Model for screened, charge-regulated electrostatics of an eye lens protein: Bovine gammaB-crystallin.
We model screened, site-specific charge regulation of the eye lens protein bovine gammaB-crystallin (γB) and study the probability distributions of its proton occupancy patterns. Using a simplified dielectric model, we solve the linearized Poisson-Boltzmann equation to calculate a 54×54 work-of-charging matrix, each entry being the modeled voltage at a given titratable site, due to an elementary charge at another site. The matrix quantifies interactions within patches of sites, including γB charge pairs. We model intrinsic pK values that would occur hypothetically in the absence of other charges, with use of experimental data on the dependence of pK values on aqueous solution conditions, the dielectric model, and literature values. We use Monte Carlo simulations to calculate a model grand-canonical partition function that incorporates both the work-of-charging and the intrinsic pK values for isolated γB molecules and we calculate the probabilities of leading proton occupancy configurations, for 4<pH<8 and Debye screening lengths from 6 to 20 Å. We select the interior dielectric value to model γB titration data. At pH 7.1 and Debye length 6.0 Å, on a given γB molecule the predicted top occupancy pattern is present nearly 20% of the time, and 90% of the time one or another of the first 100 patterns will be present. Many of these occupancy patterns differ in net charge sign as well as in surface voltage profile. We illustrate how charge pattern probabilities deviate from the multinomial distribution that would result from use of effective pK values alone and estimate the extents to which γB charge pattern distributions broaden at lower pH and narrow as ionic strength is lowered. These results suggest that for accurate modeling of orientation-dependent γB-γB interactions, consideration of numerous pairs of proton occupancy patterns will be needed.


Moment analysis of chromatographic behavior of separation media for fast HPLC.
The van Deemter equation and moment equations were used for analyzing the flow rate dependence of HETP experimentally measured in order to clarify chromatographic behavior from the kinetic points of view in columns packed with C18-silica monolith and C18-core-shell particles under RPLC conditions. They provided some information about molecular diffusion, eddy diffusion, and mass transfer kinetics in the columns. Additionally, the value of intra-stationary phase diffusivity was determined in the range of 10(-7)-10(-6) cm(2) s(-1) by the moment analysis. Information about the contribution of the mass transfer resistance in the external liquid film around the stationary phase to HETP was also obtained. Its contribution increases with an increase in the flow velocity of the mobile phase. It was concluded that the moment equations can provide more detailed information about the kinetic behavior in the columns than the van Deemter equation.


Stress and work-related upper extremity disorders: implications for prevention and management.
A causal link between stress and work-related musculoskeletal disorders of the upper extremities (WRUEDs) has been established, but there is less evidence for a beneficial effect of stress reduction interventions on WRUED symptoms and incidence. Searches of Medline, Ergonomics Abstracts, and Psychlit from 1990 to 2001 identified studies that either targeted stress and measured WRUED outcomes, or described other interventions with both stress and WRUED outcomes. Workplace interventions, including discrete improvements in technology, work organization and ergonomics, and more comprehensive approaches can reduce levels of stress. In a few studies, these interventions have been associated with decreases in WRUED symptoms. Similar effects are noted in stress-related interventions targeting individuals before WRUEDs have appeared, and at several stages of these conditions. Health care providers can recognize stress-WRUED interactions through careful, directed inquiry. Both individual as well as workplace-targeted interventions, delivered in the primary care setting or workplace, may be helpful. Future research priorities include prospective studies of well-defined interventions, with ample measures of subject, intervention and workplace characteristics that can impact outcomes, and adequate follow-up to determine sustained effects.


Myogenic regulatory protein (MyoD1) expression in childhood solid tumors: diagnostic utility in rhabdomyosarcoma.
Transcripts for the muscle regulatory gene MyoD1 are expressed during normal skeletal muscle myogenesis and in rhabdomyosarcomas but not in other tissues or in soft-tissue sarcomas. Here we report the distribution of MyoD1 protein, determined by reactivity with anti-MyoD1 polyclonal sera in normal tissues, rhabdomyosarcoma cell lines, and in a variety of pediatric solid tumors. The distribution of MyoD1 protein was highly restricted in normal tissues and was detected only in fetal skeletal muscle and more faintly in adult skeletal muscle. All six human rhabdomyosarcoma cell lines analyzed expressed MyoD1 mRNA transcripts as well as immunoreactive protein. The immunohistochemical expression of MyoD1 protein was then examined in 49 surgical specimens from a variety of pediatric solid tumors. Each of 16 rhabdomyosarcoma specimens was positive for MyoD1, including four that did not express the intermediate filament protein desmin. Two of five specimens originally designated sarcoma type indeterminate (STI) and two of three specimens originally designated extraosseous Ewing's sarcoma (EOE) were positive for MyoD1, suggesting commitment to myogenic differentiation. Three of eight Wilms' tumors, which also expressed desmin and had clearly evident myogenic elements, also were positive for MyoD1. Tumors that failed to express MyoD1 protein included neuroblastoma, primitive neuroectodermal tumor, non-Hodgkins lymphoma, embryonal sarcoma of the liver, malignant fibrous histiocytoma, malignant rhabdoid tumor, and Ewing's sarcoma of the bone. These results indicate that expression of MyoD1 protein is highly restricted in normal human tissues and that expression of this gene product in malignant tissue may be diagnostic for rhabdomyosarcoma. Furthermore MyoD1 staining may be a valuable adjunct in the classification of pediatric soft-tissue sarcomas.


Protocol for a randomised controlled trial of telemonitoring and self-management in the control of hypertension: telemonitoring and self-management in hypertension. [ISRCTN17585681].
Controlling blood pressure with drugs is a key aspect of cardiovascular disease prevention, but until recently has been the sole preserve of health professionals. Self-management of hypertension is an under researched area in which potential benefits for both patients and professionals are great. The telemonitoring and self-management in hypertension trial (TASMINH2) will be a primary care based randomised controlled trial with embedded economic and qualitative analyses in order to evaluate the costs and effects of increasing patient involvement in blood pressure management, specifically with respect to home monitoring and self titration of antihypertensive medication compared to usual care. Provision of remote monitoring results to participating practices will ensure that practice staff are able to engage with self management and provide assistance where required. 478 patients will be recruited from general practices in the West Midlands, which is sufficient to detect clinically significant differences in systolic blood pressure between self-management and usual care of 5 mmHg with 90% power. Patients will be excluded if they demonstrate an inability to self monitor, their blood pressure is below 140/90 or above 200/100, they are on three or more antihypertensive medications, have a terminal disease or their blood pressure is not managed by their general practitioner. The primary end point is change in mean systolic blood pressure (mmHg) between baseline and each follow up point (6 months and 12 months). Secondary outcomes will include change in mean diastolic blood pressure, costs, adverse events, health behaviours, illness perceptions, beliefs about medication, medication compliance and anxiety. Modelling will evaluate the impact of costs and effects on a system wide basis. The qualitative analysis will draw upon the views of users, informal carers and professionals regarding the acceptability of self-management and prerequisites for future widespread implementation should the trial show this approach to be efficacious. The TASMINH2 trial will provide important new evidence regarding the costs and effects of self monitoring with telemonitoring in a representative primary care hypertensive population.


'We are afraid of them': attitudes and behaviours of community members towards tuberculosis in Ghana and implications for TB control efforts.
One major set back to the success of TB control globally is the stigma attached to the disease in most societies. This article explores community's understanding of, and attitudes and behaviours towards TB and examines the implications for disease control efforts. Individual in-depth interviews and focus groups were held with community members and the generated data analysed using Grounded Theory techniques and procedures. At the core of feelings towards TB in the community is the fear of infection leading to imposition of socio-physical distance and participatory restrictions on those suffering from the disease. Because of fear of infection, most of the community members were of the view that TB patients should not be part of the society and said they will not marry a TB patient or encourage any family member to enter such a relationship. They also pointed out that TB patients should not sell in the community and would not be allowed to represent them at any public function because they can infect others. Whenever it becomes unavoidable for the community members to interact with someone with TB, they indicated that they would cover their mouth with a handkerchief, turn their head or sit in the opposite direction of the wind from the TB patient to avoid inhaling the air. When a TB patient joins the community members at any function, he/she is expected to abide by certain 'codes of conduct'. The stigmatising attitudes and behaviours of the community members towards the disease and its sufferers may lead individuals with very obvious signs and symptoms of TB to attribute it to other non-stigmatising conditions or hide the diagnosis from others as well as default from treatment.


The Historical Development of Cultivation Techniques for Methanogens and Other Strict Anaerobes and Their Application in Modern Microbiology.
The cultivation and investigation of strictly anaerobic microorganisms belong to the fields of anaerobic microbial physiology, microbiology, and biotechnology. Anaerobic cultivation methods differ from classic microbiological techniques in several aspects. The requirement for special instruments, which are designed to prevent the contact of the specimen with air/molecular oxygen by different means of manipulation, makes this field more challenging for general research compared to working with aerobic microorganisms. Anaerobic microbiological methods are required for many purposes, such as for the isolation and characterization of new species and their physiological examination, as well as for anaerobic biotechnological applications or medical indications. This review presents the historical development of methods for the cultivation of strictly anaerobic microorganisms focusing on methanogenic archaea, anaerobic cultivation methods that are still widely used today, novel methods for anaerobic cultivation, and almost forgotten, but still relevant, techniques.


