common wombats (Vombatus ursinius). In total, six novel herpesviruses (one alphaherpesvirus and five gammaherpesviruses) were identified in various host species. The overall prevalence of detection of herpesvirus DNA in our study population was 27.2% (95% confidence interval (CI) of 22.6-32.2%), but this varied between species and reached as high as 45.4% (95% CI 28.1-63.7%) in common wombats. Serum antibodies to two closely related macropodid herpesviruses (macropodid herpesvirus 1 and 2) were detected in 44.3% (95% CI 33.1-55.9%) of animals tested. This also varied between species and was as high as 92% (95% CI 74.0-99.0%) in eastern grey kangaroos. A number of epidemiological variables were identified as positive predictors for the presence of herpesvirus DNA in the marsupial samples evaluated. The most striking association was observed in koalas, where the presence of Chlamydia pecorum DNA was strongly associated with the presence of herpesvirus DNA (Odds Ratio = 60, 95% CI 12.1-297.8). Our results demonstrate the common presence of herpesviruses in Australian marsupials and provide directions for future research.


A case-comparison study of the subdural evacuating port system in treating chronic subdural hematomas.
The Subdural Evacuating Port System (SEPS) was recently introduced as a novel method of treating chronic subdural hematomas (SDHs). This system is a variation of the existing twist-drill craniostomy methods for treating chronic SDH. Compared with craniotomy or bur hole treatment of chronic SDH, this system offers the possibility of treatment at bedside without general anesthesia. In comparison with existing twist-drill methods, the system theoretically offers the advantage of a hermetically closed system that can evacuate a hematoma without an intracranial catheter. The authors performed a case-control study of all chronic SDHs treated at a single institution over a 5-year period and compared the efficacy and safety of the SEPS to bur hole evacuation. Patients were matched for age, injury mechanism, medical comorbidities, use of anticoagulation, and radiographic appearance of the SDH. The primary outcome of interest was the recurrence rate in each group, which was evaluated by radiographic evidence as well as the number of patients requiring a second procedure. Secondary outcomes examined were mortality, infection, acute hematoma formation, seizure, length of hospital stay, length of intensive care unit stay, and discharge location. The authors found that there were no appreciable differences in symptoms on presentation, existing comorbidities, home medications, or laboratory values between the treatment groups. The average Hounsfield units of preoperative CT scanning was similar in both groups. Radiographic recurrence was statistically similar between the SEPS group (25.9%) and the bur hole group (18.5%; p = 0.37). Although there was a trend toward higher reoperation rates in the SEPS group, the need for a subsequent procedure was also statistically similar between the SEPS group (25.9%) and the bur hole group (14.8%; p = 0.25). The mortality rate was not significantly different between the SEPS group (9.5%) and the bur hole group (4.8%; p = 0.50). The SEPS procedure provided a mean reduction in SDH thickness of 27.3% compared with 37.9% with bur hole (p = 0.05) when comparing the preoperative CT scan with the first postoperative CT scan. The percentage of reduction in SDH thickness when comparing the preoperative CT scan with the most recent postoperative CT scan was 40.5% in the SEPS group and 45.4% in the bur hole group (p = 0.31). The SEPS offers an alternative type of twist-drill craniostomy for the treatment of chronic SDH with a trend toward higher recurrence in our experience. The efficacy and safety of SEPS is similar to that of other twist-drill methods reported in the literature. In the authors' experience, the efficacy of this treatment as measured by radiographic worsening or the need for a subsequent procedure is statistically similar to that of bur hole treatment. There was no difference in mortality or other adverse outcomes associated with SEPS.


Apoptosis resistance and PKC signaling: distinguishing features of high and low metastatic cells.
The complexity of the process of metastasis is widely recognized. We report herein on a recurrent feature of high compared to low metastatic cells that is linked to their ability to survive early after their arrival at secondary sites. Using novel fluorescent-based imaging strategies that assess tumor cell interaction with the lung microenvironment, we have determined that most high and low metastatic cells can be distinguished within 6 hours of their arrival in the lung and further that this difference is defined by the ability of high metastatic cells to resist apoptosis at the secondary site. Despite the complexity of the metastatic cascade, the performance of cells during this critical window is highly defining of their metastatic proclivity. To explore mechanisms, we next evaluated biochemical pathways that may be linked to this survival phenotype in highly metastatic cells. Interestingly, we found no association between the Akt survival pathway and this metastatic phenotype. Of all pathways examined, only protein kinase C (PKC) activation was significantly linked to survival of highly metastatic cells. These data provide a conceptual understanding of a defining difference between high and low metastatic cells. The connection to PKC activation may provide a biologic rationale for the use of PKC inhibition in the prevention of metastatic progression.


