The stress-activated protein kinase FgOS-2 is a key regulator in the life cycle of the cereal pathogen Fusarium graminearum.
Fusarium graminearum is one of the most destructive pathogens of cereals and a threat to food and feed production worldwide. It is an ascomycetous plant pathogen and the causal agent of Fusarium head blight disease in small grain cereals and of cob rot disease in maize. Infection with F. graminearum leads to yield losses and mycotoxin contamination. Zearalenone (ZEA) and deoxynivalenol (DON) are hazardous mycotoxins; the latter is necessary for virulence toward wheat. Deletion mutants of the F. graminearum orthologue of the Saccharomyces cerevisiae Hog1 stress-activated protein kinase, FgOS-2 (ΔFgOS-2), showed drastically reduced in planta DON and ZEA production. However, ΔFgOS-2 produced even more DON than the wild type under in vitro conditions, whereas ZEA production was similar to that of the wild type. These deletion strains are dramatically reduced in pathogenicity toward maize and wheat. We constitutively expressed the fluorescent protein dsRed in the deletion strains and the wild type. Microscopic analysis revealed that ΔFgOS-2 is unable to reach the rachis node at the base of wheat spikelets. During vegetative growth, ΔFgOS-2 strains exhibit increased resistance against the phenylpyrrole fludioxonil. Growth of mutant colonies on agar plates supplemented with NaCl is reduced but conidia formation remained unchanged. However, germination of mutant conidia on osmotic media is severely impaired. Germ tubes are swollen and contain multiple nuclei. The deletion mutants completely fail to produce perithecia and ascospores. Furthermore, FgOS-2 also plays a role in reactive oxygen species (ROS)-related signaling. The transcription and activity of fungal catalases is modulated by FgOS-2. Among the genes regulated by FgOS-2, we found a putative calcium-dependent NADPH-oxidase (noxC) and the transcriptional regulator of ROS metabolism, atf1. The present study describes new aspects of stress-activated protein kinase signaling in F. graminearum.


Thymus-autonomous T cell development in the absence of progenitor import.
Thymus function is thought to depend on a steady supply of T cell progenitors from the bone marrow. The notion that the thymus lacks progenitors with self-renewal capacity is based on thymus transplantation experiments in which host-derived thymocytes replaced thymus-resident cells within 4 wk. Thymus grafting into T cell-deficient mice resulted in a wave of T cell export from the thymus, followed by colonization of the thymus by host-derived progenitors, and cessation of T cell development. Compound Rag2(-/-)γ(c)(-/-)Kit(W/Wv) mutants lack competitive hematopoietic stem cells (HSCs) and are devoid of T cell progenitors. In this study, using this strain as recipients for wild-type thymus grafts, we noticed thymus-autonomous T cell development lasting several months. However, we found no evidence for export of donor HSCs from thymus to bone marrow. A diverse T cell antigen receptor repertoire in progenitor-deprived thymus grafts implied that many thymocytes were capable of self-renewal. Although the process was most efficient in Rag2(-/-)γ(c)(-/-)Kit(W/Wv) hosts, γ(c)-mediated signals alone played a key role in the competition between thymus-resident and bone marrow-derived progenitors. Hence, the turnover of each generation of thymocytes is not only based on short life span but is also driven via expulsion of resident thymocytes by fresh progenitors entering the thymus.


Large-scale brain networks in cognition: emerging methods and principles.
An understanding of how the human brain produces cognition ultimately depends on knowledge of large-scale brain organization. Although it has long been assumed that cognitive functions are attributable to the isolated operations of single brain areas, we demonstrate that the weight of evidence has now shifted in support of the view that cognition results from the dynamic interactions of distributed brain areas operating in large-scale networks. We review current research on structural and functional brain organization, and argue that the emerging science of large-scale brain networks provides a coherent framework for understanding of cognition. Critically, this framework allows a principled exploration of how cognitive functions emerge from, and are constrained by, core structural and functional networks of the brain.


Salmonella in eggs: From shopping to consumption-A review providing an evidence-based analysis of risk factors.
Nontyphoidal salmonellae are among the most prevalent foodborne pathogens causing gastrointestinal infections worldwide. A high number of cases and outbreaks of salmonellosis are associated with the consumption of eggs and egg products, and several of these occur at the household level. The aim of the current study is to critically evaluate the current status of knowledge on Salmonella in eggs from a consumer's perspective, analyzing the hazard occurrence and the good practices that should be applied to reduce salmonellosis risk. Following a HACCP (Hazard Analysis and Critical Control Point) based approach, some steps along the food journey were identified as Critical Consumer Handling (CCH)-steps in which consumers, through their behavior or choice, can significantly reduce the level of Salmonella in eggs and egg products. From shopping/collecting to consumption, each of these steps is discussed in this review to provide an evidence-based overview of risk factors of human salmonellosis related to egg consumption. The main message to consumers is to choose Salmonella-free eggs (those that some official entity or producer guarantees that does not contain Salmonella), when available, especially for dishes that are not fully heat treated. Second, as guaranteed Salmonella-free eggs are only available in a few countries, refrigerated storage from the point of collection and proper cooking will significantly reduce the risk of salmonellosis. This will require a revision of the actual recommendations/regulations, as not all ensure that eggs are maintained at temperatures that prevent growth of Salmonella from collection until the time of purchasing.


Cost-effectiveness analysis of a brief intervention delivered to problem drinkers presenting at an inner-city hospital emergency department.
Alcohol screening and brief intervention (SBI) has gained widespread acceptance as an effective method for reducing problem drinking in at-risk populations. This study examines the cost and cost-effectiveness of an SBI pilot program delivered in an inner-city hospital emergency department (ED) to a traditionally underserved population. A total of 1,036 subjects were screened for problem drinking during their visit to an ED. Eligible participants (N = 294) were randomly assigned to either a brief intervention group or a control group. As the result of attrition, a final sample of 194 (90 brief intervention; 104 control) participants remained at follow-up. The intervention consisted of a brief counseling session and a health information packet. The control group received only the packet. Intervention cost data were collected and analyzed using the Drug Abuse Treatment Cost Analysis Program. Selected outcomes at the 3-month follow-up included the raw Alcohol Use Disorders Identification Test score, average weekly number of drinks and engaging in heavy drinking in the past month (>6 drinks on one occasion for men, >4 for women). Outcome differences between the intervention and control groups were estimated with both bivariate and multivariate techniques. The average economic cost of the brief intervention was dollars 632 per subject, of which screening (dollars 497) was the largest component. In all cases, intervention subjects had better 3-month outcomes than control subjects, but the differences were not always statistically significant. Cost-effectiveness ratios were relatively small for all three outcomes, suggesting this type of intervention has the potential to be cost-effective under full implementation. The preliminary results demonstrate the potential advantage of further research in this area with larger samples and a longer follow-up period.


Patient Handoffs: Is Cross Cover or Night Shift Better?
Studies show singular handoffs between health care providers to be risky. Few describe sequential handoffs or compare handoffs from different provider types. We investigated the transfer of information across 2 handoffs using a piloted survey instrument. We compared cross-cover (every fourth night call) with dedicated night-shift residents. Surveys assessing provider knowledge of hospitalized patients were administered to pediatric residents. Primary teams were surveyed about their handoff upon completion of daytime coverage of a patient. Night-shift or cross-covering residents were surveyed about their handoff of the same patient upon completion of overnight coverage. Pediatric hospitalists rated the consistency of information between the surveys. Absolute difference was calculated between the 2 providers' rating of a patient's (a) complexity and (b) illness severity. Scores were compared across provider type. Fifty-nine complete handoff pairs were obtained. Fourteen and 45 handoff surveys were completed by a cross-covering and a night-shift provider, respectively. There was no significant difference in information consistency between primary and night-shift (median, 4.0; interquartile range [IQR], 3-4) versus primary and cross-covering providers (median, 4.0; IQR, 3-4). There was no significant difference in median patient complexity ratings (night shift, 3.0; IQR, 1-5, versus cross cover, 3.5; IQR, 1-5) or illness severity ratings (night shift, 2.0; IQR, 1-4, versus cross-cover, 3.0; IQR, 1-6) when comparing provider types giving a handoff. We did not find a difference in physicians' transfer of information during 2 handoffs among providers taking traditional call or on night shift. Development of tools to measure handoff consistency is needed.


OPTICAL COHERENCE TOMOGRAPHY FINDINGS IN CYTOMEGALOVIRUS RETINITIS: A Longitudinal Study.
To evaluate the vitreal, retinal, and choroidal features using spectral domain optical coherence tomography (SD-OCT) in eyes affected by cytomegalovirus (CMV) retinitis. Patients diagnosed with either active or inactive CMV retinitis were included in the study. Complete ophthalmic examination, serial color fundus photography, and SD-OCT (with and without enhanced depth imaging function) were performed for all the subjects at baseline and follow-up visits. The SD-OCT images were analyzed by two independent graders to evaluate the structural changes in areas of CMV retinitis. Prevalence data for vitreal, retinal, and choroidal SD-OCT features were collected. Twelve eyes from 9 patients (6 males, mean age: 52.7 ± 10.3 years) were enrolled. Nine eyes were diagnosed with active CMV retinitis at baseline. Active disease SD-OCT characteristic findings included nebulous vitritis (100%), posterior hyaloid thickening (83.3%), epiretinal membrane (100%), and retinal swelling (100%). Two distinct patterns of chorioretinal involvement were observed in active retinitis: 1) full-thickness retinitis (Full thickness retinitis) (n = 7 eyes) with choriocapillaris alterations and retinal pigment epithelial thickening and 2) cavernous retinitis (n = 3 eyes) characterized by inner retinal hyperreflectivity, large empty spaces in outer nuclear layer, and bridges of retinal tissue but retinal pigment epithelium and choriocapillaris sparing. Patients with cavernous retinitis develop retinal detachment during follow-up. Eyes with Full thickness retinitis developed choriocapillaris atrophy and choroidal thinning and retinal scars as the lesions healed. There are two distinct patterns of chorioretinal involvement in CMV retinitis. SD-OCT is a useful tool in the diagnosis, management, and prediction of the outcome of CMV retinitis.