Inhibition of GSK-3 selectively reduces glucose-6-phosphatase and phosphatase and phosphoenolypyruvate carboxykinase gene expression.
A major action of insulin is to regulate the transcription rate of specific genes. The expression of these genes is dramatically altered in type 2 diabetes. For example, the expression of two hepatic genes, glucose-6-phosphatase and PEPCK, is normally inhibited by insulin, but in type 2 diabetes, their expression is insensitive to insulin. An agent that mimics the effect of insulin on the expression of these genes would reduce gluconeogenesis and hepatic glucose output, even in the presence of insulin resistance. The repressive actions of insulin on these genes are dependent on phosphatidylinositol (PI) 3-kinase. However, the molecules that lie between this lipid kinase and the two gene promoters are unknown. Glycogen synthase kinase-3 (GSK-3) is inhibited following activation of PI 3-kinase and protein kinase B. In hepatoma cells, we find that selectively reducing GSK-3 activity strongly reduces the expression of both gluconeogenic genes. The effect is at the level of transcription and is observed with induced or basal gene expression. In addition, GSK-3 inhibition does not result in the subsequent activation of protein kinase B or inhibition of the transcription factor FKHR, which are candidate regulatory molecules for these promoters. Thus, GSK-3 activity is required for basal activity of each promoter. Inhibitors of GSK-3 should therefore reduce hepatic glucose output, as well as increase the synthesis of glycogen from L-glucose. These findings indicate that GSK-3 inhibitors may have greater therapeutic potential for lowering blood glucose levels and treating type 2 diabetes than previously realized.


Screening measure for early detection of depressive symptoms: the depressive cognition scale.
Nearly 10% of American adults experience depressive symptoms each year. Negative thought patterns associated with risk for depression can be identified using a psychometrically sound measure, such as the Depressive Cognition Scale (DCS). However, no meaningful cutoff score has been established for the DCS. This study used a receiver operating characteristic (ROC) curve to establish a DCS cutoff score for risk for depression, using the Center for Epidemiological Studies-Depression Scale (CES-D) as the gold standard measure. In a national nondepressed sample of 629 adults, the ROC showed that the DCS accurately discriminated between participants with and without serious depressive thinking in 80% of cases and established an optimum balance of sensitivity (73.9-76.6%) and specificity (69.0-75.3%) at a score of 7. Although findings indicate that the DCS may overidentify risk for clinical depression, the instrument is useful for screening and assessment, with possible initiation of psychological treatment to prevent clinical depression.


Cytokine expression and cancer detection.
The purpose of the present article is to review the links between cancer and cytokine expression. Cytokines are proteins produced by cells that act as mediators of cell-to-cell communication. Many recent reports indicate that uncontrolled, constitutive cytokine expression in tumors contributes to tumor growth, tumor progression and immuno-suppression, activities that dexceed their usual functions in host anti-tumor response. In addition, cancer susceptibility and severity seem to be associated with functional polymorphisms in cytokine genes. Thus, cytokine expression genomics may have clinical applications. Here we propose approaches to cancer detection in the clinic based on altered patterns of cytokine expression. Although the function and diagnostic importance of cytokines needs to be studied in more detail, examining the relationship between aberrant cytokine expression and cancer promises to be extremely useful for the identification of a new generation of biomarkers, and to advance cancer diagnosis, prevention, and treatment.


Electrooptic Fabry-Perot filter: development for the study of solar oscillations.
Observations of nonradial solar oscillations require Doppler velocity measurement at many points over the photosphere with a velocity resolution better than 1 m/s. An attractive form of imaging spectrophotometer for such a task utilizes a thin, solid, electrically tunable Fabry-Perot interference filter or etalon made of an electrooptic material such as lithium niobate (LiNbO(3)). The problems to be overcome in producing such an etalon for an imaging spectrophotometer are discussed and practical solutions demonstrated on the basis of measurements made on prototype devices.


A fluidic demultiplexer for controlling large arrays of soft actuators.
The field of soft robotics endeavors to create robots that are mostly, if not entirely, soft. While there have been significant advances in both soft actuators and soft sensors, there has been relatively little work done in the development of soft control systems. This work proposes a soft microfluidic demultiplexer as a potential control system for soft robotics. Demultiplexers enable the control of many outputs with just a few inputs, increasing a soft robot's complexity while minimizing its reliance on external valves and other off-board components. The demultiplexer in this work improves upon earlier microfluidic demultiplexers with its nearly two-fold reduction of inputs, a design feature that simplifies control and increases efficiency. Additionally, the demultiplexer in this work is designed to accommodate the high pressures and flow rates that soft robotics demands. The demultiplexer is characterized from the level of individual valves to full system parameters, and its functionality is demonstrated by controlling an array of individually addressable soft actuators.


Tumors as chaotic attractors.
Malignant tumor growth, progression and evolution share several of the features associated with strange attractors, a special type of dynamical behavior of non-linear systems. In this framework, the genetic instability of tumor cells represents a local-scale driving force for instability that lets the tumor evolve with time, while selective pressures discarding inefficient cell clones play the role of a dissipative process, providing the tumor with global stability and robustness with respect to perturbations. This setup induces global stability combined with local instability, and is in our opinion the real source of tumor robustness and plasticity, and ultimately the origin of the remarkable resistance of many tumors to anti-cancer therapies. A scientific program taking into consideration the vision of tumors as strange attractors requires the development of experimental and computational tools to link the micro- and mesoscopic perspectives of tumor biology. We here develop the idea of a tumor as a dynamical system, sharing characteristics with strange attractors and investigate several features of such systems, including: (a) local instability combined with global stability, a property inherent to the tremendous non-linearity of the biochemical regulatory circuits governing the individual fate and the interactions between tumor cells; (b) self-similarity at different levels; (c) and strong sensitivity to initial conditions in the composition and features of the tumor and its microenvironment.


Rural blood availability: regulations must meet ethics.
Rural physicians have been practising the technique of emergency bleeding and transfusion called Unbanked Directed (to a specific recipient) Blood Transfusion (UDBT), which has been declared illegal, to meet the need for blood in rural and inaccessible areas. As a result, a crisis has emerged in the availability of blood. Is UDBT a second rate technology for the poor and the disadvantaged? And should we not rather advocate for rapid scaling up of the establishment of blood banks in all areas? We examine the ethical issues related to blood availability in the rural areas. We argue that a regulated and licensed UDBT passes muster on the ethical principles of beneficence, lack of maleficence, justice and Swaraj. Using this issue as a case in point, we further examine the idea of what constitutes appropriate or acceptable technology. While affirming that any technology has to pass muster on a litmus test of acceptability, we discuss the difference between "ideal" and "acceptable" (but less than ideal) technology. We argue there is a dynamic push and pull between the urge to regulate and restrict the use of skills by all versus the need to communitise technology. Regulated use of UDBT will allow blood to be available where it is needed most in the foreseeable future in India.


Deaths due to thermal injury from cigarette smoking in a 13-year national cohort of nursing home residents.
To examine the nature and frequency of deaths due to thermal injuries from cigarette smoking reported to Australian coroners and to examine the decisions which surround these deaths. Retrospective cohort study. Residents dwelling in accredited nursing homes whose deaths were reported to coroners between 1 July 2000 and 30 June 2013 and attributed to thermal injuries from cigarette smoking. A descriptive analysis was undertaken to report socio-demographic characteristics of the deceased, medical history, mobility, level of observation, safety equipment provided/used, nursing home location, decision to smoke, timing of incident, time from incident to death, incident findings, mechanism of death, formal reports attached and coroners' recommendations. Ten deaths of nursing home residents due to thermal injury from cigarette smoking were reported in Australia over a 13-year period. The median age of residents was 78 years (IQR = 15.25); nine residents were female and one was male. Seven residents had impaired mobility with three residents being wheelchair bound and one resident bed bound. None of the residents were supervised by staff while they smoked, and none of the residents utilised any safety equipment to minimise harm. Burns/thermal injury was the mechanism of harm in most cases. This national study confirms that thermal injuries caused by cigarette smoking in nursing homes result in fatalities, particularly in the absence of supervision. It also demonstrates the complex tension arising from balancing autonomy with safety. Nurses and aged care practitioners should endeavour to give effect to each resident's wishes while mitigating the risk of harm. The supervision requirements for cigarette smoking residents should be tailored to the needs of individual residents and staff should try to ensure that residents who require supervision receive it.


Fertility and pregnancy in the Fontan population.
Women with a Fontan circulation are deemed at significantly increased risk of maternal morbidity and mortality during pregnancy. Publications describe a small number of pregnancies worldwide and a high rate of miscarriage. We compiled the experience of women enrolled in the Australia and New Zealand Fontan (ANZ) Registry with regard to menarche, contraceptive use, pregnancy advice and pregnancy outcomes. Women within the ANZ Fontan Registry were contacted and asked to consent to receiving sequential questionnaires. 156 women ≥ 18 years of age (including 4 deceased individuals) were identified, 101 women consented and 97 completed the initial questionnaire. Women were aged (median) 25 years (23-32); menarche occurred at a median 14 years (13-16). A wide variety of contraceptive methods was reported. 81% of women reported having received advice that pregnancy carried an increased risk or was inadvisable. Pregnancy was reported in a minority (n=27). Miscarriage (42.5%) and termination (7.5%) accounted for half the pregnancy outcomes and the babies were born early (median 31.5 weeks) and small (median 1350 g). Maternal complications of bleeding, arrhythmia and heart failure were reported with no early maternal mortality. In women with a Fontan circulation the fertility onset is delayed and pregnancy has a higher rate of miscarriage. Successful pregnancy resulted in small and premature babies. Significant maternal morbidity occurred. Whether pregnancy with its volume loading has an adverse effect on the long-term outcome of women with a single ventricle remains to be elucidated.