Comparison of low-intensity warfarin therapy with conventional-intensity warfarin therapy for long-term prevention of recurrent venous thromboembolism.
Warfarin is very effective in preventing recurrent venous thromboembolism but is also associated with a substantial risk of bleeding. After three months of conventional warfarin therapy, a lower dose of anticoagulant medication may result in less bleeding and still prevent recurrent venous thromboembolism. We conducted a randomized, double-blind study, in which 738 patients who had completed three or more months of warfarin therapy for unprovoked venous thromboembolism were randomly assigned to continue warfarin therapy with a target international normalized ratio (INR) of 2.0 to 3.0 (conventional intensity) or a target INR of 1.5 to 1.9 (low intensity). Patients were followed for an average of 2.4 years. Of 369 patients assigned to low-intensity therapy, 16 had recurrent venous thromboembolism (1.9 per 100 person-years), as compared with 6 of 369 assigned to conventional-intensity therapy (0.7 per 100 person-years; hazard ratio, 2.8; 95 percent confidence interval, 1.1 to 7.0). A major bleeding episode occurred in nine patients assigned to low-intensity therapy (1.1 events per 100 person-years) and eight patients assigned to conventional-intensity therapy (0.9 event per 100 person-years; hazard ratio, 1.2; 95 percent confidence interval, 0.4 to 3.0). There was no significant difference in the frequency of overall bleeding between the two groups (hazard ratio, 1.3; 95 percent confidence interval, 0.8 to 2.1). Conventional-intensity warfarin therapy is more effective than low-intensity warfarin therapy for the long-term prevention of recurrent venous thromboembolism. The low-intensity warfarin regimen does not reduce the risk of clinically important bleeding.


Quantitative assessment of human and pet exposure to Salmonella associated with dry pet foods.
Recent Salmonella outbreaks associated with dry pet foods and treats highlight the importance of these foods as previously overlooked exposure vehicles for both pets and humans. In the last decade efforts have been made to raise the safety of this class of products, for instance by upgrading production equipment, cleaning protocols, and finished product testing. However, no comprehensive or quantitative risk profile is available for pet foods, thus limiting the ability to establish safety standards and assess the effectiveness of current and proposed Salmonella control measures. This study sought to develop an ingredients-to-consumer quantitative microbial exposure assessment model to: 1) estimate pet and human exposure to Salmonella via dry pet food, and 2) assess the impact of industry and household-level mitigation strategies on exposure. Data on prevalence and concentration of Salmonella in pet food ingredients, production process parameters, bacterial ecology, and contact transfer in the household were obtained through literature review, industry data, and targeted research. A probabilistic Monte Carlo modeling framework was developed to simulate the production process and basic household exposure routes. Under the range of assumptions adopted in this model, human exposure due to handling pet food is null to minimal if contamination occurs exclusively before extrusion. Exposure increases considerably if recontamination occurs post-extrusion during coating with fat, although mean ingested doses remain modest even at high fat contamination levels, due to the low percent of fat in the finished product. Exposure is highly variable, with the distribution of doses ingested by adult pet owners spanning 3Log CFU per exposure event. Child exposure due to ingestion of 1g of pet food leads to significantly higher doses than adult doses associated with handling the food. Recontamination after extrusion and coating, e.g., via dust or equipment surfaces, may also lead to exposure due to the absence of pathogen reduction steps after extrusion or at consumer households. Exposure is potentially highest when Salmonella is transferred to human food that is left at growth-promoting conditions. This model can be applied to evaluate the impact of alternative Salmonella control measures during production, risk communication to consumers, and regulatory standards.