Peroxisome Proliferator Activated Receptor Gamma Controls Mature Brown Adipocyte Inducibility through Glycerol Kinase.
Peroxisome proliferator-activated receptors (PPARs) have been suggested as the master regulators of adipose tissue formation. However, their role in regulating brown fat functionality has not been resolved. To address this question, we generated mice with inducible brown fat-specific deletions of PPARα, β/δ, and γ, respectively. We found that both PPARα and β/δδ are dispensable for brown fat function. In contrast, we could show that ablation of PPARγ in vitro and in vivo led to a reduced thermogenic capacity accompanied by a loss of inducibility by β-adrenergic signaling, as well as a shift from oxidative fatty acid metabolism to glucose utilization. We identified glycerol kinase (Gyk) as a partial mediator of PPARγ function and could show that Gyk expression correlates with brown fat thermogenic capacity in human brown fat biopsies. Thus, Gyk might constitute the link between PPARγ-mediated regulation of brown fat function and activation by β-adrenergic signaling.


Long-term results of the Leeds-Keio anterior cruciate ligament reconstruction.
This paper discusses the long-term results of the anterior cruciate ligament (ACL) reconstruction with the Leeds-Keio (LK) prosthetic ligament. For this type of reconstruction we used arthrotomy and an arthroscopy-assisted technique. The fixation was obtained with two bone plugs, and the distal portion was also attached with a staple. A postoperative protocol was used with a progressive range of motion and weight bearing after 50 days. We performed 50 LK operations in professional and amateur athletes aged 17-39 years with an isolated anterior instability. We reviewed at follow-up (5-7 years) 37 patients; 8 were lost, and 5 had a subsequent failure. At the Lysholm score the patients were classified: 19 excellent, 13 good, 3 fair, and 2 poor. At the IKDC grading the patients were classified as follows: 2 class A, 22 B, 8 C, and 5 D. The Lachmann test was 1+ in 15 patients, 2+ in 7, 3+ in 2, and negative in 13; pivot shift was 1+ in 9, 2+ in 7, 3+ in 2, and negative in 25. Results of the KT 1000 test at 30 lb side to side was < 3 mm in 23 patients, 3-5 mm in 6, 6-10 mm in 6, and > 10 mm in 2. In view of the results observed and the progressive deterioration over the years, this procedure should no longer be performed as an ACL substitute.


Community-based interventions for the prevention and control of helmintic neglected tropical diseases.
In this paper, we aim to systematically analyze the effectiveness of community-based interventions (CBIs) for the prevention and control of helminthiasis including soil-transmitted helminthiasis (STH) (ascariasis, hookworms, and trichuriasis), lymphatic filariasis, onchocerciasis, dracunculiasis, and schistosomiasis. We systematically reviewed literature published before May 2013 and included 32 studies in this review. Findings from the meta-analysis suggest that CBIs are effective in reducing the prevalence of STH (RR: 0.45, 95% CI: 0.38, 0.54), schistosomiasis (RR: 0.40, 95% CI: 0.33, 0.50), and STH intensity (SMD: -3.16, 95 CI: -4.28, -2.04). They are also effective in improving mean hemoglobin (SMD: 0.34, 95% CI: 0.20, 0.47) and reducing anemia prevalence (RR: 0.90, 95% CI: 0.85, 0.96). However, it did not have any impact on ferritin, height, weight, low birth weight (LBW), or stillbirths. School-based delivery significantly reduced STH (RR: 0.49, 95% CI: 0.39, 0.63) and schistosomiasis prevalence (RR: 0.50, 95% CI: 0.33, 0.75), STH intensity (SMD: -0.22, 95% CI: -0.26, -0.17), and anemia prevalence (RR: 0.87, 95% CI: 0.81, 0.94). It also improved mean hemoglobin (SMD: 0.24, 95% CI: 0.16, 0.32). We did not find any conclusive evidence from the quantitative synthesis on the relative effectiveness of integrated and non-integrated delivery strategies due to the limited data available for each subgroup. However, the qualitative synthesis from the included studies supports community-based delivery strategies and suggests that integrated prevention and control measures are more effective in achieving greater coverage compared to the routine vertical delivery, albeit it requires an existing strong healthcare infrastructure. Current evidence suggests that effective community-based strategies exist and deliver a range of preventive, promotive, and therapeutic interventions to combat helminthic neglected tropical diseases (NTDs). However, there is a need to implement and evaluate efficient integrated programs with the existing disease control programs on a larger scale throughout resource-limited regions especially to reach the unreachable.


Tetradecylthioacetic acid increases hepatic mitochondrial β-oxidation and alters fatty acid composition in a mouse model of chronic inflammation.
The administration of tetradecylthioacetic acid (TTA), a hypolipidemic and anti-inflammatory modified bioactive fatty acid, has in several experiments based on high fat diets been shown to improve lipid transport and utilization. It was suggested that increased mitochondrial and peroxisomal fatty acid oxidation in the liver of Wistar rats results in reduced plasma triacylglycerol (TAG) levels. Here we assessed the potential of TTA to prevent tumor necrosis factor (TNF) α-induced lipid modifications in human TNFα (hTNFα) transgenic mice. These mice are characterized by reduced β-oxidation and changed fatty acid composition in the liver. The effect of dietary treatment with TTA on persistent, low-grade hTNFα overexpression in mice showed a beneficial effect through decreasing TAG plasma concentrations and positively affecting saturated and monounsaturated fatty acid proportions in the liver, leading to an increased anti-inflammatory fatty acid index in this group. We also observed an increase of mitochondrial β-oxidation in the livers of TTA treated mice. Concomitantly, there were enhanced plasma levels of carnitine, acetyl carnitine, propionyl carnitine, and octanoyl carnitine, no changed levels in trimethyllysine and palmitoyl carnitine, and a decreased level of the precursor for carnitine, called γ-butyrobetaine. Nevertheless, TTA administration led to increased hepatic TAG levels that warrant further investigations to ascertain that TTA may be a promising candidate for use in the amelioration of inflammatory disorders characterized by changed lipid metabolism due to raised TNFα levels.


Ser46 phosphorylation of p53 is an essential event in prolyl-isomerase Pin1-mediated p53-independent apoptosis in response to heat stress.
Heat stroke has increased in frequency worldwide in recent years and continues to have a high morbidity and mortality. Identification of the mechanisms mediating heat stoke is important and necessary. Our preliminary study revealed heat stress (HS)-induced apoptosis of vascular endothelial cells was associated with reactive oxygen species (ROS)-induced p53 translocation into mitochondria. Previous studies have suggested the prolyl-isomerase Pin1 regulates p53 functioning through specific binding to p53 phosphorylation sites. Based on these studies, we presumed Pin1 is a key intermediate in regulation of mitochondrial p53 translocation through a HS-induced ROS-p53 transcription-independent apoptosis pathway. In this context, we revealed p53 had a crucial role in a HS-induced mitochondrial apoptotic pathway, where p53 protein rapidly translocated into mitochondria in endothelial cells both in vitro and in vivo. In particular, HS caused an increase in p53 phosphorylation at Ser46 that facilitated interactions with phosphorylation-dependent prolyl-isomerase Pin1, which has a key role in promoting HS-induced localization of p53 to mitochondria. Furthermore, we also found ROS production was a critical mediator in HS-induced Pin1/p53 signaling and was involved in regulating mitochondrial apoptosis pathway activation. Therefore, we have contributed to our profound understanding of the mechanism underlying HS-induced endothelial dysfunction in an effort to reduce the mortality and morbidity of heat stroke.


A retrospective characterization of worsening renal function in patients with acute decompensated heart failure receiving nesiritide.
Nesiritide is approved by Food and Drug Administration (FDA) for the treatment of patients with acute decompensated heart failure (ADHF) due its ability to rapidly reduce cardiac filling pressures and improve dyspnea. Numerous studies have shown that renal dysfunction is associated with unfavorable outcomes in patients with heart failure. In addition, there have been reports suggesting that nesiritide may adversely affect renal function and mortality. The purpose of this retrospective analysis was to assess the effect of dose and duration of nesiritide use and the dose and duration of diuretic therapy on worsening renal function and increased in-hospital mortality in this patient population. Seventy-five patients who were hospitalized for ADHF and who were treated with nesiritide for at least 12 hours were reviewed retrospectively. The mean increase in SCr was 0.5 mg/dL (range 0 - 4.4 mg/dL). Thirty-six percent of patients (27/75) met the primary endpoint with an increase in SCr>0.5 mg/dL. Treatment dose and duration of nesiritide did not differ between those patients who had an increase in SCr>0.5 mg/dL and those who did not (p=0.44 and 0.61). Concomitant intravenous diuretics were used in 85% of patients with an increase in SCr >0.5 mg/dL compared to 90% of patients without an increase in SCr>0.5 mg/dL (p=0.57). The in-hospital mortality rate was also higher at 35% in those patients with an increase in creatinine >0.5 mg/dL compared to 11% in those without (p=0.01). Nesiritide was associated with an increase in SCr > 0.5 mg/dL in approximately one-third of patients. The increase occurred independently of dose, duration of nesiritide therapy, blood pressure changes, and concomitant intravenous diuretic use. However, the increase in SCr was associated with an increase in hospital stay and in hospital mortality consistent with previous reports in the literature.


Differential effects of non-REM and REM sleep on memory consolidation?
Sleep benefits memory consolidation. Previous theoretical accounts have proposed a differential role of slow-wave sleep (SWS), rapid-eye-movement (REM) sleep, and stage N2 sleep for different types of memories. For example the dual process hypothesis proposes that SWS is beneficial for declarative memories, whereas REM sleep is important for consolidation of non-declarative, procedural and emotional memories. In fact, numerous recent studies do provide further support for the crucial role of SWS (or non-REM sleep) in declarative memory consolidation. However, recent evidence for the benefit of REM sleep for non-declarative memories is rather scarce. In contrast, several recent studies have related consolidation of procedural memories (and some also emotional memories) to SWS (or non-REM sleep)-dependent consolidation processes. We will review this recent evidence, and propose future research questions to advance our understanding of the role of different sleep stages for memory consolidation.