Nano-design of quantum dot-based photocatalysts for hydrogen generation using advanced surface molecular chemistry.
Efficient photocatalytic hydrogen generation in a suspension system requires a sophisticated nano-device that combines a photon absorber with effective redox catalysts. This study demonstrates an innovative molecular linking strategy for fabricating photocatalytic materials that allow effective charge separation of excited carriers, followed by efficient hydrogen evolution. The method for the sequential replacement of ligands with appropriate molecules developed in this study tethers both quantum dots (QDs), as photosensitizers, and metal nanoparticles, as hydrogen evolution catalysts, to TiO2 surfaces in a controlled manner at the nano-level. Combining hydrophobic and hydrophilic interactions on the surface, CdSe-ZnS core-shell QDs and an Au-Pt alloy were attached to TiO2 without overlapping during the synthesis. The resultant nano-photocatalysts achieved substantially high-performance visible-light-driven photocatalysis for hydrogen evolution. All syntheses were conducted at room temperature and in ambient air, providing a promising route for fabricating visible-light-responsive photocatalysts.


Reactivity of the gold/water interface during selective oxidation catalysis.
The selective oxidation of alcohols in aqueous phase over supported metal catalysts is facilitated by high-pH conditions. We have studied the mechanism of ethanol and glycerol oxidation to acids over various supported gold and platinum catalysts. Labeling experiments with (18)O(2) and H(2)(18)O demonstrate that oxygen atoms originating from hydroxide ions instead of molecular oxygen are incorporated into the alcohol during the oxidation reaction. Density functional theory calculations suggest that the reaction path involves both solution-mediated and metal-catalyzed elementary steps. Molecular oxygen is proposed to participate in the catalytic cycle not by dissociation to atomic oxygen but by regenerating hydroxide ions formed via the catalytic decomposition of a peroxide intermediate.


Assessing "dangerous climate change": required reduction of carbon emissions to protect young people, future generations and nature.
We assess climate impacts of global warming using ongoing observations and paleoclimate data. We use Earth's measured energy imbalance, paleoclimate data, and simple representations of the global carbon cycle and temperature to define emission reductions needed to stabilize climate and avoid potentially disastrous impacts on today's young people, future generations, and nature. A cumulative industrial-era limit of ∼500 GtC fossil fuel emissions and 100 GtC storage in the biosphere and soil would keep climate close to the Holocene range to which humanity and other species are adapted. Cumulative emissions of ∼1000 GtC, sometimes associated with 2°C global warming, would spur "slow" feedbacks and eventual warming of 3-4°C with disastrous consequences. Rapid emissions reduction is required to restore Earth's energy balance and avoid ocean heat uptake that would practically guarantee irreversible effects. Continuation of high fossil fuel emissions, given current knowledge of the consequences, would be an act of extraordinary witting intergenerational injustice. Responsible policymaking requires a rising price on carbon emissions that would preclude emissions from most remaining coal and unconventional fossil fuels and phase down emissions from conventional fossil fuels.


Does Temporal Expectation Driven by Rhythmic Cues Differ From That Driven by Symbolic Cues Across the Millisecond and Second Range?
Temporal expectation relies on different predictive information, such as regular rhythms and symbolic cues, to direct attention to a future moment in time to optimize behaviour. However, whether differences exist between temporal expectations driven by regular rhythms and symbolic cues has not been clearly established. In this study, 20 participants performed two temporal expectation tasks in which a rhythmic cue or a symbolic cue indicated (70% expected) that the target would appear after an interval of 500 ms (short), 1,500 ms (medium), or 2,500 ms (long). We found larger cueing effects for the rhythmic cued task than for the symbolic cued task during the short interval, indicating that rhythmic cues were more effective in improving performance. Furthermore, no significant difference was found during the longer interval, reflect that the behavioural differences between the two forms of temporal expectations were likely to diminish as the time interval increased. Thus, we speculate that the temporal expectation driven by rhythmic cues differs from that driven by symbolic cues only in the limited time range; however, the mechanisms underlying the two forms of temporal expectations trend to become more similar over increasing temporal scales.


Deletion of the membrane protein Lmo0412 increases the virulence of Listeria monocytogenes.
Listeria monocytogenes is a facultative intracellular pathogen that causes gastroenteritis, meningitis, encephalitis and maternofetal infections. 20-30% of eubacterial ORFs are predicted to encode membrane proteins. The bacterial cytoplasmic membrane is a macromolecular structure, which plays a key role for the pathogenesis. Despite this, little knowledge exists regarding the function of cytoplasmic membrane proteins of Listeria during infection. Here, we investigated a predicted membrane protein of the pathogen L. monocytogenes, Lmo0412, of unknown function. Lmo0412 is only present in the Listeria genus and low conserved in the non-pathogenic species L. innocua. Bacterial fractionation and western blot analyses showed that Lmo0412 was only detectable in the membrane of L. monocytogenes EGDe during logarithmic growth phase. lmo0412 expression in L. monocytogenes was down-regulated during in vitro infection of JEG-3 epithelial cells. An L. monocytogenes mutant deficient in this membrane protein showed increased invasion of Caco-2 and NRK-49F host cells using in vitro infection models. Moreover, the lack of Lmo0412 in this deletion mutant increased the viable bacteria counts in the spleen and liver of mice compared to the wild type strain. Taken together, these data suggest a selective advantage conferred by the absence of Lmo0412 for the virulence of L. monocytogenes.


Critical role of aquaporin-4 (AQP4) in astrocytic Ca2+ signaling events elicited by cerebral edema.
Aquaporin-4 (AQP4) is a primary influx route for water during brain edema formation. Here, we provide evidence that brain swelling triggers Ca(2+) signaling in astrocytes and that deletion of the Aqp4 gene markedly interferes with these events. Using in vivo two-photon imaging, we show that hypoosmotic stress (20% reduction in osmolarity) initiates astrocytic Ca(2+) spikes and that deletion of Aqp4 reduces these signals. The Ca(2+) signals are partly dependent on activation of P2 purinergic receptors, which was judged from the effects of appropriate antagonists applied to cortical slices. Supporting the involvement of purinergic signaling, osmotic stress was found to induce ATP release from cultured astrocytes in an AQP4-dependent manner. Our results suggest that AQP4 not only serves as an influx route for water but also is critical for initiating downstream signaling events that may affect and potentially exacerbate the pathological outcome in clinical conditions associated with brain edema.


Serotonin receptor 2A gene polymorphisms and schizophrenia: association with family history, diagnostic subtype and height in patients.
The 102T/C single nucleotide polymorphism (SNP) in the 5-hydroxytryptamine receptor 2A (HTR2A) gene has been reported to be associated with schizophrenia. However, SNPs of the HTR2A gene other than the 102T/C have attracted only limited studies in relation to schizophrenia, and also on the whole SNPs of the HTR2A gene have been little studied in relation to clinical parameters in patients. Therefore, the aim of this study was to evaluate the impact of main functionally characterized SNPs of the HTR2A gene on both the schizophrenia and clinical parameters. Ninety-four patients with schizophrenia and 57 control subjects were genotyped for the -1438A/G, -783A/G, 102T/C and His452Tyr SNPs of the HTR2A gene. The four SNPs were then investigated in relation to the schizophrenia and clinical parameters. No differences were found in genotype-, allele- or haplotype frequencies between schizophrenia patients and control subjects. However, the 452Tyr variant of the His452Tyr polymorphism occurred more often in patients with a family history of schizophrenia compared with patients without heredity (p=0.028). The 452Tyr variant was also more common in female patients with paranoid schizophrenia than in those with non-paranoid schizophrenia (p=0.018). Moreover, the male patients carrying the A/A or T/T genotypes of the -1438A/G and 102T/C polymorphisms were shorter than those carrying the G/A or C/T genotypes (p=0.007; p=0.006). The present findings bring further support to the view that the -1438A/G, 102T/C and His452Tyr polymorphisms of the HTR2A gene are connected with a constitutive cellular change that causes susceptibility to schizophrenia.


Self-medication Hypothesis and Family Socialization Theory: Examining Independent and Common Mechanisms Responsible for Binge Drinking.
For many, binge drinking behaviors start early and become a persistent pattern of use throughout the lifespan. In an effort to strengthen understanding of etiology, this study considered the mechanisms from the self-medication hypothesis and family socialization theory. The goal was to identify whether emotional distress is a potential shared mechanism that accounts for the development of binge drinking in different developmental periods. This study used the National Longitudinal Study of Adolescent to Adult Health (Add Health) dataset to examine binge drinking across time for n = 9,421 participants ranging in age from 11 to 18 (M = 15.39, SD = 1.62) at Wave I and ranging from 24 to 32 (M = 28.09, SD = 1.61) at Wave IV of the study. Using an autoregressive cross-lagged model, I examined how parent-child closeness, depressive symptoms, and binge drinking were related over three developmental periods. In examining cross-sectional and longitudinal relations, depressive symptoms were significantly related to binge drinking more often than parent-child closeness; however, results indicated the self-medication model may primarily account for concurrent drinking behaviors rather than long-term. The family socialization theory was indicated to account for some variability above and beyond the self-medication hypothesis. No indirect association between binge drinking and the parent-child relationship was detected through depressive symptoms, failing to support a shared mechanism between the two theories. The results provide support for a multifaceted assessment process for substance using clients, and support the use of Multisystemic Family Therapy, Multidimensional Family Therapy, and perhaps Attachment-Based Family Therapy.