Chemical chaperones reduce ER stress and restore glucose homeostasis in a mouse model of type 2 diabetes.
Endoplasmic reticulum (ER) stress is a key link between obesity, insulin resistance, and type 2 diabetes. Here, we provide evidence that this mechanistic link can be exploited for therapeutic purposes with orally active chemical chaperones. 4-Phenyl butyric acid and taurine-conjugated ursodeoxycholic acid alleviated ER stress in cells and whole animals. Treatment of obese and diabetic mice with these compounds resulted in normalization of hyperglycemia, restoration of systemic insulin sensitivity, resolution of fatty liver disease, and enhancement of insulin action in liver, muscle, and adipose tissues. Our results demonstrate that chemical chaperones enhance the adaptive capacity of the ER and act as potent antidiabetic modalities with potential application in the treatment of type 2 diabetes.


Short-term regular aerobic exercise reduces oxidative stress produced by acute in the adipose microvasculature.
High blood pressure has been shown to elicit impaired dilation in the vasculature. The purpose of this investigation was to elucidate the mechanisms through which high pressure may elicit vascular dysfunction and determine the mechanisms through which regular aerobic exercise protects arteries against high pressure. Male C57BL/6J mice were subjected to 2 wk of voluntary running (~6 km/day) for comparison with sedentary controls. Hindlimb adipose resistance arteries were dissected from mice for measurements of flow-induced dilation (FID; with or without high intraluminal pressure exposure) or protein expression of NADPH oxidase II (NOX II) and superoxide dismutase (SOD). Microvascular endothelial cells were subjected to high physiological laminar shear stress (20 dyn/cm2) or static condition and treated with ANG II + pharmacological inhibitors. Cells were analyzed for the detection of ROS or collected for Western blot determination of NOX II and SOD. Resistance arteries from exercised mice demonstrated preserved FID after high pressure exposure, whereas FID was impaired in control mouse arteries. Inhibition of ANG II or NOX II restored impaired FID in control mouse arteries. High pressure increased superoxide levels in control mouse arteries but not in exercise mouse arteries, which exhibited greater ability to convert superoxide to H2O2 Arteries from exercised mice exhibited less NOX II protein expression, more SOD isoform expression, and less sensitivity to ANG II. Endothelial cells subjected to laminar shear stress exhibited less NOX II subunit expression. In conclusion, aerobic exercise prevents high pressure-induced vascular dysfunction through an improved redox environment in the adipose microvasculature.NEW & NOTEWORTHY We describe potential mechanisms contributing to aerobic exercise-conferred protection against high intravascular pressure. Subcutaneous adipose microvessels from exercise mice express less NADPH oxidase (NOX) II and more superoxide dismutase (SOD) and demonstrate less sensitivity to ANG II. In microvascular endothelial cells, shear stress reduced NOX II but did not influence SOD expression.


PLEKHA7 is an adherens junction protein with a tissue distribution and subcellular localization distinct from ZO-1 and E-cadherin.
The pleckstrin-homology-domain-containing protein PLEKHA7 was recently identified as a protein linking the E-cadherin-p120 ctn complex to the microtubule cytoskeleton. Here we characterize the expression, tissue distribution and subcellular localization of PLEKHA7 by immunoblotting, immunofluorescence microscopy, immunoelectron microscopy, and northern blotting in mammalian tissues. Anti-PLEKHA7 antibodies label the junctional regions of cultured kidney epithelial cells by immunofluorescence microscopy, and major polypeptides of M(r) approximately 135 kDa and approximately 145 kDa by immunoblotting of lysates of cells and tissues. Two PLEKHA7 transcripts ( approximately 5.5 kb and approximately 6.5 kb) are detected in epithelial tissues. PLEKHA7 is detected at epithelial junctions in sections of kidney, liver, pancreas, intestine, retina, and cornea, and its tissue distribution and subcellular localization are distinct from ZO-1. For example, PLEKHA7 is not detected within kidney glomeruli. Similarly to E-cadherin, p120 ctn, beta-catenin and alpha-catenin, PLEKHA7 is concentrated in the apical junctional belt, but unlike these adherens junction markers, and similarly to afadin, PLEKHA7 is not localized along the lateral region of polarized epithelial cells. Immunoelectron microscopy definitively establishes that PLEKHA7 is localized at the adherens junctions in colonic epithelial cells, at a mean distance of 28 nm from the plasma membrane. In summary, we show that PLEKHA7 is a cytoplasmic component of the epithelial adherens junction belt, with a subcellular localization and tissue distribution that is distinct from that of ZO-1 and most AJ proteins, and we provide the first description of its distribution and localization in several tissues.