Cannabinoid CB2 receptor potentiates obesity-associated inflammation, insulin resistance and hepatic steatosis.
Obesity-associated inflammation is of critical importance in the development of insulin resistance and non-alcoholic fatty liver disease. Since the cannabinoid receptor CB2 regulates innate immunity, the aim of the present study was to investigate its role in obesity-induced inflammation, insulin resistance and fatty liver. Murine obesity models included genetically leptin-deficient ob/ob mice and wild type (WT) mice fed a high fat diet (HFD), that were compared to their lean counterparts. Animals were treated with pharmacological modulators of CB2 receptors. Experiments were also performed in mice knock-out for CB2 receptors (Cnr2 -/-). In both HFD-fed WT mice and ob/ob mice, Cnr2 expression underwent a marked induction in the stromal vascular fraction of epididymal adipose tissue that correlated with increased fat inflammation. Treatment with the CB2 agonist JWH-133 potentiated adipose tissue inflammation in HFD-fed WT mice. Moreover, cultured fat pads isolated from ob/ob mice displayed increased Tnf and Ccl2 expression upon exposure to JWH-133. In keeping, genetic or pharmacological inactivation of CB2 receptors decreased adipose tissue macrophage infiltration associated with obesity, and reduced inductions of Tnf and Ccl2 expressions. In the liver of obese mice, Cnr2 mRNA was only weakly induced, and CB2 receptors moderately contributed to liver inflammation. HFD-induced insulin resistance increased in response to JWH-133 and reduced in Cnr2 -/- mice. Finally, HFD-induced hepatic steatosis was enhanced in WT mice treated with JWH-133 and blunted in Cnr2 -/- mice. These data unravel a previously unrecognized contribution of CB2 receptors to obesity-associated inflammation, insulin resistance and non-alcoholic fatty liver disease, and suggest that CB2 receptor antagonists may open a new therapeutic approach for the management of obesity-associated metabolic disorders.


Comparison of the prognostic values of preoperative inflammation-based parameters in patients with breast cancer.
Peripheral blood-derived inflammation-based markers, including C-reactive protein (CRP), neutrophil-to-lymphocyte ratio (NLR), lymphocyte-to-monocyte ratio (LMR), and platelet-to-lymphocyte ratio (PLR) are indicators of prognosis in various malignant tumors. The present study aimed to identify the inflammation-based parameters that are most suitable for predicting outcomes in patients with breast cancer. Two hundred ninety-six patients who underwent surgery for localized breast cancer were reviewed retrospectively. The association between clinicopathological factors and inflammation-based parameters were investigated. Univariate and multivariate Cox regression analyses were performed to identify independent prognostic indicators associated with disease-free survival (DFS). The NLR level correlated significantly with tumor size (P<0.05). The PLR level correlated with the expression of estrogen receptor and lymph node involvement (P<0.05). Univariate analysis revealed that lower CRP and PLR values as well as tumor size, lymph node involvement, and nuclear grade were significantly associated with superior DFS (CRP: P<0.01; PLR, tumor size, lymph node involvement, and nuclear grade: P<0.05). On multivariate analysis, CRP (hazard ratio [HR]: 2.85, 95% confidence interval [CI]: 1.03-7.88, P<0.05), PLR (HR: 2.61, 95% CI: 1.07-6.36, P<0.05) and nuclear grade (HR: 3.066, 95% CI: 1.26-7.49, P<0.05) were significant prognostic indicators of DFS in patients with breast cancer. Neither LMR nor NLR significantly predicted DFS. Both preoperative CRP and PLR values were independently associated with poor prognosis in patients with breast carcinoma; these were superior to other inflammation-based scores in terms of prognostic ability.


Embryonal neural tumours and cell death.
Medulloblastoma and neuroblastoma are malignant embryonal childhood tumours of the central and peripheral nervous systems, respectively, which often show poor clinical prognosis due to resistance to current chemotherapy. Both these tumours have deficient apoptotic machineries adopted from their respective progenitor cells. This review focuses on the specific background for tumour development, and highlights biological pathways that present potential targets for novel therapeutic approaches.


Helicobacter pylori cag pathogenicity island's role in B7-H1 induction and immune evasion.
During Helicobacter pylori (H. pylori) infection CD4+ T cells in the gastric lamina propria are hyporesponsive and polarized by Th1/Th17 cell responses controlled by Treg cells. We have previously shown that H. pylori upregulates B7-H1 expression on GEC, which, in turn, suppress T cell proliferation, effector function, and induce Treg cells in vitro. In this study, we investigated the underlying mechanisms and the functional relevance of B7-H1 induction by H. pylori infection to chronic infection. Using H. pylori wild type (WT), cag pathogenicity island (cag PAI-) and cagA- isogenic mutant strains we demonstrated that H. pylori requires its type 4 secretion system (T4SS) as well as its effector protein CagA and peptidoglycan (PG) fragments for B7-H1 upregulation on GEC. Our study also showed that H. pylori uses the p38 MAPK pathway to upregulate B7-H1 expression in GEC. In vivo confirmation was obtained when infection of C57BL/6 mice with H. pylori PMSS1 strain, which has a functional T4SS delivery system, but not with H. pylori SS1 strain lacking a functional T4SS, led to a strong upregulation of B7-H1 expression in the gastric mucosa, increased bacterial load, induction of Treg cells in the stomach, increased IL-10 in the serum. Interestingly, B7-H1-/- mice showed less Treg cells and reduced bacterial loads after infection. These studies demonstrate how H. pylori T4SS components activate the p38 MAPK pathway, upregulate B7-H1 expression by GEC, and cause Treg cell induction; thus, contribute to establishing a persistent infection characteristic of H. pylori.


Socio-economic inequality in multiple health complaints among adolescents: international comparative study in 37 countries.
To use comparable data from many countries to examine 1) socio-economic inequality in multiple health complaints among adolescents, 2) whether the countries' absolute wealth and economic inequality was associated with symptom load among adolescents, and 3) whether the countries' absolute wealth and economic inequality explained part of the individual level socio-economic variation in health complaints. The Health Behaviour in School-aged Children (HBSC) international study from 2005/06 provided data on 204,534 11-, 13- and 15-year old students from nationally random samples of schools in 37 countries in Europe and North America. The outcome measure was prevalence of at least two daily health complaints, measured by the HBSC Symptom Check List. We included three independent variables at the individual level (sex, age group, family affluence measured by the Family Affluence Scale FAS) and two macro level measures on the country's economic situation: wealth measured by Gross National Product (GNP) and distribution of income measured by the Gini coefficient. There was a significant socio-economic variation in health complaints in 31 of the 37 countries. The overall OR (95 % CI) for 2+ daily health complaints for all countries was 1.31 (1.27-1.36) in the medium versus high FAS group and 2.07 (2.00-2.14) in the low versus high FAS group. This socio-economic gradient in health complaints attenuated somewhat in the multilevel models which included macro level data. There was no association between GNP and health complaints. The OR for high symptom load was 1.35 (1.08-1.69) per 10 % increase in Gini coefficient. The socio-economic gradient in health complaints at the individual level was somewhat attenuated in the multilevel models which included macro level data. There was a significant association between low FAS and high level of health complaints in 30 of 37 countries. Health complaints increased significantly by increasing income inequality in the country.


Application of Consistency Criteria To Calculate BET Areas of Micro- And Mesoporous Metal-Organic Frameworks.
Metal-organic frameworks (MOFs) can exhibit exceptionally high surface areas, which are experimentally estimated by applying the BET theory to measured nitrogen isotherms. The Brunauer, Emmett, and Teller (BET)-estimated nitrogen monolayer loading is thus converted to a "BET area," but the meaning of MOF BET areas remains under debate. Recent emphasis has been placed on the usage of four so-called "BET consistency criteria." Using these criteria and simulated nitrogen isotherms for perfect crystals, we calculated BET areas for graphene and 25 MOFs having different pore-size distributions. BET areas were compared with their corresponding geometrically calculated, nitrogen-accessible surface areas (NASAs). Analysis of simulation snapshots elucidated the contributions of "pore-filling" and "monolayer-formation" to the nitrogen adsorption loadings in different MOF pores, revealing the origin of inaccuracies in BET-calculated monolayer loadings, which largely explain discrepancies between BET areas and NASAs. We also find that even if all consistency criteria are satisfied, the BET calculation can significantly overestimate the true monolayer loading, especially in MOFs combining mesopores (d ≥ 20 Å) and large micropores (d = 10-20 Å), due to the overlap of pore-filling and monolayer-formation regimes of these two kinds of pores. While it is not always possible to satisfy all consistency criteria, it is critical to minimize the deviation from these criteria during BET range selection to consistently compare BET areas of different MOFs and for comparing simulated and experimental BET areas of a given MOF. To accurately assess the quality of a MOF sample, it is best to compare experimental BET areas with simulated BET areas rather than with calculated NASAs.


Assessing Time-Resolved fNIRS for Brain-Computer Interface Applications of Mental Communication.
Brain-computer interfaces (BCIs) are becoming increasingly popular as a tool to improve the quality of life of patients with disabilities. Recently, time-resolved functional near-infrared spectroscopy (TR-fNIRS) based BCIs are gaining traction because of their enhanced depth sensitivity leading to lower signal contamination from the extracerebral layers. This study presents the first account of TR-fNIRS based BCI for "mental communication" on healthy participants. Twenty-one (21) participants were recruited and were repeatedly asked a series of questions where they were instructed to imagine playing tennis for "yes" and to stay relaxed for "no." The change in the mean time-of-flight of photons was used to calculate the change in concentrations of oxy- and deoxyhemoglobin since it provides a good compromise between depth sensitivity and signal-to-noise ratio. Features were extracted from the average oxyhemoglobin signals to classify them as "yes" or "no" responses. Linear-discriminant analysis (LDA) and support vector machine (SVM) classifiers were used to classify the responses using the leave-one-out cross-validation method. The overall accuracies achieved for all participants were 75% and 76%, using LDA and SVM, respectively. The results also reveal that there is no significant difference in accuracy between questions. In addition, physiological parameters [heart rate (HR) and mean arterial pressure (MAP)] were recorded on seven of the 21 participants during motor imagery (MI) and rest to investigate changes in these parameters between conditions. No significant difference in these parameters was found between conditions. These findings suggest that TR-fNIRS could be suitable as a BCI for patients with brain injuries.


The mucosal immune system for vaccine development.
Mucosal surfaces are continuously exposed to the external environment and therefore represent the largest lymphoid organ of the body. In the mucosal immune system, gut-associated lymphoid tissues (GALTs), including Peyer's patches and isolated lymphoid follicles, play an important role in the induction of antigen-specific immune responses in the gut. GALTs have unique organogenesis characteristics and interact with the network of dendritic cells and T cells for the simultaneous induction and regulation of IgA responses and oral tolerance. In these lymphoid tissues, antigens are up taken by M cells in the epithelial layer, and antigen-specific immune responses are subsequently initiated by GALT cells. Nasopharynx- and tear-duct-associated lymphoid tissues (NALTs and TALTs) are key organized lymphoid structures in the respiratory tract and ocular cavities, respectively, and have been shown to interact with each other. Mucosal surfaces are also characterized by host-microbe interactions that affect the genesis and maturation of mucosa-associated lymphoid tissues and the induction and regulation of innate and acquired mucosal immune responses. Because most harmful pathogens enter the body through mucosal surfaces by ingestion, inhalation, or sexual contact, the mucosa is a candidate site for vaccination. Mucosal vaccination has some physiological and practical advantages, such as decreased costs and reduced risk of needle-stick injuries and transmission of bloodborne diseases, and it is painless. Recently, the application of modern bioengineering and biochemical engineering technologies, including gene transformation and manipulation systems, resulted in the development of systems to express vaccine antigens in transgenic plants and nanogels, which will usher in a new era of delivery systems for mucosal vaccine antigens. In this review, based on some of our research group's thirty seven years of progress and effort, we highlight the unique features of mucosal immune systems and the application of mucosal immunity to the development of a new generation of vaccines.