Thought-feeling discrimination in people with dementia: adaptation and preliminary validation of the first dementia-specific measure.
There is emerging evidence that cognitive behavioral therapy (CBT) can be effective for treating anxiety and depression in people living with dementia (PLWD). Discriminating between thoughts and feelings is a critical element of CBT and also of relevance to emotional understanding more generally. The aim of the present study was the structured adaptation and preliminary validation of an existing measure of thought-feeling discrimination for use in PLWD. The Behavior Thought Feeling Questionnaire (BTFQ) was adapted via expert and service-user consultation for use in PLWD. One hundred two PLWD and 77 people aged over 65 years who did not have measurable cognitive impairments completed the adapted measure along with two measures of emotional recognition and reasoning. The factor structure of this measure was examined and the measure reduced. Factor analysis suggested a two-factor solution with thought and feeling items loading on separate factors. The behavior items were not included in scoring due to high cross-loading and ceiling effects, leaving a 14-item measure with two subscales. Thus, an adapted measure was created (named the BTFQ-D), which showed moderate convergent validity in the PLWD but not the older adult sample. Both thought and feeling subscales showed good internal consistency. The BTFQ-D showed preliminary validity as a measure of thought-feeling discrimination in PLWD. It may have utility in measuring readiness for CBT as part of clinical assessment. Further validation is required.


Cross-talk between angiotensin II and IGF-1-induced connexin 43 expression in human saphenous vein smooth muscle cells.
Vascular restenosis following coronary artery bypass graft can cause major clinical complications due to intimal hyperplasia in venous conduits. However, the precise underlying mechanisms of intimal hyperplasia are still unclear. We have recently reported that increased expression of connexin43 (Cx43) is involved in the proliferation of vascular smooth muscle cells (SMCs) in human saphenous vein (SV). In this study, we investigated the signalling transduction pathway involved in Cx43 expression and SV SMC proliferation. Angiotensin-II (AT-II, 100 ng/ml) increased AT-II receptor 1 (AT-1R) protein expression and insulin-like growth factor-1 (IGF-1) (100 ng/ml) up-regulated IGF-1 receptor (IGF-1R) protein expression in SV SMCs. Interestingly, AT-1R expression was also increased by IGF-1 treatment, and IGF-1R expression was increased by AT-II treatment, which was blocked by siRNA-IGF-1R and siRNA-AT-1R, respectively. Furthermore, the effect of AT-II and IGF-1 signal cross-talk i nducing up-regulation of their reciprocal receptors was blocked by siRNA against extracellular signal-regulated kinases 1/2 (Erk 1/2) in SMCs of SV. Moreover, AT-II and IGF-1-induced Cx43 expression via phosphorylation of Erk 1/2 and activation of transcription factor activator protein 1 (AP-1) through their reciprocal receptors in SV SMCs. These data demonstrate a cross-talk between IGF-1R and AT-1R in AT-II and IGF-1-induced Cx43 expression in SV SMCs involving Erk 1/2 and downstream activation of the AP-1 transcription factor.


THE COMPARATIVE RESISTANCE OF BACTERIA AND HUMAN TISSUE CELLS TO CERTAIN COMMON ANTISEPTICS.
The comparative resistance of bacteria and human tissue cells to antiseptics and other chemicals may be easily tested by tissue cultures under conditions which approximate those found in the living body. A comparative study shows that while human cells (connective tissue and wandering cells) are highly resistant to many antiseptics, they are in general more easily killed than bacteria (Staphylococcus aureus). Of the antiseptics tested, which include mercuric chloride, iodine, potassium mercuric iodide, phenol, tricresol, hydrogen peroxide, hypochlorites (Dakin's solution), argyrol, and alcohol, the one which approaches most closely the ideal disinfectant is iodine, which kills bacteria in strengths that do not seriously injure connective tissue cells or wandering cells.


Developmental control of the DNA replication and transcription programs.
Polyploid or polytene cells, which have more than 2C DNA content, are widespread throughout nature and present in most differentiated Drosophila tissues. These cells also can display differential replication, that is, genomic regions of increased or decreased DNA copy number relative to overall genomic ploidy. How frequently differential replication is used as a developmental strategy remains unclear. Here, we use genome-wide array-based comparative genomic hybridization (aCGH) to profile differential DNA replication in isolated and purified larval fat body and midgut tissues of Drosophila, and we compare them with recent aCGH profiles of the larval salivary gland. We identify sites of euchromatic underreplication that are common to all three tissues and others that are tissue specific. We demonstrate that both common and tissue-specific underreplicated sites are dependent on the Suppressor of Underreplication protein, SUUR. mRNA-seq profiling shows that whereas underreplicated regions are generally transcriptionally silent in the larval midgut and salivary gland, transcriptional silencing and underreplication have been uncoupled in the larval fat body. In addition to revealing the prevalence of differential replication, our results show that transcriptional silencing and underreplication can be mechanistically uncoupled.


Early history of mammals is elucidated with the ENCODE multiple species sequencing data.
Understanding the early evolution of placental mammals is one of the most challenging issues in mammalian phylogeny. Here, we addressed this question by using the sequence data of the ENCODE consortium, which include 1% of mammalian genomes in 18 species belonging to all main mammalian lineages. Phylogenetic reconstructions based on an unprecedented amount of coding sequences taken from 218 genes resulted in a highly supported tree placing the root of Placentalia between Afrotheria and Exafroplacentalia (Afrotheria hypothesis). This topology was validated by the phylogenetic analysis of a new class of genomic phylogenetic markers, the conserved noncoding sequences. Applying the tests of alternative topologies on the coding sequence dataset resulted in the rejection of the Atlantogenata hypothesis (Xenarthra grouping with Afrotheria), while this test rejected the second alternative scenario, the Epitheria hypothesis (Xenarthra at the base), when using the noncoding sequence dataset. Thus, the two datasets support the Afrotheria hypothesis; however, none can reject both of the remaining topological alternatives.


Mosquito ageing modulates the development, virulence and transmission potential of pathogens.
Host age variation is a striking source of heterogeneity that can shape the evolution and transmission dynamic of pathogens. Compared with vertebrate systems, our understanding of the impact of host age on invertebrate-pathogen interactions remains limited. We examined the influence of mosquito age on key life-history traits driving human malaria transmission. Females of Anopheles coluzzii, a major malaria vector, belonging to three age classes (4-, 8- and 12-day-old), were experimentally infected with Plasmodium falciparum field isolates. Our findings revealed reduced competence in 12-day-old mosquitoes, characterized by lower oocyst/sporozoite rates and intensities compared with younger mosquitoes. Despite shorter median longevities in older age classes, infected 12-day-old mosquitoes exhibited improved survival, suggesting that the infection might act as a fountain of youth for older mosquitoes specifically. The timing of sporozoite appearance in the salivary glands remained consistent across mosquito age classes, with an extrinsic incubation period of approximately 13 days. Integrating these results into an epidemiological model revealed a lower vectorial capacity for older mosquitoes compared with younger ones, albeit still substantial owing to extended longevity in the presence of infection. Considering age heterogeneity provides valuable insights for ecological and epidemiological studies, informing targeted control strategies to mitigate pathogen transmission.


Nurses' experiences with hospice patients who refuse food and fluids to hasten death.
Voluntary refusal of food and fluids has been proposed as an alternative to physician-assisted suicide for terminally ill patients who wish to hasten death. There are few reports of patients who have made this choice. We mailed a questionnaire to all nurses employed by hospice programs in Oregon and analyzed the results. Of 429 eligible nurses, 307 (72 percent) returned the questionnaire, and 102 of the respondents (33 percent) reported that in the previous four years they had cared for a patient who deliberately hastened death by voluntary refusal of food and fluids. Nurses reported that patients chose to stop eating and drinking because they were ready to die, saw continued existence as pointless, and considered their quality of life poor. The survey showed that 85 percent of patients died within 15 days after stopping food and fluids. On a scale from 0 (a very bad death) to 9 (a very good death), the median score for the quality of these deaths, as rated by the nurses, was 8. On the basis of the hospice nurses' reports, the patients who stopped eating and drinking were older than 55 patients who died by physician-assisted suicide (74 vs. 64 years of age, P<0.001), less likely to want to control the circumstances of their death (P<0.001), and less likely to be evaluated by a mental health professional (9 percent vs. 45 percent, P<0.001). On the basis of reports by nurses, patients in hospice care who voluntarily choose to refuse food and fluids are elderly, no longer find meaning in living, and usually die a "good" death within two weeks after stopping food and fluids.