A migratory northern ungulate in the pursuit of spring: jumping or surfing the green wave?
The forage-maturation hypothesis (FMH) states that herbivores migrate along a phenological gradient of plant development in order to maximize energy intake. Despite strong support for the FMH, the actual relationship between plant phenology and ungulate movement has remained enigmatic. We linked plant phenology (MODIS-normalized difference vegetation index [NDVI] data) and space use of 167 migratory and 78 resident red deer (Cervus elaphus), using a space-time-time matrix of "springness," defined as the instantaneous rate of green-up. Consistent with the FMH, migrants experienced substantially greater access to early plant phenology than did residents. Deer were also more likely to migrate in areas where migration led to greater gains in springness. Rather than "surfing the green wave" during migration, migratory red deer moved rapidly from the winter to the summer range, thereby "jumping the green wave." However, migrants and, to a lesser degree, residents did track phenological green-up through parts of the growing season by making smaller-scale adjustments in habitat use. Despite pronounced differences in their life histories, we found only marginal differences between male and female red deer in this study. Those differences that we did detect pointed toward additional constraints on female space-use tactics, such as those posed by calving and caring for dependent offspring. We conclude that whereas in some systems migration itself is a way to surf the green wave, in others it may simply be a means to reconnect with phenological spring at the summer range. In the light of ubiquitous anthropogenic environmental change, understanding the relationship between the green wave and ungulate space use has important consequences for the management and conservation of migratory ungulates and the phenomenon of migration itself.


Incidence and management of subdural hematoma/hygroma with variable- and fixed-pressure differential valves: a randomized, controlled study of programmable compared with conventional valves.
Shunt systems with differential pressure valves are prone to the complications of overdrainage. A programmable valve permits adjustment of the opening pressure of the valve. In this paper the authors report the incidence of subdural fluid collections in a randomized trial of programmable compared with conventional valves, and they describe methodologies used in management of this complication. A multiinstitutional, prospective, randomized trial of the Codman Hakim programmable valve and conventional fixed-pressure valves was undertaken. Two classes were defined: "new" and "replacement" valves. Randomization of the type of valve in each group was performed at each study site. Clinical and radiological studies were required at fixed intervals over a 104-week period. All complications were reported. The experimental valves were required to be reprogrammed after magnetic resonance imaging studies, but all other decisions regarding pressure setting were left to each investigator. Three hundred seventy-seven patients were randomized; 194 were treated with a programmable valve and 183 with a fixed-pressure valve. The two groups were statistically similar in demographic composition, as were the "new" and "replacement" categories. The investigators made 540 valve pressure changes (five per patient; range one-41 changes). More than half of the reprogramming adjustments were made in the first 3 months postplacement; 70% were made within 6 months. More than half of all reprogramming adjustments were required in a group of 30 patients. Four treatment modalities were observed: 1) 30% of the fluid collections resolved spontaneously (25% in the patients with programmable valves and 36.3% in those with conventional valves) and were largely found to be hygromas in infants and children; 2) four subdural fluid collections were unresolved and under observation; 3) the subdural hematoma was drained and the shunt removed (in 8.3% of patients with the programmable valve and 36.3% of those with the control valve); 4) the pressure of programmable valve was raised in 58% of patients (seven of 12), and this increase in opening pressure was a feature used by investigators to affect treatment. There was no significant difference in the incidence of subdural fluid collections between the programmable and fixed-pressure valve treatment groups. The programmable feature provided a considerable advantage in treatment when subdural collections occurred.