Transition of Care Practices from Emergency Department to Inpatient: Survey Data and Development of Algorithm.
We aimed to assess the current scope of handoff education and practice among resident physicians in academic centers and to propose a standardized handoff algorithm for the transition of care from the emergency department (ED) to an inpatient setting. This was a cross-sectional survey targeted at the program directors, associate or assistant program directors, and faculty members of emergency medicine (EM) residency programs in the United States (U.S.). The web-based survey was distributed to potential subjects through a listserv. A panel of experts used a modified Delphi approach to develop a standardized algorithm for ED to inpatient handoff. 121 of 172 programs responded to the survey for an overall response rate of 70.3%. Our survey showed that most EM programs in the U.S. have some form of handoff training, and the majority of them occur either during orientation or in the clinical setting. The handoff structure from ED to inpatient is not well standardized, and in those places with a formalized handoff system, over 70% of residents do not uniformly follow it. Approximately half of responding programs felt that their current handoff system was safe and effective. About half of the programs did not formally assess the handoff proficiency of trainees. Handoffs most commonly take place over the phone, though respondents disagree about the ideal place for a handoff to occur, with nearly equivalent responses between programs favoring the bedside over the phone or face-to-face on a computer. Approximately two-thirds of responding programs reported that their residents were competent in performing ED to inpatient handoffs. Based on this survey and on the review of the literature, we developed a five-step algorithm for the transition of care from the ED to the inpatient setting. Our results identified the current trends of education and practice in transitions of care, from the ED to the inpatient setting in U.S. academic medical centers. An algorithm, which guides this process, is proposed to address the current gap in the standardized approach to ED to inpatient handoffs that were identified in the survey's assessment of needs.


The Use of Female Sex Workers Among Men in Nepal: Prevalence, STIs/HIV-Related Risk Behaviors, and Gender Ideology.
Heterosexual sex involving female sex workers (FSWs) is widely documented for its role in facilitating the spread of sexually transmitted infections (STIs)/HIV. Critical to such studies, and increasingly considered essential to HIV prevention efforts, is the gender constructs and power dynamics within relationships. However, little efforts have been made, which focus on male clients of FSWs, particularly on the relationship between gender ideologies and men's sexual contact with FSWs, within the Nepali context. The present study aims to fill this critical gap by assessing the prevalence of use of FSWs and its association with STIs/HIV-related risk behaviors and gender ideologies among Nepali men. We used data from the nationally representative Nepal Demographic Health Survey (NDHS) 2011. For the purpose of analyses, we included a sample of 4,121 men, aged 15-49 years. During data analyses, we used multivariate logistic regression models, adjusted for the following variables: age, region, residence, religion, educational level, wealth index, employment status, and cigarette smoking status. Of the total sample, approximately 5% reported the use of FSWs in their lifetime. In regression models, men who had sex with FSWs were more likely to report a history of STIs [adjusted odds ratio (aOR): 3.03; 95% confidence interval (CI): 1.69-5.43; P < 0.001], not using condom all the time (aOR: 1.31; 95% CI: 1.05-2.12; P = 0.010), more than one sexual partner (aOR: 3.75; 95% CI: 2.18-5.23; P < 0.001), and have had early sexual debut (aOR: 2.60; 95% CI: 1.85-3.67; P < 0.001). Respondents reporting the endorsement of violence against wives (aOR: 1.65; 95% CI: 1.01-2.84; P = 0.04) and male sexual entitlement (aOR: 1.63; 95% CI: 1.21-2.32; P = 0.001) were significantly more likely to report sexual contact with FSWs. Our findings highlight the need to develop and implement specifically tailored interventions toward male clients of FSWs, with a particular emphasis on promoting equitable gender roles and beliefs.


Dynamics of mismatched base pairs in DNA.
The structural dynamics of mismatched base pairs in duplex DNA have been studied by time-resolved fluorescence anisotropy decay measurements on a series of duplex oligodeoxynucleotides of the general type d[CGG(AP)GGC].d[GCCXCCG], where AP is the fluorescent adenine analogue 2-aminopurine and X = T, A, G, or C. The anisotropy decay is caused by internal rotations of AP within the duplex, which occur on the picosecond time scale, and by overall rotational diffusion of the duplex. The correlation time and angular range of internal rotation of AP vary among the series of AP.X mismatches, showing that the native DNA bases differ in their ability to influence the motion of AP. These differences are correlated with the strength of base-pairing interactions in the various AP.X mismatches. The interactions are strongest with X = T or C. The ability to discern differences in the strength of base-pairing interactions at a specific site in DNA by observing their effect on the dynamics of base motion is a novel aspect of the present study. The extent of AP stacking within the duplex is also determined in this study since it influences the excited-state quenching of AP. AP is thus shown to be extrahelical in the AP.G mismatch. The association state of the AP-containing oligodeoxynucleotide strand is determined from the temperature-dependent tumbling correlation time. An oligodeoxynucleotide triplex is formed with a particular base sequence in a pH-dependent manner.


Pre-hospital delay and emergency medical services in acute myocardial infarction.
Minimising total ischemic time (TIT) is important for improving clinical outcomes in patients with ST-segment elevation myocardial infarction who have undergone percutaneous coronary intervention (PCI). TIT has not shown a significant improvement due to persistent pre-hospital delay. This study aimed to investigate the risk factors associated with pre-hospital delay. Individuals enrolled in the Korea Acute Myocardial Infarction Registry-National Institutes of Health between 2011 and 2015 were included in this study. The study population was analyzed according to the symptom-to-door time (STDT; within 60 or > 60 minutes), and according to the type of hospital visit (emergency medical services [EMS], non-PCI center, or PCI center). A total of 4,874 patients were included in the analysis, of whom 28.4% arrived at the hospital within 60 minutes of symptom-onset. Old age (> 65 years), female gender, and renewed ischemia were independent predictors of delayed STDT. Utilising EMS was the only factor shown to reduce STDT within 60 minutes, even when cardiogenic shock was evident. The overall frequency of EMS utilisation was low (21.7%). Female gender was associated with not utilising EMS, whereas cardiogenic shock, previous myocardial infarction, familial history of ischemic heart disease, and off-hour visits were associated with utilising EMS. Factors associated with delayed STDT and not utilising EMS could be targets for preventive intervention to improve STDT and TIT.


Which Food Security Determinants Predict Adequate Vegetable Consumption among Rural Western Australian Children?
Improving the suboptimal vegetable consumption among the majority of Australian children is imperative in reducing chronic disease risk. The objective of this research was to determine whether there was a relationship between food security determinants (FSD) (i.e., food availability, access, and utilisation dimensions) and adequate vegetable consumption among children living in regional and remote Western Australia (WA). Caregiver-child dyads (n = 256) living in non-metropolitan/rural WA completed cross-sectional surveys that included questions on FSD, demographics and usual vegetable intake. A total of 187 dyads were included in analyses, which included descriptive and logistic regression analyses via IBM SPSS (version 23). A total of 13.4% of children in this sample had adequate vegetable intake. FSD that met inclusion criteria (p ≤ 0.20) for multivariable regression analyses included price; promotion; quality; location of food outlets; variety of vegetable types; financial resources; and transport to outlets. After adjustment for potential demographic confounders, the FSD that predicted adequate vegetable consumption were, variety of vegetable types consumed (p = 0.007), promotion (p = 0.017), location of food outlets (p = 0.027), and price (p = 0.043). Food retail outlets should ensure that adequate varieties of vegetable types (i.e., fresh, frozen, tinned) are available, vegetable messages should be promoted through food retail outlets and in community settings, towns should include a range of vegetable purchasing options, increase their reliance on a local food supply and increase transport options to enable affordable vegetable purchasing.


Role of nitric oxide and prostaglandin E2 in acute renal hypoperfusion.
Although acute renal ischaemia alters the production of various paracrines, there has been little investigation examining the role of intrarenal vasoactive substances. In the present study, we investigated the role of intrarenal nitric oxide and prostaglandins in modulating the acute renal hypoperfusion-induced alterations in renal function. After a 90% clipping of the left renal artery for 60 min, the clip was released, and the renal haemodynamics and sodium excretion were evaluated in both clipped and non-clipped kidneys of anaesthetized dogs. Furthermore, the changes in renal contents of nitrate/nitrite (NOx) and prostaglandin E2 (PGE2) were assessed by using the renal microdialysis technique. The release of the clipping elicited a gradual recovery of renal plasma flow and glomerular filtration rate, and a sustained increase in fractional sodium excretion (FENa) in the clipped kidney. Renal interstitial NOx was reduced in both the cortex (from 8.2 +/- 1.1 to 2.5 +/- 0.3 micromol/L, P < 0.01) and medulla (from 10.1 +/- 0.9 to 3.1 +/- 0.2 micromol/L, P < 0.01), but the levels gradually elevated after declamping. The treatment with nitro-l-arginine methylester only modestly impaired the recovery of renal plasma flow (RPF; at hour 4) and glomerular filtration rate (GFR; at hours 3 and 4 after declamping), without affecting FENa. Conversely, the renal PGE2 levels increased prominently upon the onset of ischaemia (medulla, from 149 +/- 19 to 378 +/- 39 pg/mL, P < 0.01; cortex, from 107 +/- 13 to 302 +/- 34 pg/mL, P < 0.01). Furthermore, the pretreatment with a non-specific cyclo-oxygenase (COX) inhibitor, sulpyrine, and a COX-2-specific inhibitor, NS398, prominently inhibited the increases in FENa induced by the acute renal arterial clipping in a similar manner. In conclusion, in acute renal hypoperfusion, nitric oxide (NO) plays a permissive role in the recovery of the renal haemodynamics. In contrast, sustained increases in renal PGE2 in both clipped and non-clipped kidneys indicate that the COX-2-mediated PGE2 contributes importantly to the failure of the sodium reabsorption in response to acute renal hypoperfusion.