Impact of previous virological treatment failures and adherence on the outcome of antiretroviral therapy in 2007.
Combination antiretroviral treatment (cART) has been very successful, especially among selected patients in clinical trials. The aim of this study was to describe outcomes of cART on the population level in a large national cohort. Characteristics of participants of the Swiss HIV Cohort Study on stable cART at two semiannual visits in 2007 were analyzed with respect to era of treatment initiation, number of previous virologically failed regimens and self reported adherence. Starting ART in the mono/dual era before HIV-1 RNA assays became available was counted as one failed regimen. Logistic regression was used to identify risk factors for virological failure between the two consecutive visits. Of 4541 patients 31.2% and 68.8% had initiated therapy in the mono/dual and cART era, respectively, and been on treatment for a median of 11.7 vs. 5.7 years. At visit 1 in 2007, the mean number of previous failed regimens was 3.2 vs. 0.5 and the viral load was undetectable (<50 copies/ml) in 84.6% vs. 89.1% of the participants, respectively. Adjusted odds ratios of a detectable viral load at visit 2 for participants from the mono/dual era with a history of 2 and 3, 4, >4 previous failures compared to 1 were 0.9 (95% CI 0.4-1.7), 0.8 (0.4-1.6), 1.6 (0.8-3.2), 3.3 (1.7-6.6) respectively, and 2.3 (1.1-4.8) for >2 missed cART doses during the last month, compared to perfect adherence. From the cART era, odds ratios with a history of 1, 2 and >2 previous failures compared to none were 1.8 (95% CI 1.3-2.5), 2.8 (1.7-4.5) and 7.8 (4.5-13.5), respectively, and 2.8 (1.6-4.8) for >2 missed cART doses during the last month, compared to perfect adherence. A higher number of previous virologically failed regimens, and imperfect adherence to therapy were independent predictors of imminent virological failure.


Specific isotope labeling of colicin E1 and B channel domains for membrane topological analysis by oriented solid-state NMR spectroscopy.
An approach is presented to selectively label the methionines of the colicin E1 and B channel domains, each about 200 residues in size, and use them for oriented solid-state NMR investigations. By combining site-directed mutagenesis, bacterial overexpression in a methionine auxotroph E. coli strain and biochemical purification, quantitative amounts of the proteins for NMR structural investigations were obtained. The proteins were selectively labeled with (15)N at only one, or at a few, selected sites. Multidimensional heteronuclear correlation high-resolution NMR spectroscopy and mass spectrometry were used to monitor the quality of isotopic labeling. Thereafter the proteins were reconstituted into oriented phospholipid bilayers and investigated by proton-decoupled (15)N solid-state NMR spectroscopy. The colicin E1 thermolytic fragment that carries a single (15)N methionine within its hydrophobic helix 9 region exhibited (15)N resonances that are characteristic of helices that are oriented predominantly parallel to the membrane surface at low temperature, and a variety of alignments and conformations at room temperature. This suggests that the protein can adopt both umbrella and pen-knife conformations.


Single molecule desorption studies on immobilized nanoclay particle surfaces.
AFM-based single molecule force spectroscopy was performed on sheetlike inorganic particles of Na-montmorillonite to study the pH-dependent adsorption and desorption behavior of polyelectrolytes in aqueous solutions. Polyallylamine macromolecules were covalently attached on gold-coated AFM cantilevers. Heterogeneous surfaces were formed by immobilizing the nanoclay sheets on mica-stripped ultraflat Au(111) surfaces using aminothiol chemistry. Because of the constant surface charge of the particles over a wide pH range, polymer line charge density was the only parameter that affected the adsorption and desorption behavior when the ionic concentration was kept constant. Polarization modulation infrared-reflection absorption spectroscopy (PM-IRRAS) was performed on cast polyallylamine films to study the pH-dependent charge density of polyallylamine molecules. A good correlation was found between the line charge density and the adsorption characteristics of polyallylamine.


Interval-valued fuzzy hypergraph and fuzzy partition.
This paper extends the work of H. Lee-Kwang and L.M. Lee (1995) to present the concept of the interval-valued fuzzy hypergraph. In the interval-valued fuzzy hypergraph, the concepts of the dual interval-valued fuzzy hypergraph, the crisp-valued alpha-cut hypergraph, and the interval-valued [alpha(1),alpha(2 )]-cut at beta level hypergraph are developed, where alphain [0, 1], 0</=alpha(1)</=alpha(2)</=1, and betain [0, 1]. We also use some examples to show that the proposed concepts are useful for the analysis and fuzzy partition of a system.


COMBINING NONEXCHANGEABLE FUNCTIONAL OR SURVIVAL DATA SOURCES IN ONCOLOGY USING GENERALIZED MIXTURE COMMENSURATE PRIORS.
Conventional approaches to statistical inference preclude structures that facilitate incorporation of supplemental information acquired from similar circumstances. For example, the analysis of data obtained using perfusion computed tomography to characterize functional imaging biomarkers in cancerous regions of the liver can benefit from partially informative data collected concurrently in non-cancerous regions. This paper presents a hierarchical model structure that leverages all available information about a curve, using penalized splines, while accommodating important between-source features. Our proposed methods flexibly borrow strength from the supplemental data to a degree that reflects the commensurability of the supplemental curve with the primary curve. We investigate our method's properties for nonparametric regression via simulation, and apply it to a set of liver cancer data. We also apply our method for a semiparametric hazard model to data from a clinical trial that compares time to disease progression for three colorectal cancer treatments, while supplementing inference with information from a previous trial that tested the current standard of care.


TRP-channels as key integrators of lipid pathways in nociceptive neurons.
TRP-channels are the most prominent family of ligand-gated ion channels for pain perception. In sensory neurons, TRPV1-V4, TRPA1 and TRPM8 are expressed and are responsible for the conversion of external stimuli to painful sensations. Under pathophysiological conditions, excessive activity of TRP-channels leads to mechanical allodynia and thermal hyperalgesia. Among the endogenous TRP-channel sensitizers, activators and inhibitors, more than 50 arachidonic acid- and linoleic acid-metabolites from the COX-, LOX- and CYP-pathways, as well as lysophospholipids and isoprenoids can be found. As a consequence, these lipids represent the vast majority of endogenous TRP-channel modulators in sensory neurons. Although the precise mechanisms of TRP-channel modulation by most lipids are still unknown, it became clear that lipids can either bind directly to the target TRP-channel or modulate TRP-channels indirectly by activating G-protein coupled receptors. Thus, TRP-channels seem to be key sensors for lipids, integrating and interpreting incoming signals from the different metabolic lipid pathways. Here, we discuss the specific properties of the currently known endogenous lipid-derived TRP-channel modulators concerning their ability to activate or inhibit TRP-channels, the molecular mechanisms of lipid/TRP-channel interactions and specific TRP-regulatory characteristics of the individual lipid families.


APOE genotype and extent of bleeding and outcome in lobar intracerebral haemorrhage: a genetic association study.
Carriers of APOE ε2 and ε4 have an increased risk of intracerebral haemorrhage (ICH) in lobar regions, presumably because of the effects of these gene variants on risk of cerebral amyloid angiopathy. We aimed to assess whether these variants also associate with severity of ICH, in terms of haematoma volume at presentation and subsequent outcome. We investigated the association of APOE ε2 and ε4 with ICH volume and outcomes in patients with primary ICH in three phases: a discovery phase of 865 individuals of European ancestry from the Genetics of Cerebral Hemorrhage on Anticoagulation study, and replication phases of 946 Europeans (replication 1) and 214 African-Americans (replication 2) from an additional six studies. We also assessed the association of APOE variants with ICH volume and outcomes in meta-analyses of results from all three phases, and the association of APOE ε4 with mortality in a further meta-analysis including data from previous reports. Admission ICH volume was quantified on CT scan. We assessed functional outcome (modified Rankin scale score 3-6) and mortality at 90 days. We used linear regression to establish the effect of genotype on haematoma volume and logistic regression to assess the effect on outcome from ICH. For patients with lobar ICH, carriers of the APOE ε2 allele had larger ICH volumes than did non-carriers in the discovery phase (p=2·5×10(-5)), in both replication phases (p=0·008 in Europeans and p=0·016 in African-Americans), and in the meta-analysis (p=3·2×10(-8)). In the meta-analysis, each copy of APOE ε2 increased haematoma size by a mean of 5·3 mL (95% CI 4·7-5·9; p=0·004). Carriers of APOE ε2 had increased mortality (odds ratio [OR] 1·50, 95% CI 1·23-1·82; p=2·45×10(-5)) and poorer functional outcomes (modified Rankin scale score 3-6; 1·52, 1·25-1·85; p=1·74×10(-5)) compared with non-carriers after lobar ICH. APOE ε4 was not associated with lobar ICH volume, functional outcome, or mortality in the discovery phase, replication phases, or meta-analysis of these three phases; in our further meta-analysis of 2194 patients, this variant did not increase risk of mortality (1·08, 0·86-1·36; p=0·52). APOE allele variants were not associated with deep ICH volume, functional outcome, or mortality. Vasculopathic changes associated with the APOE ε2 allele might have a role in the severity and clinical course of lobar ICH. Screening of patients who have ICH to identify the ε2 variant might allow identification of those at increased risk of mortality and poor functional outcomes. US National Institutes of Health-National Institute of Neurological Disorders and Stroke, Keane Stroke Genetics Research Fund, Edward and Maybeth Sonn Research Fund, and US National Center for Research Resources.