Explaining the increase in the prevalence of autism spectrum disorders: the proportion attributable to changes in reporting practices.
The prevalence of autism spectrum disorders (ASDs) has increased markedly in recent decades, which researchers have suggested could be caused in part by nonetiologic factors such as changes in diagnosis reporting practices. To our knowledge, no study has quantified the degree to which changes in reporting practices might explain this increase. Danish national health registries have undergone a change in diagnostic criteria in 1994 and the inclusion of outpatient contacts to health registries in 1995. To quantify the effect of changes in reporting practices in Denmark on reported ASD prevalence. We used a population-based birth cohort approach that includes information on all individuals with permanent residence in Denmark. We assessed all children born alive from January 1, 1980, through December 31, 1991, in Denmark (n=677915). The children were followed up from birth until ASD diagnosis, death, emigration, or the end of follow-up on December 31, 2011, whichever occurred first. The analysis uses a stratified Cox proportional hazards regression model with the changes in reporting practices modeled as time-dependent covariates. The change in diagnostic criteria in 1994 and the inclusion of outpatient diagnoses in 1995. Autism spectrum disorders. For Danish children born during the study period, 33% (95% CI, 0%-70%) of the increase in reported ASD prevalence could be explained by the change in diagnostic criteria alone; 42% (95% CI, 14%-69%), by the inclusion of outpatient contacts alone; and 60% (95% CI, 33%-87%), by the change in diagnostic criteria and the inclusion of outpatient contacts. Changes in reporting practices can account for most (60%) of the increase in the observed prevalence of ASDs in children born from 1980 through 1991 in Denmark. Hence, the study supports the argument that the apparent increase in ASDs in recent years is in large part attributable to changes in reporting practices.


Intensity and correlates of multidimensional problems in HIV patients receiving integrated palliative care in sub-Saharan Africa.
Despite global clinical guidance that HIV patients should have multidimensional care integrated into their management, there has been very limited data to guide practice since the advent of treatment. This study aimed to determine the three-day period intensity of problems (physical, psychological, social and spiritual) among HIV patients receiving integrated palliative care in sub-Saharan Africa, and to identify associations with problem severity. A sample of 230 consecutive adult patients attending five sites in South Africa and Uganda gave self-report data using a well-validated outcome scale. Multivariable regression models determine the association of patient characteristics with intensity of three scale factors. The most burdensome problems were (in descending order) pain, worry, symptoms, and adequate information to plan for the future. Interestingly, CD4 counts were available on file for only 59.1% of patients. In multivariate analyses, being cared for at home was associated with poorer physical/psychological factor score (B=-0.192, 95% CI -2.566 -0.464, p=0.005), while being on ART was associated with better factor score (B=0.187, 95% CI=0.424 23.80, p=0.005). For the existential/spiritual factor, being cared for at home was associated with a worse factor score (B=-0.306, 95% CI -2.776 -1.128, p<0.001). ART use was not associated with either the interpersonal or spiritual/existential factors. These self-report data reveal a high burden of both physical and psychological problems, and that communication from professionals is insufficient. Patients receiving home care may require additional support to enhance wellbeing, and treatment may not affect interpersonal and existential/spiritual wellbeing.


Occupational physical activity, energy expenditure and 11-year progression of carotid atherosclerosis.
This study prospectively assessed the effects of occupational physical activity on atherosclerosis progression. This population-based prospective study of ultrasonographically assessed carotid intima media thickness (IMT) used repeated measures of occupational physical activity during baseline, 4-year, and 11-year examinations of 612 Finnish men 42-60 years of age at baseline. The association between five measures of energy expenditure and the 11-year change in maximum IMT was evaluated in regression models adjusting for 21 potential confounders, including biological factors, leisure-time physical activity, smoking, socioeconomic status, psychosocial job factors, and baseline health status. At baseline, 31% of all the men and 51% of those with ischemic heart disease (IHD) exceeded the recommended maximum levels of relative aerobic strain. All five measures of energy expenditure were significantly associated with adjusted 11-year IMT change. Significant interactions were found between IHD and several measures of energy expenditure. Maximum relative aerobic strain resulted in a 90% increase in IMT among the men with IHD compared with a 46% increase among those without IHD. The men with preexisting carotid stenosis also had higher rates of IMT progression than the men without this condition. This study shows that high energy expenditures at work are associated with an accelerated progression of atherosclerosis even after control for virtually all known cardiovascular risk factors, especially among older workers and workers with preexisting IHD or carotid artery stenosis. The findings support the hemodynamic theory of atherosclerosis and have important implications for workplace surveillance and disease prevention.