Lower-extremity arterial disease in older hypertensive adults.
Lower-extremity arterial disease (LEAD) is common in older adults, particularly those with systolic hypertension. In a subgroup of 1,775 participants of the Systolic Hypertension in the Elderly Program, LEAD was assessed noninvasively by the ratio of the ankle to arm blood pressure, the ankle-arm index (AAI). LEAD was defined as an AAI of < or = 0.9 in either leg. The prevalence of LEAD was 25% in white men, 38% in black men, 23% in white women, and 41% in black women. About half of those with LEAD had mild disease (AAI, 0.8-0.9), and only 1-3% had a positive Rose questionnaire for intermittent claudication. The prevalence increased with age (p < 0.01) and was consistently higher in blacks than whites (p < 0.01), although there were no significant differences between men and women. Even in the absence of risk factors such as smoking and diabetes, blacks had a higher prevalence of LEAD than whites. Associations of LEAD with cardiovascular risk factors (high density lipoprotein cholesterol, systolic blood pressure, and smoking) appeared to be similar in blacks and whites, although relations were not always statistically significant in subgroups stratified by race and sex. Independent factors associated with the presence of LEAD included age, black race, smoking, diabetes mellitus, history of myocardial infarction or angina, systolic blood pressure, lower high density lipoprotein cholesterol, and body mass index. LEAD is common in older men and women with systolic hypertension, particularly blacks. However, very few have symptoms of claudication.(ABSTRACT TRUNCATED AT 250 WORDS)


Biopsies of the normal-appearing urothelium in primary bladder cancer.
The aim of the study was to determine the incidence of "positive" findings in biopsies of the normal-appearing urothelium near primary cancer and their influence on therapeutic decisions. Between January 2001 and October 2008, in 230 patients with primary bladder cancer during initial resection of tumor, we also performed random biopsy of surrounding normal-appearing urothelium. We analyzed retrospectively the number and type of positive biopsy findings and their impact on further treatment. There were 40% of patients (92/230) whose normal-appearing urothelium biopsy revealed pathological findings such as tumor tissue, Tis, and dysplasia. In 24.4% of patients, the stage of the primary tumor was Ta (32/131), in 50% it was T1 stage (30/61), and in 79% T2 stage (30/38). When we assessed the grade of malignancy, we found 18% of biopsies with G1 tumors (16/88), 33% with G2 tumors (19/59), and 69% with G3 tumors (57/83). Tumor tissue that was found in the normal-appearing urothelium in biopsy specimens in 13% of patients was in stage Ta (17/131), in 16% it was T1 stage (10/61), and in 39% of patients, the tumor was in T2 stage (15/38). Pathological findings of random biopsies were crucial in changing therapeutical decisions in 4.6% (9/192) of patients. Biopsy of the normal-appearing urothelial tissue is easy to perform and may help in identifying patients with high risk of disease progression and recurrence. Based on our results and results from the literature we recommend this simple tool as part of the routine management during transurethral resection of primary bladder cancer.


The dynamics of rising oil-coated bubbles: experiments and simulations.
Air bubbles rising through an aqueous medium have been studied extensively and are routinely used for the separation of particulates via froth flotation, a key step in many industrial processes. Oil-coated bubbles can be more effective for separating hydrophilic particles with low affinity for the air-water interface, but the rise dynamics of oil-coated bubbles has not yet been explored. In the present work, we report the first systematic study of the shape and rise trajectory of bubbles engulfed in a layer of oil. Results from direct observation of the coated bubbles with a high-speed camera are compared to computer simulations and confirm a pronounced effect of the oil coat on the bubble dynamics. We consistently find that the oil-coated bubbles display a more spherical shape and straighter trajectory, yet slower rise than uncoated bubbles of comparable size. These characteristics may provide practical benefits for flotation separations with oil-coated bubbles.


Chimeric antigen receptor T-cell therapy - assessment and management of toxicities.
Immunotherapy using T cells genetically engineered to express a chimeric antigen receptor (CAR) is rapidly emerging as a promising new treatment for haematological and non-haematological malignancies. CAR-T-cell therapy can induce rapid and durable clinical responses, but is associated with unique acute toxicities, which can be severe or even fatal. Cytokine-release syndrome (CRS), the most commonly observed toxicity, can range in severity from low-grade constitutional symptoms to a high-grade syndrome associated with life-threatening multiorgan dysfunction; rarely, severe CRS can evolve into fulminant haemophagocytic lymphohistiocytosis (HLH). Neurotoxicity, termed CAR-T-cell-related encephalopathy syndrome (CRES), is the second most-common adverse event, and can occur concurrently with or after CRS. Intensive monitoring and prompt management of toxicities is essential to minimize the morbidity and mortality associated with this potentially curative therapeutic approach; however, algorithms for accurate and consistent grading and management of the toxicities are lacking. To address this unmet need, we formed a CAR-T-cell-therapy-associated TOXicity (CARTOX) Working Group, comprising investigators from multiple institutions and medical disciplines who have experience in treating patients with various CAR-T-cell therapy products. Herein, we describe the multidisciplinary approach adopted at our institutions, and provide recommendations for monitoring, grading, and managing the acute toxicities that can occur in patients treated with CAR-T-cell therapy.


Testing the paradox of enrichment along a land use gradient in a multitrophic aboveground and belowground community.
In the light of ongoing land use changes, it is important to understand how multitrophic communities perform at different land use intensities. The paradox of enrichment predicts that fertilization leads to destabilization and extinction of predator-prey systems. We tested this prediction for a land use intensity gradient from natural to highly fertilized agricultural ecosystems. We included multiple aboveground and belowground trophic levels and land use-dependent searching efficiencies of insects. To overcome logistic constraints of field experiments, we used a successfully validated simulation model to investigate plant responses to removal of herbivores and their enemies. Consistent with our predictions, instability measured by herbivore-induced plant mortality increased with increasing land use intensity. Simultaneously, the balance between herbivores and natural enemies turned increasingly towards herbivore dominance and natural enemy failure. Under natural conditions, there were more frequently significant effects of belowground herbivores and their natural enemies on plant performance, whereas there were more aboveground effects in agroecosystems. This result was partly due to the "boom-bust" behavior of the shoot herbivore population. Plant responses to herbivore or natural enemy removal were much more abrupt than the imposed smooth land use intensity gradient. This may be due to the presence of multiple trophic levels aboveground and belowground. Our model suggests that destabilization and extinction are more likely to occur in agroecosystems than in natural communities, but the shape of the relationship is nonlinear under the influence of multiple trophic interactions.


Medication-related Self-management Behaviors among Arthritis Patients: Does Attentional Coping Style Matter?
The aim of this study was to investigate the relationship between the attentional coping styles (monitoring and blunting) of rheumatoid arthritis (RA) and osteoarthritis (OA) patients and: (a) receipt of medication information; (b) receipt of conflicting medication information; (c) ambiguity aversion; (d) medication-related discussions with doctors and spouse/partners; and (e) medication adherence. A sample of 328 adults with a self-reported diagnosis of arthritis (RA n=159; OA n=149) completed an Internet-based survey. Coping style was assessed using the validated short version of the Miller Behavioral Style Scale. Measures related to aspects of medication information receipt and discussion and validated measures of ambiguity aversion and medication adherence (Vasculitis Self-Management Survey) were collected. Pearson correlation coefficients, ANOVA, independent samples t-tests and multiple regression models were used to assess associations between coping style and the other variables of interest. Arthritis patients in our sample were more likely to be high monitors (50%) than high blunters (36%). Among RA patients, increased information-receipt was significantly associated with decreased monitoring (b = -1.06, p = .001). Among OA patients, increased information-receipt was significantly associated with increased blunting (b = .60, p = .02). In our sample of patients with arthritis, attentional coping style is not in accordance with the characteristic patterns outlined in the acute and chronic disease coping literature.


Baseline serum cholesterol is selectively associated with motor speed and not rates of cognitive decline: the Women's Health and Aging Study II.
Although several studies have investigated the association between cholesterol and dementia, few have examined cholesterol and decline across cognitive domains. We examined serum total and high-density lipoprotein (HDL) cholesterol, total-to-HDL ratio, and trajectories across cognitive domains. Participants were 436 community-residing women (70-79 years old) in the Women's Health and Aging Study II; they were screened to be physically high-functioning and cognitively intact at baseline. Cognition and other health-related variables were assessed at five intervals spanning 9 years. Cognitive assessments included Trail Making Test Parts A (TMT-A) and B (TMT-B), Hopkins Verbal Learning Test-Revised, Purdue Pegboard, and Mini-Mental State Examination (MMSE). The association between baseline levels of serum lipids and cognitive trajectories were evaluated using Generalized Estimating Equations (GEE). Covariates included age, education, race, vascular disease, serum creatinine, depression, and lipid-lowering medications. In multivariate analyses, baseline higher total (p =.02) and HDL (p =.03) cholesterol were associated with better performance on the Purdue Pegboard. Using clinical cholesterol cutoffs, baseline serum total cholesterol levels >240 mg/dL were associated with the best performance (p =.02). Baseline lipids were not associated with any other cognitive tests; there were no Lipid x Time interactions. Higher baseline serum lipid levels predicted better performance over time on a measure of motor speed, but not memory or psychomotor or executive functioning in this population of elderly women. This association suggests that peripheral cholesterol levels, measured in late-life, may not be a good predictor of subsequent cognitive decline. Future research examining peripheral cholesterol over the life span and its relationship with cognition is needed.