The effect of carbohydrate availability following exercise on whole-body insulin action.
One bout of exercise enhances insulin-stimulated glucose uptake (insulin action), but the effect is blunted by consumption of carbohydrate-containing food after exercise. The independent roles of energy and carbohydrate in mediating post-exercise insulin action have not been systematically evaluated in humans. The purpose of this study was to determine if varying carbohydrate availability, with energy intake held constant, mediates post-exercise insulin action. Ten young (21 +/- 2 y, overweight (body fat 37% +/- 3%) men and women completed 3 conditions in random order: (i) no-exercise (BASE), (ii) exercise with energy balance but carbohydrate deficit (C-DEF), and (iii) exercise with energy and carbohydrate balance (C-BAL). In the exercise conditions, subjects expended 30% of total daily energy expenditure on a cycle ergometer at 70% VO2 peak. Following exercise, subjects consumed a meal that replaced expended energy (~3000 kJ) and was either balanced (intake = expenditure) or deficient (-100 g) in carbohydrate. Twelve hours later, insulin action was measured by continuous infusion of glucose with stable isotope tracer (CIG-SIT). Changes in insulin action were evaluated using a one-way ANOVA with repeated measures. During CIG-SIT, non-oxidative glucose disposal (i.e., glucose storage) was higher in C-DEF than in BASE (27.2 +/- 3.2 vs. 16.9 +/- 3.5 micromol.L-1.kg-1.min-1, p < 0.05). Conversely, glucose oxidation was lower in C-DEF (8.6 +/- 1.3 micromol.L-1.kg-1.min-1) compared with C-BAL (12.2 +/- 1.2 micromol.L-1.kg-1.min-1), and BASE (17.1 +/- 2.2 micromol.L-1.kg-1.min-1), p < 0.05). Fasting fat oxidation was higher in C-DEF than in BASE (109.8 +/- 10.5 vs. 80.7 +/- 9.6 mg.min-1, p < 0.05). In C-DEF, enhanced insulin action was correlated with the magnitude of the carbohydrate deficit (r = 0.82, p < 0.01). Following exercise, re-feeding expended energy, but not carbohydrate, increased fasting fat oxidation, and shifted insulin-mediated glucose disposal toward increased storage and away from oxidation.


Genetic Connectivity among Populations of an Endangered Snake Species from Southeastern Australia (Hoplocephalus bungaroides, Elapidae).
For endangered species that persist as apparently isolated populations within a previously more extensive range, the degree of genetic exchange between those populations is critical to conservation and management. A lack of gene flow can exacerbate impacts of threatening processes and delay or prevent colonization of sites after local extirpation. The broad-headed snake, Hoplocephalus bungaroides, is a small venomous species restricted to a handful of disjunct reserves near Sydney, Australia. Mark-recapture studies have indicated low vagility for this ambush predator, suggesting that gene flow also may be low. However, our analyses of 11 microsatellite loci from 163 snakes collected in Morton National Park, from six sites within a 10-km diameter, suggest relatively high rates of gene flow among sites. Most populations exchange genes with each other, with one large population serving as a source area and smaller populations apparently acting as sinks. About half of the juvenile snakes, for which we could reliably infer parentage, were collected from populations other than those in which we collected their putative parents. As expected from the snakes' reliance on rocky outcrops during cooler months of the year, most gene flow appears to be along sandstone plateaux rather than across the densely forested valleys that separate plateaux. The unexpectedly high rates of gene flow on a landscape scale are encouraging for future conservation of this endangered taxon. For example, wildlife managers could conserve broad-headed snakes by restoring habitats near extant source populations in areas predicted to be least affected by future climate change.


Laparoscopic radical prostatectomy: Washington University initial experience and prospective evaluation of quality of life.
The laparoscopic approach to radical prostatectomy offers an alternative to the open surgical procedure with less morbidity. We prospectively collected data including a validated quality-of-life questionnaires on our first 38 laparoscopic radical prostatectomies (LRPs). The first 10 patients (group 1), second 10 patients (group II), and the most recent 18 patients (group III) were examined separately to study the learning curve for this procedure. In addition, we determined the pattern of recovery of urinary continence, potency, and quality of life. Between July 1999 and July 2002, 38 consecutive transperitoneal laparoscopic radical prostatectomies were performed for clinically localized prostate carcinoma. Patients completed quality-of-life questionnaires (Rand 36 Health Survey) before surgery as well as at 1, 3, 6, and 12 months and every 6 months thereafter. The patients were also interviewed by an individual not directly involved in patient care. One patient (the second in our experience) was converted to the open approach because of failure to progress. The average operating time for the whole series was 423 +/- 137.6 minutes (range 215-825 minutes), the last 10 procedures taking 305 +/- 63 minutes (range 215-420 minutes). Complications consisted of one case each of intraoperative bladder injury, transient superficial peroneal nerve palsy, pulmonary embolism, and bladder neck obstruction. The bladder injury was closed laparoscopically without further complication. Bladder neck obstruction was secondary to a bladder wall fold that was treated with transurethral resection 14 months after surgery with good results. Four patients in group 1 had minor anastomotic leaks, while only one patient after that had a leak (group III). Four patients required transfusion, two intraoperatively and two postoperatively. In group III, the urethral catheter remained in place for an average of 8 days (range 6-10 days). With a mean follow-up of 22.8 months (range 9-43 months), 84.8% of the patients had perfect urinary control. Postoperatively, 9 patients (27%) were fully continent on removal of the Foley catheter. At 1, 3, 6, and 9 months postoperatively, diurnal urinary control was reported by 30.3%, 48%, 72.7%, and 84.8% of the patients, respectively. One patient needed an artificial urinary sphincter. Among the incontinent patients, 24.2% had urinary urgency, and one third of these patients reported urge incontinence. Laparoscopic prostatectomy is a reproducible technique with a steep learning curve. Operating times and the incidence of anastomotic leaks and urinary incontinence decrease significantly after the initial 10 patients.


Comparing levels of perfluorinated compounds in processed marine products.
Perfluorinated compounds (PFCs) are widely distributed in nature and have many applications due to their unique chemical and physicochemical properties. While, PFCs are present in soil, water, and air, their pathway for entry into the human body is circumstantially via contaminated food. The demand for seafood has been increasing. In this study, we investigated via LC-MS/MS, the content of 19 different types of PFCs in 302 samples belonging to five different categories of the typical South Korean seafood. The highest levels of PFOA, PFTrDA, PFOS, and PFPeA were found in dried seafood, canned and salted seafood, processed fish food, and seasoned laver, respectively. The levels of PFOA and PFOS were compared on the basis of various criteria including the nomenclature, biological classification, and habitat of the source of seafood. High levels of PFOA and PFOS were detected in anchovy, sea squirt, and mackerel based on the nomenclature of raw seafood, in crustaceans based on the biological classification, and in demersal organisms based on the habitat. The human intake values of PFOA and PFOS from the processed marine products in South Korea were lower than the tolerable daily intake, indicating that the consumption of these processed seafood poses no immediate harm.


Experiences of acute mental health care in an ethnically diverse inner city: qualitative interview study.
Ethnic inequalities in experiences of mental health care persist in the UK, although most evidence derives from in-patient settings. We aimed to explore service users' and carers' accounts of recent episodes of severe mental illness and of the care received in a multi-cultural inner city. We sought to examine factors impacting on these experiences, including whether and how users and carers felt that their experiences were mediated by ethnicity. Forty service users and thirteen carers were recruited following an acute psychotic episode using typical case sampling. In-depth interviews explored illness and treatment experiences. Ethnicity was allowed to emerge in participants' narratives and was prompted if necessary. Ethnicity was not perceived to impact significantly on therapeutic relationships, and nor were there ethnic differences in care pathways, or in the roles of families and friends. Ethnic diversity was commonplace among both service users and mental health professionals. This was tolerated in community settings if efforts were made to ensure high-quality care. Home Treatment was rated highly, irrespective of service users' ethnicity. In-patient care was equally unpopular and was the one setting where ethnicity appeared to mediate unsatisfactory care experiences. These findings highlight the risks of generalising from reports of (dis)satisfaction with care based predominantly on in-patient experiences. Home treatment was popular but hard to deliver in deprived surroundings and placed a strain on carers. Interventions to enhance community treatments in deprived areas are needed, along with remedial interventions to improve therapeutic relationships in hospital settings.


Lyme Carditis Buried Beneath ST-Segment Elevations.
Lyme disease is caused by the spirochete Borrelia burgdorferi and is carried to human hosts by infected ticks. There are nearly 30,000 cases of Lyme disease reported to the CDC each year, with 3-4% of those cases reporting Lyme carditis. The most common manifestation of Lyme carditis is partial heart block following bacterial-induced inflammation of the conducting nodes. Here we report a 45-year-old gentleman that presented to the hospital with intense nonradiating chest pressure and tightness. Lab studies were remarkable for elevated troponins. EKG demonstrated normal sinus rhythm with mild ST elevations. Three weeks prior to hospital presentation, patient had gone hunting near Madison. One week prior to admission, he noticed an erythematous lesion on his right shoulder. Because of his constellation of history, arthralgias, and carditis, he was started on ceftriaxone to treat probable Lyme disease. This case illustrates the importance of thorough history taking and extensive physical examination when assessing a case of possible acute myocardial infarction. Because Lyme carditis is reversible, recognition of this syndrome in young patients, whether in the form of AV block, myocarditis, or acute myocardial ischemia, is critical to the initiation of appropriate antibiotics in order to prevent permanent heart block, or even death.


c/ebpdelta Null mouse as a model for the double knock-out of slc5a8 and slc5a12 in kidney.
slc5a8 and slc5a12 represent the high affinity and low affinity Na+/lactate co-transporters, respectively, in the kidney. Here we show that these transporters are expressed in the apical membrane of the proximal tubular cells in mouse kidney, indicating that these transporters are likely to mediate the first step in the renal reabsorption of lactate. Interestingly, the renal expression of both transporters is almost completely ablated in mice homozygous for the deletion of the transcription factor c/ebpdelta. This effect is tissue-specific since the expression of the transporters is not affected in non-renal tissues. The functional role of C/EBPdelta in the expression of SLC5A8 and SLC5A12 is demonstrable in HEK293 cells in reporter assays using gene-specific promoters. The ablation of the transporters in the kidney is accompanied by a marked increase in urinary excretion of lactate as well as a decrease in blood levels of lactate in c/ebpdelta-/- mice. These data provide evidence for an obligatory role for slc5a8 and slc5a12 in the renal absorption of lactate. In addition, we show that urinary excretion of urate is significantly elevated in c/ebpdelta-/- mice even though the expression of URAT1, the transporter responsible for the apical membrane uptake of urate in renal proximal tubule, is not altered. These data provide in vivo evidence for the functional coupling between lactate reabsorption and urate reabsorption in the kidney. Thus, the fortuitous double knock-out of slc5a8 and slc5a12 in kidney in c/ebpdelta-/- mice reveals the physiologic role of these transporters in the renal handling of lactate and urate.