Prevalence and predictors for sustained remission in rheumatoid arthritis.
Remission is a key goal in managing rheumatoid arthritis (RA), with sustained remission as the preferred sequelae of short-term remission. However little is known about the predictors of sustained remission for patients reaching remission. Using two independent cohorts, we aimed to evaluate the prevalence and predictors for sustained remission. The study cohort consisted of subjects with RA from the Brigham and Women's Hospital Rheumatoid Arthritis Sequential Study (BRASS) and the Korean Observational Study Network for Arthritis (KORONA). We analyzed subjects who reached remission in 2009 with follow up data for two consecutive years. Remission was defined by the Disease Activity Score 28- (DAS28-CRP) of less than 2.6. Sustained remission was defined as three consecutive annual visits in remission. Predictors for sustained remission were identified by multivariate logistic regression analysis. A total of 465 subjects were in remission in 2009. Sustained remission was achieved by 53 of 92 (57.5%) in BRASS and by 198 of 373 (53.1%) in KORONA. In multivariate analyses, baseline predictors of sustained remission were: disease duration less than 5 years [odds ratio (OR) 1.96, 95% confidence interval (95% CI) 1.08-3.58], Modified Health Assessment Questionnaire (MHAQ) score of 0 (OR 1.80, 95% CI 1.18-2.74), and non-use of oral glucocorticoid (OR 1.58, 95% CI 1.01-2.47). More than half of RA subjects in remission in 2009 remained in remission through 2011. Short disease duration, no disability, and non-use of oral glucocorticoid at baseline were associated with sustained remission.


High levels of unprotected anal intercourse and never testing for HIV among men who have sex with men in Nigeria: evidence from a cross-sectional survey for the need for innovative approaches to HIV prevention.
To describe sexual risk behaviour, correlates of unprotected anal intercourse (UAI) and never testing for HIV and its implications for HIV prevention interventions among men who have sex with men (MSM) in Nigeria and other similar contexts. A cross-sectional survey was administered to 712 MSM in Abuja, Ibadan and Lagos, recruited through respondent-driven sampling (RDS). Levels of sexual risk behaviour and never having tested for HIV prior to the survey were calculated using weighted data for each city and unweighted data for the pooled sample. Correlates of UAI and never testing for HIV were determined using multiple logistic regression. The risk for HIV and STI among MSM in Nigeria is high, with 43.4% reporting UAI at last sex, 45.1% never having been tested for HIV and 53.9% reporting exchange of sex for resources in the past 6 months. Correlates of UAI in multivariate analysis included living in Ibadan, marriage or cohabitation with a woman, identification as bisexual, not having tested for HIV and being HIV-positive. Correlates of not having tested for HIV in multivariate analysis included living in Ibadan, young age, less education, unemployment and report of UAI. HIV testing is low and associated with UAI. Findings merit targeted and innovative approaches for HIV prevention for MSM, especially access to HIV self-testing. Attention to social and structural determinants of health-seeking and sexual risk behaviour is also needed, including the criminalisation of homosexuality and social marginalisation of MSM.


Focusing through random media in space and time: a transmission matrix approach.
We exploit the evolution in time of the transmission matrix following pulse excitation of a random medium to focus radiation at a selected time delay t' and position r. The temporal profile of a focused microwave pulse is the same as the incident Gaussian pulse. The contrast in space at time t' of the focused wave is determined by the participation number of transmission eigenvalues M' and the size N' of the measured transmission matrix. The initial rise and subsequent decay of the contrast observed reflect the distribution of decay rates of the quasi-normal modes within the sample.


DNA damage induces Cdt1 proteolysis in fission yeast through a pathway dependent on Cdt2 and Ddb1.
Cdt1 is an essential protein required for licensing of replication origins. Here, we show that in Schizosaccharomyces pombe, Cdt1 is proteolysed in M and G1 phases in response to DNA damage and that this mechanism seems to be conserved from yeast to Metazoa. This degradation does not require Rad3 and Cds1, indicating that it is independent of classic DNA damage and replication checkpoint pathways. Damage-induced degradation of Cdt1 is dependent on Cdt2 and Ddb1, which are components of a Cul4 ubiquitin ligase. We also show that Cdt2 and Ddb1 are needed for cell-cycle changes in Cdt1 levels in the absence of DNA damage. Cdt2 and Ddb1 have been shown to be involved in the degradation of the Spd1 inhibitor of ribonucleotide reductase after DNA damage, and we speculate that Cdt1 downregulation might contribute to genome stability by reducing demand on dNTP pools during DNA repair.