Seasonal and geographical variations in lung cancer prognosis in Norway. Does Vitamin D from the sun play a role?
Vitamin D derivatives can modulate proliferation and differentiation of cancer cells. Our main source of Vitamin D is ultraviolet (UV) radiation-induced synthesis in skin following sun exposure. UV measurements show that the ambient annual UV exposures increase by about 50% from north to south in Norway. As judged from the incidence rates of squamous cell carcinoma, the same is true for the average personal UV exposures. Solar ultraviolet B (UVB) (280-320nm) exhibits a strong seasonal variation with a minimum during the winter months. The present work aims at investigating the impact of season of diagnosis and residential region, both influencing the Vitamin D level, on the risk of death from lung cancer in patients diagnosed in Norway. Data on all incident cases of lung cancer between 1964 and 2000 were collected. Risk estimates were calculated as relative risk (RR), with 95% confidence intervals using Cox regression model. The seasonal variation of 25-hydroxyvitamin D was assessed from routine measurements of 15,616 samples performed at The Hormone Laboratory of Aker University Hospital. Our results indicate that season of diagnosis is of prognostic value for lung cancer patients, with a approximately 15% lower case fatality for young male patients diagnosed during autumn versus winter (RR=0.85; 95% CI, -0.73 to 0.99; p=0.04). Residing in a high UV region resulted in a further lowering of the death risk than residing in a low UV region. We propose, in agreement with earlier findings for prostate-, breast- colon cancer and Hodgkins lymphoma, that a high level of sun-induced 25-hydroxyvitamin D can be a prognostic advantage for certain groups of lung cancer patients, notably for young men. Lung cancer has for several decades been the leading cause of cancer-related mortality in men in Norway and during the last two decades, became the second most common cause of cancer-related death in women . There are two main types of lung cancer: small cell lung cancer for which chemotherapy is the primary treatment and non-small cell lung cancer, which in its early stages is treated primarily with surgery. Gender-related differences have been described in the literature with respect to survival after therapy, male gender being a significant independent negative prognostic factor . In Norway the 5 years relative survival for localized tumours is about 30% for females and 20% for males. Calcitriol, which is the most active form of Vitamin D, is involved in key regulatory processes such as proliferation, differentiation and apoptosis in a wide variety of cells . Mechanisms for these actions have been proposed to be the interaction of active Vitamin D derivatives with a specific nuclear receptor (VDR receptor) and/or with membrane targets . In vitro studies, performed with lung cancer cell lines, have shown an inhibitive effect of Vitamin D derivatives on cell-growth and proliferation . Furthermore, animal studies have demonstrated the capability of these compounds to suppress invasion, metastasis and angiogenesis in vivo , suggesting that administration of Vitamin D derivatives may be used as adjuvant therapy for lung cancer. Humans get optimal Vitamin D levels by exposure to sun or artificial ultraviolet B (UVB, 280-320nm) sources , and possibly also by consumption of food rich in this nutrient (fat fish, eggs, margarine, etc.) or of vitamin supplements . Among these sources, solar radiation appears to be the most important one . Thus, the Vitamin D status (assessed by the serum levels of 25-hydroxyvitamin D, calcidiol) exhibits a strong seasonal variation that parallels the seasonal change in the fluence of solar UVB that reaches the ground. During winter, the UVB fluence rate in the Nordic countries (50-71 degrees N) is below the level required for Vitamin D synthesis in skin . The maximal level of calcidiol is reached between the months July and September, and is 20-120% higher than the corresponding winter level . Recently we hypothesised that the seasonal variation of calcidiol might be of prognostic significance for colon-, breast- prostate cancer as well as for Hodgkins lymphoma in Norway. Patients diagnosed during summer and autumn have a better survival after standard treatment than patients diagnosed during the winter season . This might be a consequence of a higher Vitamin D level. An American study investigated the effect of season of surgery and recent Vitamin D intake on the survival of non-small cell lung cancer patients. The authors reported a significant beneficial joint effect of summer season and high Vitamin D intake compared with winter season and low Vitamin D intake while Vitamin D intake alone did not affect prognosis. Similar results were recently reported from a large study in United Kingdom involving over a million cancer patients including over 190,000 patients diagnosed with lung cancer . Norway (58-71 degrees N) has a significant north-south variation in UV fluence. This makes the country suitable for studies relating cancer epidemiology to UV levels . We investigated whether variations in UV, and, consequently, in Vitamin D level, influence the prognosis of lung cancer, using season of diagnosis and residential regions as variables. Survival data obtained for patients diagnosed over a 40 years period were compared with variations in serum Vitamin D levels obtained from routine measurements performed in The Hormone Laboratory of Aker University Hospital during the period 1996-2001. Seasonal and gender variations in Vitamin D level have been estimated from the analyses.


Diffusion-weighted Renal MRI at 9.4 Tesla Using RARE to Improve Anatomical Integrity.
Diffusion-weighted magnetic resonance imaging (DWI) is a non-invasive imaging technique sensitive to tissue water movement. By enabling a discrimination between tissue properties without the need of contrast agent administration, DWI is invaluable for probing tissue microstructure in kidney diseases. DWI studies commonly make use of single-shot Echo-Planar Imaging (ss-EPI) techniques that are prone to suffering from geometric distortion. The goal of the present study was to develop a robust DWI technique tailored for preclinical magnetic resonance imaging (MRI) studies that is free of distortion and sensitive to detect microstructural changes. Since fast spin-echo imaging techniques are less susceptible to B0 inhomogeneity related image distortions, we introduced a diffusion sensitization to a split-echo Rapid Acquisition with Relaxation Enhancement (RARE) technique for high field preclinical DWI at 9.4 T. Validation studies in standard liquids provided diffusion coefficients consistent with reported values from the literature. Split-echo RARE outperformed conventional ss-EPI, with ss-EPI showing a 3.5-times larger border displacement (2.60 vs. 0.75) and a 60% higher intra-subject variability (cortex = 74%, outer medulla = 62% and inner medulla = 44%). The anatomical integrity provided by the split-echo RARE DWI technique is an essential component of parametric imaging on the way towards robust renal tissue characterization, especially during kidney disease.


The integration of symbolic and non-symbolic representations of exact quantity in preschool children.
Preschoolers (n=62) completed tasks that tapped their knowledge of symbolic and non-symbolic exact quantities, their ability to translate among different representations of exact quantity (i.e., digits, number words, and non-symbolic quantities), and their non-symbolic, digit, and spoken number comparison skills (e.g., which is larger, 2 or 4?). As hypothesized, children's knowledge about non-symbolic exact quantities, spoken number words, and digits predicted their ability to map between symbolic and non-symbolic exact quantities. Further, their knowledge of the mappings between digits and non-symbolic quantities predicted symbolic number comparison (i.e., of spoken number words or written digits). Mappings between written digits and non-symbolic exact quantities developed later than the other mappings. These results support a model of early number knowledge in which integration across symbolic and non-symbolic representations of exact quantity underlies the development of children's number comparison skills.


Regulation of oncogenic KRAS signaling via a novel KRAS-integrin-linked kinase-hnRNPA1 regulatory loop in human pancreatic cancer cells.
Integrin-linked kinase (ILK) is a mediator of aggressive phenotype in pancreatic cancer. On the basis of our finding that knockdown of either KRAS or ILK has a reciprocal effect on the other's expression, we hypothesized the presence of an ILK-KRAS regulatory loop that enables pancreatic cancer cells to regulate KRAS expression. This study aimed to elucidate the mechanism by which this regulatory circuitry is regulated and to investigate the translational potential of targeting ILK to suppress oncogenic KRAS signaling in pancreatic cancer. Interplay between KRAS and ILK and the roles of E2F1, c-Myc and heterogeneous nuclear ribonucleoprotein as intermediary effectors in this feedback loop was interrogated by genetic manipulations through small interfering RNA/short hairpin RNA knockdown and ectopic expression, western blotting, PCR, promoter-luciferase reporter assays, chromatin immunoprecipitation and pull-down analyses. In vivo efficacy of ILK inhibition was evaluated in two murine xenograft models. Our data show that KRAS regulated the expression of ILK through E2F1-mediated transcriptional activation, which, in turn, controlled KRAS gene expression via hnRNPA1-mediated destabilization of the G-quadruplex on the KRAS promoter. Moreover, ILK inhibition blocked KRAS-driven epithelial-mesenchymal transition and growth factor-stimulated KRAS expression. The knockdown or pharmacological inhibition of ILK suppressed pancreatic tumor growth, in part, by suppressing KRAS signaling. These studies suggest that this KRAS-E2F1-ILK-hnRNPA1 regulatory loop enables pancreatic cancer cells to promote oncogenic KRAS signaling and to interact with the tumor microenvironment to promote aggressive phenotypes. This regulatory loop provides a mechanistic rationale for targeting ILK to suppress oncogenic KRAS signaling, which might foster new therapeutic strategies for pancreatic cancer.


Modeling stereopsis via Markov random field.
Markov random field (MRF) and belief propagation have given birth to stereo vision algorithms with top performance. This article explores their biological plausibility. First, an MRF model guided by physiological and psychophysical facts was designed. Typically an MRF-based stereo vision algorithm employs a likelihood function that reflects the local similarity of two regions and a potential function that models the continuity constraint. In our model, the likelihood function is constructed on the basis of the disparity energy model because complex cells are considered as front-end disparity encoders in the visual pathway. Our likelihood function is also relevant to several psychological findings. The potential function in our model is constrained by the psychological finding that the strength of the cooperative interaction minimizing relative disparity decreases as the separation between stimuli increases. Our model is tested on three kinds of stereo images. In simulations on images with repetitive patterns, we demonstrate that our model could account for the human depth percepts that were previously explained by the second-order mechanism. In simulations on random dot stereograms and natural scene images, we demonstrate that false matches introduced by the disparity energy model can be reliably removed using our model. A comparison with the coarse-to-fine model shows that our model is able to compute the absolute disparity of small objects with larger relative disparity. We also relate our model to several physiological findings. The hypothesized neurons of the model are selective for absolute disparity and have facilitative extra receptive field. There are plenty of such neurons in the visual cortex. In conclusion, we think that stereopsis can be implemented by neural networks resembling MRF.


Mitochondrial DNA defects: a widening clinical spectrum of disorders.
1. Mitochondrial DNA has a number of interesting properties including maternal transmission, the ability to replicate in post-mitotic cells, a high mutation rate and an extremely compact molecular architecture with no introns and no large non-coding sequences. 2. Point mutations, deletions and duplications of mitochondrial DNA may occur. Mitochondrial DNA defects may co-exist with wild-type sequence within a cell (heteroplasmy). The level of heteroplasmy may vary in different tissues within the same individual (segregative replication). 3. A number of neurological disorders are characterized by morphological and biochemical mitochondrial defects. It is now clear that mitochondrial DNA mutations underlie these conditions although there is not always a clear correlation between a particular mutation and clinical presentation. 4. Mitochondrial DNA defects, particularly deletions, accumulate in senescent tissue and studies have been performed with the aim of linking such somatic mutations with degenerative disorders. 5. Recently mitochondrial DNA mutations have been implicated in a wider range of clinical disorders including diabetes and nerve deafness. 6. Nuclear gene defects may result in mitochondrial disorders by predisposing to multiple mitochondrial DNA deletions or quantitative depletions of mitochondrial DNA content.


Epitope mapping using randomly generated peptide libraries.
Characterizing the immune response towards a pathogen is of high interest for vaccine development and diagnosis. However, the characterization of disease-related antigen-antibody interactions is of enormous complexity. Here, we present a method comprising binding studies of serum antibody pools to synthetic random peptide libraries, and data analysis of the resulting binding patterns. The analysis can be applied to classify and predict different groups of individuals and to detect the peptides which best discriminate the investigated groups. As an example, the analysis of antibody repertoire binding patterns of different mice strains and of mice infected with helminth parasites is shown. Due to the design of the library and the sophisticated analysis, the method is able to classify and predict the different mice strains and the infection with very high accuracy and with a very small number of peptides, illustrating the potential of random library screenings in determining molecular markers for diagnosis.