Cyber-T web server: differential analysis of high-throughput data.
The Bayesian regularization method for high-throughput differential analysis, described in Baldi and Long (A Bayesian framework for the analysis of microarray expression data: regularized t-test and statistical inferences of gene changes. Bioinformatics 2001: 17: 509-519) and implemented in the Cyber-T web server, is one of the most widely validated. Cyber-T implements a t-test using a Bayesian framework to compute a regularized variance of the measurements associated with each probe under each condition. This regularized estimate is derived by flexibly combining the empirical measurements with a prior, or background, derived from pooling measurements associated with probes in the same neighborhood. This approach flexibly addresses problems associated with low replication levels and technology biases, not only for DNA microarrays, but also for other technologies, such as protein arrays, quantitative mass spectrometry and next-generation sequencing (RNA-seq). Here we present an update to the Cyber-T web server, incorporating several useful new additions and improvements. Several preprocessing data normalization options including logarithmic and (Variance Stabilizing Normalization) VSN transforms are included. To augment two-sample t-tests, a one-way analysis of variance is implemented. Several methods for multiple tests correction, including standard frequentist methods and a probabilistic mixture model treatment, are available. Diagnostic plots allow visual assessment of the results. The web server provides comprehensive documentation and example data sets. The Cyber-T web server, with R source code and data sets, is publicly available at http://cybert.ics.uci.edu/.


Bisphosphonates in multiple myeloma: a network meta-analysis.
Bisphosphonates are specific inhibitors of osteoclastic activity and used in the treatment of patients with multiple myeloma (MM). While bisphosphonates are shown to be effective in reducing vertebral fractures and pain, their role in improving overall survival (OS) remains unclear. This is an update of a Cochrane review first published in 2002 and previously updated in 2010. To assess the evidence related to benefits and harms associated with use of various types of bisphosphonates (aminobisphosphonates versus nonamino bisphosphonates) in the management of patients with MM. Our primary objective was to determine whether adding bisphosphonates to standard therapy in MM improves OS and progression-free survival (PFS), and decreases skeletal-related morbidity. Our secondary objectives were to determine the effects of bisphosphonates on pain, quality of life, incidence of hypercalcemia, incidence of bisphosphonate-related gastrointestinal toxicities, osteonecrosis of jaw and hypocalcemia. We searched MEDLINE, LILACS, EMBASE (December 2009 to October 2011) and the Cochrane Controlled Trials Register (all years, latest Issue September 2011) to identify all randomized trials in MM up to October 2011 using a combination of text and MeSH terms. We also handsearched relevant meeting proceedings (December 2009 to October 2011). Any randomized controlled trial (RCT) assessing the role of bisphosphonates and observational studies or case reports examining bisphosphonate-related osteonecrosis of the jaw in patients with MM were eligible for inclusion. Two review authors extracted the data. Data were pooled and reported as hazard ratio (HR) or risk ratio (RR) under a random-effects model. Statistical heterogeneity was explored using metaregression. In this update, we included 2 studies (2464 patients) that were not part of our last Cochrane review published in 2010. In this review we included 16 RCTs comparing bisphosphonates with either placebo or no treatment and 4 RCTs with a different bisphosphonate as a comparator. The 20 included RCTs enrolled 6692 patients. Overall methodological quality of reporting was moderate. Thirty per cent (6/20) of trials reported the method of generating the randomization sequence. Forty per cent (8/20) of trials had adequate allocation concealment. Withdrawals and dropouts were described in 60% (12/20) of trials. Pooled results showed no direct effect of bisphosphonates on OS compared with placebo or no treatment (HR 0.96, 95% CI 0.82 to 1.13; P = 0.64). However, there was a statistically significant heterogeneity among the included RCTs (I(2) = 55%, P = 0.01) for OS. To explain this heterogeneity we performed a metaregression assessing the relationship between bisphosphonate potency and improvement in OS, which found indicating an OS benefit with zoledronate (P = 0.058). This provided a further rationale for performing network meta-analyses of the various types of bisphosphonates that were not compared head to head in RCTs. Results from network meta-analyses showed superior OS with zoledronate compared with etidronate (HR 0.43, 95% CI 0.16 to 0.86) and placebo (HR 0.61, 95% CI 0.28 to 0.98). However, there was no difference between zoledronate and other bisphosphonates. Pooled analysis did not demonstrate a beneficial effect of bisphosphonates compared with placebo or no treatment in improving PFS (HR 0.70, 95% CI 0.41 to 1.19; P = 0.18) There was no heterogeneity among trials reporting PFS estimates (I(2) = 35%, P = 0.20).Pooled analysis demonstrated a beneficial effect of bisphosphonates compared with placebo or no treatment on prevention of pathological vertebral fractures (RR 0.74, 95% CI 0.62 to 0.89; I(2) = 7%), skeletal-related events (SRE) (RR 0.80, 95% CI 0.72 to 0.89; I(2) = 2%) and amelioration of pain (RR 0.75, 95% CI 0.60 to 0.95; I(2) = 63%). The network meta-analysis did not show any difference in the incidence of osteonecrosis of the jaw (5 RCTs, 3198 patients) between bisphosphonates. Rates of osteonecrosis of the jaw in observational studies (9 studies, 1400 patients) ranged from 0% to 51%. The pooled results (6 RCTs, 1689 patients) showed no statistically significant increase in frequency of gastrointestinal symptoms with the use of bisphosphonates compared with placebo or no treatment (RR 1.23, 95% CI 0.95 to 1.60; P = 0.11).The pooled results (3 RCTs, 1002 patients) showed no statistically significant increase in frequency of hypocalcemia with the use of bisphosphonates compared with placebo or no treatment (RR 2.19, 95% CI 0.49 to 9.74). The network meta-analysis did not show any differences in the incidence of hypocalcemia, renal dysfunction and gastrointestinal toxicity between the bisphosphonates used. Use of bisphosphonates in patients with MM reduces pathological vertebral fractures, SREs and pain. Assuming a baseline risk of 20% to 50% for vertebral fracture without treatment, between 8 and 20 MM patients should be treated to prevent vertebral fracture(s) in one patient. Assuming a baseline risk of 31% to 76% for pain amelioration without treatment, between 5 and 13 MM patients should be treated to reduce pain in one patient. With a baseline risk of 35% to 86% for SREs without treatment, between 6 and 15 MM patients should be treated to prevent SRE(s) in one patient. Overall, there were no significant adverse effects associated with the administration of bisphosphonates identified in the included RCTs. We found no evidence of superiority of any specific aminobisphosphonate (zoledronate, pamidronate or ibandronate) or nonaminobisphosphonate (etidronate or clodronate) for any outcome. However, zoledronate appears to be superior to placebo and etidronate in improving OS.


Can Original Knee Society Scores Be Used to Estimate New 2011 Knee Society Scores?
The Knee Society Score (KSS) instrument is one of the most commonly reported primary outcome measures for total knee arthroplasty (TKA). Originally developed in 1989, the KSS was expanded and updated in 2011; however, the original KSS does not directly translate into the 2011 KSS. To date, no conversion algorithm has been developed, hindering the ability of researchers to adopt the 2011 KSS while maintaining their historical/longitudinal original KSS data. The purpose of this study is to develop regression equations to map the original KSS to the 2011 KSS, allowing original and 2011 KSS data sets to be combined. In this multicenter, nonrandomized study, a convenience sample of 815 patients undergoing primary TKA completed the original KSS questionnaire and the 2011 KSS questionnaire. Additionally, patient gender, patient age, and patient ethnicity were recorded. These data were then used to generate regression models to estimate the 2011 objective and function KSS from the original KSS. Of the 815 study patients, 476 (58%) were female and 339 (42%) were male at an average age of 67 years (SD 9.4). Roughly half of patients were assessed preoperatively (430 of 815 [53%]) with the remaining patients assessed postoperatively (386 of 815 [47%]). The average followup for postoperative patients was 4.4 years (SD 3.5 years). We have created a spreadsheet that can be used by individuals with no statistical training to crosswalk the objective and function subscores from the original KSS to the 2011 KSS [Supplemental materials are available with the online version of CORR®.]. The predictive model very accurately estimated the 2011 objective score, on average, within 0.22 points on the 100-point 2011 objective KSS at the cohort or aggregate level. The objective model accurately estimated the 2011 objective KSS within 8.83 points, on average, of the actual 2011 objective KSS at the individual patient level. However, as a result of large outliers, 37% of the estimated 2011 objective KSS were greater than 10 points from the actual 2011 objective KSS. To illustrate, if you use the model to estimate the 2011 objective KSS on a cohort of 100 patients, a patient with an original objective KSS of 88 will have an estimated objective KSS between 79 and 97 points. On the other hand, if you calculate an average original objective KSS of 88 for all 100 patients, the estimated average 2011 objective KSS will be 88 for the group. The predictive model accurately estimated the 2011 function KSS within 0.14 points on the 1000-point 2011 function KSS at the cohort level. At the patient level, the 2011 function KSS was also estimated within 8.8 points of the actual 2011 function KSS. However, 43% of the estimated function scores were greater than 10 points of the actual 2011 function KSS. Clinicians and researchers can input their original KSS with demographic data into these equations to estimate the 2011 KSS objective and function scores. The small prediction error of 0.22 points that we calculated indicates that these models can be used to estimate the 2011 objective and function KSS at the aggregated cohort level. Although the average error score was within 10 points at the individual patient level, there was a high percentage of large errors resulting from outliers in the data set. These outliers seemed to be related to patients with excellent range of motion who had substantial pain and limited function or patients who have poor range of motion with excellent function and little pain. This may be inherent with the KSS or with the study sample. Nevertheless, one must use caution when estimating at the patient level. Additionally, the accuracy of the prediction scores decreases if any of the demographic variables included in this study are not available.