Cost-effectiveness of precision medicine in the fourth-line treatment of metastatic lung adenocarcinoma: An early decision analytic model of multiplex targeted sequencing.
To identify parameters that drive the cost-effectiveness of precision medicine by comparing the use of multiplex targeted sequencing (MTS) to select targeted therapy based on tumour genomic profiles to either no further testing with chemotherapy or no further testing with best supportive care in the fourth-line treatment of metastatic lung adenocarcinoma. A combined decision tree and Markov model to compare costs, life-years, and quality-adjusted life-years over a ten-year time horizon from an Australian healthcare payer perspective. Data sources included the published literature and a population-based molecular cohort study (Cancer 2015). Uncertainty was assessed using deterministic sensitivity analyses and quantified by estimating expected value of perfect/partial perfect information. Uncertainty due to technological/scientific advancement was assessed through a number of plausible future scenario analyses. Point estimate incremental cost-effective ratios indicate that MTS is not cost-effective for selecting fourth-line treatment of metastatic lung adenocarcinoma. Lower mortality rates during testing and for true positive patients, lower health state utility values for progressive disease, and targeted therapy resulting in reductions in inpatient visits, however, all resulted in more favourable cost-effectiveness estimates for MTS. The expected value to decision makers of removing all current decision uncertainty was estimated to be between AUD 5,962,843 and AUD 13,196,451, indicating that additional research to reduce uncertainty may be a worthwhile investment. Plausible future scenarios analyses revealed limited improvements in cost-effectiveness under scenarios of improved test performance, decreased costs of testing/interpretation, and no biopsy costs/adverse events. Reductions in off-label targeted therapy costs, when considered together with the other scenarios did, however, indicate more favourable cost-effectiveness of MTS. As more clinical evidence is generated for MTS, the model developed should be revisited and cost-effectiveness re-estimated under different testing scenarios to further understand the value of precision medicine and its potential impact on the overall health budget.


Insulin resistance and cognitive performance in type 2 diabetes - The Maastricht study.
Type 2 diabetes, hyperinsulinemia, and insulin resistance are associated with cognitive impairment. Experimental studies indicate that insulin signaling in the brain is related to cognitive performance. Here we evaluated whether insulin-related variables contribute to the variance in cognitive performance among individuals with type 2 diabetes. A total of 806 individuals with type 2 diabetes (mean age 62±8years, HbA1c 6.9±1.1%) completed a neuropsychological test battery. Insulin-related variables evaluated were: fasting plasma insulin, C-peptide, and the Homeostasis Model Assessment (HOMA2-IR; in individuals without insulin treatment; n=641). The unadjusted coefficient of determination (R2), obtained from multiple linear regression analyses, was used to estimate the proportion of variance in cognition explained by insulin-related variables. Sex, age, and educational level together explained 18.0% (R2) of the variance in memory function, 26.5% in information processing speed, and 22.8% in executive function and attention. Fasting insulin, C-peptide, or HOMA2-IR did not increase the explained variance (maximum ΔR2 0.3%, P≥0.14). Similar results were obtained when insulin-related variables were added to models that additionally included glycemic control, cardiovascular risk factors, and depression. Our results show that measures of peripheral insulin resistance are unrelated to cognitive performance among individuals with adequately controlled type 2 diabetes.


Glycation as the glucose link to diabetic complications.
Hyperglycemia is considered a key causal factor in the development of diabetic vascular complications and can mediate its adverse effects through multiple pathways. This was confirmed for microangiopathy in the Diabetes Control and Complications Trial study for type 1 diabetes and corroborated for type 2 diabetes by the United Kingdom Prospective Diabetes Study published in 1998. Prevention of diabetic complications requires at least control of glycemia. This article briefly summarizes the evidence that strongly supports the role of hyperglycemia in vascular complications. After outlining the role of the polyol pathway, protein kinase C, and oxidative stress, the author focuses on one of the key biochemical mechanisms for this pathologic process: the direct deleterious action of glucose and other sugars on proteins, known as glycation or nonenzymatic glycosylation. Results of animal studies and phase III clinical trials reveal that the inhibition of this process attenuates the development of a range of these complications.