A predictive method for estimating the late angiographic results of coronary intervention despite incomplete ascertainment.
Investigations of coronary restenosis typically use late (4-6-month) angiographic end points. Since only 50-80% of patients generally undergo repeat angiography, however, restenosis for the population as a whole is usually estimated by assuming that nonrestudied and restudied patients are similar. If restudied and nonrestudied patients differ, incomplete angiographic follow-up can yield an erroneous estimate of restenosis. No suitable method has yet been devised to detect and correct these errors. We studied the clinical indications for angiographic restudy in an actual series of 301 treated lesions in 267 consecutive patients who underwent either Palmaz-Schatz stenting (126 patients) or directional coronary atherectomy (141 patients) at our institution. While only 249 (83%) treated segments underwent 4-6-month angiographic follow-up, all had clinical follow-up that described whether specific indications for restudy were present. Patients who had no clinical indications for such restudy were designated as having elective follow-up. In contrast, patients who had recurrent symptoms or positive exercise studies and were scheduled for repeat angiography at the independent recommendation of their referring cardiologist were designated as having nonelective follow-up. Mean late percent stenosis or binary restenosis rate (> 50% diameter stenosis) was determined for elective versus nonelective lesions that underwent follow-up angiography. These values were then used to input the behavior of the nonrestudied lesions according to their clinical status. From these imputations, a "predictive" model was developed to estimate the mean restenosis values that would have been found had the entire population actually undergone angiographic follow-up. Comparisons between the estimates of this predictive method and the traditional method that uses only the actual angiographic data demonstrate how alterations in various parameters influence the selection bias caused by incomplete angiographic follow-up. Of the 301 lesions available for follow-up, 100 of the 103 (97%) nonelective versus 149 of the 198 (75%, p < 0.001) elective lesions actually underwent angiographic follow-up. Mean follow-up percent stenosis (50% versus 27%) and the binary restenosis rate (53% versus 13%) differed significantly for the nonelective versus the elective lesions, respectively (both p < 0.001). Even at the fairly high (83%) angiographic follow-up rate, elective versus nonelective status was thus a confounder that caused differences between the restenosis rate estimated by the traditional (29.1%; 95% CI: 23.4, 34.7) and the predictive methods (26.3%; 95% CI: 21.4, 31.1). Larger (and even statistically significant) differences may be present under the conditions that exist in many current studies. Restenosis trials with < 90% angiographic follow-up suffer from selection bias. Traditional methods that analyze only the restudied patients fail to correct for the important confounding influence of the clinical status of the nonrestudied patients. By using this readily available clinical information about the nonrestudied patients, a predictive method may be developed that provides a closer estimate of the true restenosis behavior for the population as a whole.


Bisdiamine inhibits extracellular matrix formation and cell proliferation of atrioventricular mesenchyme from developing chick heart valves.
Abnormalities of the cushion tissues lead to atrioventricular septal defects (AVSD) and truncus arteriosus (TA). Bisdiamine exposure in the embryo frequently causes AVSD and TA in the newborn chick, mouse, or rat. We studied the effects of bisdiamine on mesenchymal cells grown in aggregate culture isolated from the developing atrioventricular valves of the stage-36 chick embryo. Fibronectin extracellular matrix formation and cell proliferation in the aggregates were assessed in various media. Chick serum stimulated the cells to produce an extracellular matrix and to divide, and the inclusion of bisdiamine inhibited both responses. If we isolated an extracellular matrix from a monolayer of mesenchymal cells and added the sonicated matrix to the medium containing serum and bisdiamine, the matrix incorporated into the aggregates and the cells entered the mitotic cycle. Our previous work established that cells need to attach to an intact extracellular matrix to begin cell division. Thus, we suggest that bisdiamine inhibits the normal formation of the extracellular matrix, leading to reduced cell proliferation, but it does not affect matrix-cell interaction. The lack of cushion growth in situ may be the cause of AVSD or TA.


A new method for closure of large donor side defects after raising the pectoralis major flap.
Although free flaps are reliable for head and neck reconstructions, the pectoralis major flap (PMF) is still often used. In cases of a large PMF, the closure of the donor side can be a challenge. A technique, originally developed for the treatment and prevention of abdominal ruptures after laparotomy, is presented as an alternative for closure of large donor side defects. The use of Ventrofil® is an additional option for large donor side defects and especially to bridge the period of postoperative swelling. If utilized special attention must be paid to possible pressure necrosis of the underlying skin.


Gene therapy with adenovirus-mediated glial cell line-derived neurotrophic factor and neural stem cells activation after ischemic brain injury.
Recent advancements in molecular biology are made to expect the appearance of the new treatment of stroke patients. One is the administration of neurotrophic factors, and another is the use of neural stem cell. In this report, we performed two experiments. First experiment is administration of glial cell line-derived neurotrophic factor (GDNF) using an adenovirus vector into ischemic rat brain. A replication-defective adenoviral vector containing GDNF gene (Ad-GDNF) was directly injected into the cerebral cortex at 1 day before 90 min of transient middle cerebral artery occlusion (MCAO) in rats. Infarct volume of the Ad-GDNF injected group at 24 h after the transient MCAO was significantly smaller than that of vehicle or Ad-LacZ treated group. These results suggest that the successful exogenous GDNF gene transfer ameliorates the ischemic brain injury after transient MCAO in association with the reduction of apoptotic signals. Second one is the neural stem cell activation after transient ischemia. We investigated a possible expression of highly polysialylated neural cell adhesion molecule (PSA-NCAM) in gerbil hippocampus after 5 min of transient global ischemia in association to the proliferation of neural stem cell labeled with bromodeoxyuridine (BrdU). The number of PSA-NCAM positive cells increased in dentate gyrus (DG) at 10 and 20 days, and that of BrdU-labeled cells increased in DG at 5 and 10 days after the reperfusion. Immunofluorescence for PSA-NCAM and BrdU showed that a few cells per section were double labeled in DG only at 10 days after the reperfusion. These results suggest different chronological change of PSA-NCAM positive and BrdU-labeled cells in DG after transient ischemia.


Persistent circulation of highly pathogenic influenza H5N1 virus in Lake Qinghai area of China.
To trace the endemic situation of highly pathogenic influenza H5N1 virus in wildlife in the Lake Qinghai area of northwest China, a continuous surveillance program was implemented from September 2005 to September 2007. A total of 2699 field samples were collected, and 95 of the samples were positive by a reverse transcription-polymerase chain reaction (RT-PCR) test of subtype H5 influenza virus. To some extent, the detection rate correlated with the species, the location, and the seasons of collection. In 2007, two H5N1 isolates were identified from two species of migratory birds. The two 2007 isolates showed high similarities of the hemagglutinin and neuraminidase genes with those of the 2005 and 2006 Qinghai isolates (98.6-99.8% for HA and 98.7-98.9% for NA at the nucleotide level). Both isolates fell into clade 2.2.2 and were experimentally highly pathogenic to chickens and mice. According to our surveillance results, HPAI H5N1 viruses still exist in this region.


Atomistic aspects of ductile responses of cubic silicon carbide during nanometric cutting.
Cubic silicon carbide (SiC) is an extremely hard and brittle material having unique blend of material properties which makes it suitable candidate for microelectromechanical systems and nanoelectromechanical systems applications. Although, SiC can be machined in ductile regime at nanoscale through single-point diamond turning process, the root cause of the ductile response of SiC has not been understood yet which impedes significant exploitation of this ceramic material. In this paper, molecular dynamics simulation has been carried out to investigate the atomistic aspects of ductile response of SiC during nanometric cutting process. Simulation results show that cubic SiC undergoes sp3-sp2 order-disorder transition resulting in the formation of SiC-graphene-like substance with a growth rate dependent on the cutting conditions. The disorder transition of SiC causes the ductile response during its nanometric cutting operations. It was further found out that the continuous abrasive action between the diamond tool and SiC causes simultaneous sp3-sp2 order-disorder transition of diamond tool which results in graphitization of diamond and consequent tool wear.


Genome Sequence of Staphylococcus aureus Strain CA-347, a USA600 Methicillin-Resistant Isolate.
The Staphylococcus aureus clonal lineage CC45 is a predominant colonizer of healthy individuals in northern Europe and constitutes a highly basal cluster of the S. aureus population. Here, we report the complete genome sequence of S. aureus strain CA-347 (NRS648), a representative of the methicillin-resistant USA600 clone predominantly found in the United States.


Tralokinumab for moderate-to-severe atopic dermatitis: results from two 52-week, randomized, double-blind, multicentre, placebo-controlled phase III trials (ECZTRA 1 and ECZTRA 2).
Tralokinumab, a fully human monoclonal antibody, specifically neutralizes interleukin-13, a key cytokine driving peripheral inflammation in atopic dermatitis (AD). In phase II studies, tralokinumab combined with topical corticosteroids provided early and sustained improvements in AD signs and symptoms. To evaluate the efficacy and safety of tralokinumab monotherapy in adults with moderate-to-severe AD who had an inadequate response to topical treatments. In two 52-week, randomized, double-blind, placebo-controlled, phase III trials, ECZTRA 1 and ECZTRA 2, adults with moderate-to-severe AD were randomized (3 : 1) to subcutaneous tralokinumab 300 mg every 2 weeks (Q2W) or placebo. Primary endpoints were Investigator's Global Assessment (IGA) score of 0 or 1 at week 16 and ≥ 75% improvement in Eczema Area and Severity Index (EASI 75) at week 16. Patients achieving an IGA score of 0 or 1 and/or EASI 75 with tralokinumab at week 16 were rerandomized to tralokinumab Q2W or every 4 weeks or placebo, for 36 weeks. The trials were registered with ClinicalTrials.gov: NCT03131648 and NCT03160885. At week 16, more patients who received tralokinumab vs. placebo achieved an IGA score of 0 or 1: 15·8% vs. 7·1% in ECZTRA 1 [difference 8·6%, 95% confidence interval (CI) 4·1-13·1; P = 0·002] and 22·2% vs. 10·9% in ECZTRA 2 (11·1%, 95% CI 5·8-16·4; P < 0·001) and EASI 75: 25·0% vs. 12·7% (12·1%, 95% CI 6·5-17·7; P < 0·001) and 33·2% vs. 11·4% (21·6%, 95% CI 15·8-27·3; P < 0·001). Early improvements in pruritus, sleep interference, Dermatology Life Quality Index, SCORing Atopic Dermatitis and Patient-Oriented Eczema Measure were observed from the first postbaseline measurements. The majority of week 16 tralokinumab responders maintained response at week 52 with continued tralokinumab treatment without any rescue medication (including topical corticosteroids). Adverse events were reported in 76·4% and 61·5% of patients receiving tralokinumab in ECZTRA 1 and ECZTRA 2, respectively, and in 77·0% and 66·0% of patients receiving placebo in ECZTRA 1 and ECZTRA 2, respectively, in the 16-week initial period. Tralokinumab monotherapy was superior to placebo at 16 weeks of treatment and was well tolerated up to 52 weeks of treatment.


Neurodegeneration prevented by lentiviral vector delivery of GDNF in primate models of Parkinson's disease.
Lentiviral delivery of glial cell line-derived neurotrophic factor (lenti-GDNF) was tested for its trophic effects upon degenerating nigrostriatal neurons in nonhuman primate models of Parkinson's disease (PD). We injected lenti-GDNF into the striatum and substantia nigra of nonlesioned aged rhesus monkeys or young adult rhesus monkeys treated 1 week prior with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Extensive GDNF expression with anterograde and retrograde transport was seen in all animals. In aged monkeys, lenti-GDNF augmented dopaminergic function. In MPTP-treated monkeys, lenti-GDNF reversed functional deficits and completely prevented nigrostriatal degeneration. Additionally, lenti-GDNF injections to intact rhesus monkeys revealed long-term gene expression (8 months). In MPTP-treated monkeys, lenti-GDNF treatment reversed motor deficits in a hand-reach task. These data indicate that GDNF delivery using a lentiviral vector system can prevent nigrostriatal degeneration and induce regeneration in primate models of PD and might be a viable therapeutic strategy for PD patients.


Choosing not to take phosphate binders: the role of dialysis patients' medication beliefs.
Patients with end-stage renal disease (ESRD) receiving haemodialysis are at risk of cardiovascular disease and bone disorders related to high levels of serum phosphate (PO(4)). Phosphate binders are an important treatment; however, non-adherence remains a significant issue. This study investigates whether patients' beliefs about medicines predict intentional non-adherence to phosphate binders. This was a cross-sectional study of ESRD patients (n = 76). Non-adherence was measured in two ways: (1) the self-report Medication Adherence Questionnaire (MAQ) and (2) 3-month average level of serum phosphate. The Beliefs about Medicines questionnaire was used to assess general and specific beliefs towards phosphate medicines. Eleven (14.5% of 76) patients reported being intentionally non-adherent to phosphate binders. Patients' beliefs that phosphate binders were less necessary were significantly associated with intentional self-reported non- adherence. Furthermore, patients with greater concerns about phosphate binders had higher serum phosphate levels. Assessing patient beliefs about medicines is a reliable indicator of intentional non-adherence to treatment with phosphate binders. These findings may help in identifying ways in which adherence rates to phosphate binders can be improved.


Flow disturbances generated by feeding and swimming zooplankton.
Interactions between planktonic organisms, such as detection of prey, predators, and mates, are often mediated by fluid signals. Consequently, many plankton predators perceive their prey from the fluid disturbances that it generates when it feeds and swims. Zooplankton should therefore seek to minimize the fluid disturbance that they produce. By means of particle image velocimetry, we describe the fluid disturbances produced by feeding and swimming in zooplankton with diverse propulsion mechanisms and ranging from 10-µm flagellates to greater than millimeter-sized copepods. We show that zooplankton, in which feeding and swimming are separate processes, produce flow disturbances during swimming with a much faster spatial attenuation (velocity u varies with distance r as u ∝ r(-3) to r(-4)) than that produced by zooplankton for which feeding and propulsion are the same process (u ∝ r(-1) to r(-2)). As a result, the spatial extension of the fluid disturbance produced by swimmers is an order of magnitude smaller than that produced by feeders at similar Reynolds numbers. The "quiet" propulsion of swimmers is achieved either through swimming erratically by short-lasting power strokes, generating viscous vortex rings, or by "breast-stroke swimming." Both produce rapidly attenuating flows. The more "noisy" swimming of those that are constrained by a need to simultaneously feed is due to constantly beating flagella or appendages that are positioned either anteriorly or posteriorly on the (cell) body. These patterns transcend differences in size and taxonomy and have thus evolved multiple times, suggesting a strong selective pressure to minimize predation risk.


Cervical cancer: is herpes simplex virus type II a cofactor?
In many ways, cervical cancer behaves as a sexually transmitted disease. The major risk factors are multiple sexual partners and early onset of sexual activity. Although high-risk types of human papillomaviruses (HPV) play an important role in the development of nearly all cases of cervical cancer, other sexually transmitted infectious agents may be cofactors. Herpes simplex virus type 2 (HSV-2) is transmitted primarily by sexual contact and therefore has been implicated as a risk factor. Several independent studies suggest that HSV-2 infections correlate with a higher than normal incidence of cervical cancer. In contrast, other epidemiological studies have concluded that infection with HSV-2 is not a major risk factor. Two separate transforming domains have been identified within the HSV-2 genome, but continued viral gene expression apparently is not necessary for neoplastic transformation. HSV infections lead to unscheduled cellular DNA synthesis, chromosomal amplifications, and mutations. These observations suggest that HSV-2 is not a typical DNA tumor virus. It is hypothesized that persistent or abortive infections induce permanent genetic alterations that interfere with differentiation of cervical epithelium and subsequently induce abnormal proliferation. Thus, HSV-2 may be a cofactor in some but not all cases of cervical cancer.


A systematic review of breast milk microbiota composition and the evidence for transfer to and colonisation of the infant gut.
The intestinal microbiota plays a major role in infant health and development. However, the role of the breastmilk microbiota in infant gut colonisation remains unclear. A systematic review was performed to evaluate the composition of the breastmilk microbiota and evidence for transfer to/colonisation of the infant gut. Searches were performed using PUBMED, OVID, LILACS and PROQUEST from inception until 18th March 2020 with a PUBMED update to December 2021. 88 full texts were evaluated before final critique based on study power, sample contamination avoidance, storage, purification process, DNA extraction/analysis, and consideration of maternal health and other potential confounders. Risk of skin contamination was reduced mainly by breast cleaning and rejecting the first milk drops. Sample storage, DNA extraction and bioinformatics varied. Several studies stored samples under conditions that may selectively impact bacterial DNA preservation, others used preculture reducing reliability. Only 15 studies, with acceptable sample size, handling, extraction, and bacterial analysis, considered transfer of bacteria to the infant. Three reported bacterial transfer from infant to breastmilk. Despite consistent evidence for the breastmilk microbiota, and recent studies using improved methods to investigate factors affecting its composition, few studies adequately considered transfer to the infant gut providing very little evidence for effective impact on gut colonisation.


Precision and accuracy of stereotactic targeting in patients undergoing repeat stereotactic surgery.
Accurate and precise stereotactic targeting is crucial in obtaining the best outcome for patients undergoing functional neurosurgical procedures. We calculated the precision and accuracy of stereotactic targeting in 20 consecutive patients who underwent repeat stereotactic surgery from January 2001 to December 2007 at one institution. Two sets of target coordinates were calculated for each patient undergoing repeat surgery from their magnetic resonance images and using Stealth Station and Framelink software. The 1st target coordinate was the initial stereotactic lesion or known functional electrode contact and the 2nd was the computer-calculated coordinate of the selected functional target (ventrointermediate, globus pallidus internus, or subthalamic nucleus ) for the repeat surgery. All patients had a good functional outcome following the initial surgery. Mean differences between coordinates (for all stereotactic targets combined) were 1.35, 1.18 and 1.28 mm for X, Y and Z, respectively. The absolute difference between target points was 2.77 mm. This demonstrates a high level of precision and accuracy with contemporary frame-based neuronavigation and stereotactic techniques. Similar data can be easily collected and analyzed for auditing purposes at any neurosurgical center to ensure optimal outcome for patients.


Lifetime mental disorders and suicidal behaviour in South Africa.
There is relatively little data on the relationship between lifetime mental disorders and suicidal behaviour in low and middle income countries. This study examines the relationship between lifetime mental disorders, and subsequent suicide ideation, plans, and suicide attempts in South Africa. A national survey of 4185 South African adults was conducted using the World Health Organization Composite International Diagnostic Interview (CIDI) to generate psychiatric diagnoses and suicidal behaviour. Bivariate, multivariate and discrete-time survival analyses were employed to investigate the associations between mental disorders and subsequent suicide ideation, plans, and attempts. Sixty-one percent of people who seriously considered killing themselves at some point in their lifetime reported having a prior DSM-IV disorder. Mental disorders predict the onset of suicidal ideation, but have weaker effects in predicting suicide plans or attempts. After controlling for comorbid mental disorders, PTSD was the strongest predictor of suicidal ideation and attempts. There is a relationship between number of mental disorders and suicidal behaviour, with comorbidity having significantly sub-additive effects. Consistent with data from the developed world, mental disorders are strong predictors of suicidal behaviour, and these associations are more often explained by the prediction of ideation, rather than the prediction of attempts amongst ideators. This suggests some universality of the relevant mechanisms underlying the genesis of suicidal thoughts, and the progression to suicide attempts.


Nuclear-localized subtype of end-binding 1 protein regulates spindle organization in Arabidopsis.
End-binding 1 (EB1) proteins are evolutionarily conserved plus-end-tracking proteins that localize to growing microtubule plus ends where they regulate microtubule dynamics and interactions with intracellular targets. Animal EB1 proteins have acidic C-terminal tails that might induce an autoinhibitory conformation. Although EB1 proteins with the same structural features occur in plants (EB1a and EB1b in Arabidopsis thaliana), a variant form (EB1c) is present that lacks the characteristic tail. We show that in Arabidopsis the tail region of EB1b, but not of EB1c, inhibits microtubule assembly in vitro. EB1a and EB1b form heterodimers with each other, but not with EB1c. Furthermore, the EB1 genes are expressed in various cell types of Arabidopsis, but the expression of EB1c is particularly strong in the meristematic cells where it is targeted to the nucleus by a nuclear localization signal in the C-terminal tail. Reduced expression of EB1c compromised the alignment of spindle and phragmoplast microtubules and caused frequent lagging of separating chromosomes at anaphase. Roots of the eb1c mutant were hypersensitive to a microtubule-disrupting drug and complete rescue of the mutant phenotype required the tail region of EB1c. These results suggest that a plant-specific EB1 subtype has evolved to function preferentially on the spindle microtubules by accumulating in the prophase nucleus.