Hypertension and lifetime risk of stroke.
The lifetime risk (LTR) articulates the probability of disease in the residual lifetime for an index age. These estimates can be useful for general audience-targeted knowledge translation activities against hypertension. There are only a few reports on lifetime of impact of hypertension on stroke events in Asians in whom stroke incidence is higher than Westerners. The Suita Study, a cohort study of cardiovascular diseases in Japan, was established in 1989. We included all participants who were stroke free at baseline. Age (in years) was used as the time scale. Age-specific incidence rates were calculated with person-year method within 10-year bands. We estimated the sex and index-age specific LTR of first-ever stroke with taking the competing risk of death into account. We followed 5783 men and women during 1989-2007 for 74 933 person-years. During the follow-up period, 276 (149 men and 127 women) participants had incident stroke. Of them, majority were cerebral infarction; 166 (102 men and 64 women). The LTR of stroke, accounted for competing risk of death, at 45 years of age for men without hypertension was 17.21% and it was 32.79% for hypertensive men. Among the hypertensive patients, participants with stage 2 or greater hypertension had higher LTR of stroke than the participants with stage 1 hypertension. This increased LTR of stroke for hypertensive patients were also observed among women and across all index ages for stroke. In this urban community-based population, we observed that hypertension has significant effect on the residual LTR of stroke among both men and women of middle age, specifically for ischemic stroke.


Training Monitoring for Resistance Exercise: Theory and Applications.
Resistance exercise is difficult to quantify owing to its inherent complexity with numerous training variables contributing to the training dose (type of exercise, load lifted, training volume, inter-set rest periods, and repetition velocity). In addition, the intensity of resistance training is often inadequately determined as the relative load lifted (% 1-repetition maximum), which does not account for the effects of inter-set recovery periods, repetition velocity, or the number of repetitions performed in each set at a given load. Methods to calculate the volume load associated with resistance training, as well as the perceived intensity of individual sets and entire training sessions have been shown to provide useful information regarding the actual training stimulus. In addition, questionnaires to subjectively assess how athletes are coping with the stressors of training and portable technologies to quantify performance variables such as concentric velocity may also be valuable. However, while several methods have been proposed to quantify resistance training, there is not yet a consensus regarding how these methods can be best implemented and integrated to complement each other. Therefore, the purpose of this review is to provide practical information for strength coaches to highlight effective methods to assess resistance training, and how they can be integrated into a comprehensive monitoring program.


Neonatal and Infantile Epilepsy: Acquired and Genetic Models.
The incidence of seizures and epilepsies is particularly high during the neonatal and infantile periods. We will review selected animal models of early-life epileptic encephalopathies that have addressed the dyscognitive features of frequent interictal spikes, the pathogenesis and treatments of infantile spasms (IS) or Dravet syndrome, disorders with mammalian target of rapamycin (mTOR) dysregulation, and selected early-life epilepsies with genetic defects. Potentially pathogenic mechanisms in these conditions include interneuronopathies in IS or Dravet syndrome and mTOR dysregulation in brain malformations, tuberous sclerosis, and related genetic disorders, or IS of acquired etiology. These models start to generate the first therapeutic drugs, which have been specifically developed in immature animals. However, there are challenges in translating preclinical discoveries into clinically relevant findings. The advances made so far hold promise that the new insights may potentially have curative or disease-modifying potential for many of these devastating conditions.


Convergence properties of the softassign quadratic assignment algorithm.
The softassign quadratic assignment algorithm is a discrete-time, continuous-state, synchronous updating optimizing neural network. While its effectiveness has been shown in the traveling salesman problem, graph matching, and graph partitioning in thousands of simulations, its convergence properties have not been studied. Here, we construct discrete-time Lyapunov functions for the cases of exact and approximate doubly stochastic constraint satisfaction, which show convergence to a fixed point. The combination of good convergence properties and experimental success makes the softassign algorithm an excellent choice for neural quadratic assignment optimization.


Rhythmic cueing, dance, resistance training, and Parkinson's disease: A systematic review and meta-analysis.
The aim of the present systematic review and meta-analysis was to synthesize evidence associated with the functional and clinical effectiveness of rhythmic cueing, dance, or resistance training (RT) on motor and non-motor parameters in Parkinson's Disease patients, and to provide a comparative perspective not offered by existing systematic reviews. Eligibility criteria for selecting studies retained no restrictions in methodological design and included interventions of rhythmic cueing, dance, RT, and measurements of motor and non-motor parameters. Animal studies, reviews, editorials, conferences, magazines, and gray literature articles were excluded. Two independent investigators searched Cochrane Library, Medline, PubMed, and SPORTDiscus from the date of their inception until 1 June 2021. The ROBINS-I tool was employed for the non-randomized controlled trials, and the updated for Risk of Bias 2 tool of Cochrane Library used for randomized controlled trials. For meta-analyses, the RevMan 5.4.13 software was used. For incompatible meta-analysis studies, a narrative data synthesis was conducted. A total of 49 studies included in the systematic review involving 3767 PD participants. Meta-analyses revealed that rhythmic cueing training assists gait velocity (p = 0.01), stride length (p = 0.01), and motor symptoms (p = 0.03). Similarly, dance training benefits stride length (p = 0.05), lower extremity function-TUG (p = 0.01), and motor symptoms (p = 0.01), whilst RT improves lower extremity function-TUG (p = 0.01), quality of life (p = 0.01), knee flexion (p = 0.02), and leg press (p = 0.01). Subgroup analyses have shown non-significant differences in gait velocity (p = 0.26), stride length (p = 0.80), functional mobility-TUG (p = 0.74), motor symptoms-UPDRS-III (p = 0.46), and quality of life-PDQ39 (p = 0.44). Rhythmic cueing, dance, or RT positively affect the examined outcomes, with rhythmic cueing to be associated with three outcomes (Gait, Stride, and UPDRS-III), dance with three outcomes (TUG, Stride, and UPDRS-III), and RT with two outcomes (TUG and PDQ-39). Subgroup analyses confirmed the beneficial effects of these forms of exercise. Clinicians should entertain the idea of more holistic exercise protocols aiming at improving PD manifestations.International Prospective Register of systematic reviews (PROSPERO) (registration number: CRD42020212380).


Pathview Web: user friendly pathway visualization and data integration.
Pathway analysis is widely used in omics studies. Pathway-based data integration and visualization is a critical component of the analysis. To address this need, we recently developed a novel R package called Pathview. Pathview maps, integrates and renders a large variety of biological data onto molecular pathway graphs. Here we developed the Pathview Web server, as to make pathway visualization and data integration accessible to all scientists, including those without the special computing skills or resources. Pathview Web features an intuitive graphical web interface and a user centered design. The server not only expands the core functions of Pathview, but also provides many useful features not available in the offline R package. Importantly, the server presents a comprehensive workflow for both regular and integrated pathway analysis of multiple omics data. In addition, the server also provides a RESTful API for programmatic access and conveniently integration in third-party software or workflows. Pathview Web is openly and freely accessible at https://pathview.uncc.edu/.


[State of infection caused by methicillin-resistant Staphylococcus aureus (MRSA) in Extremadura: susceptibility, clonality and role of community-associated MRSA].
The correct surveillance and control of infection caused by methicillin-resistant Staphylococcus aureus (MRSA) needs of update knowledge of its specific properties in each place. Our study aims to describe the current characteristics of infection due to MRSA in Extremadura. During 2010, 309 MRSA were collected from clinical samples in our region. A susceptibility test that included 17 antibiotics tested by AST -588 card Vitek 2 ® and E -test method was performed on all isolates. A sample of 100 strains, selected by stratified random sampling, were genotyped by pulsed field electrophoresis (PFGE). The prevalence of MRSA in Extremadura was 20.2%. Don Benito-Villanueva area showed the most prevalence and a higher incidence. Merida reported the most favourable situation, with a relatively low ratios of prevalence and incidence. The community acquired reached 44 % in the region, showing predominantly in less populated areas (Navalmoral and Coria). The most common multiresistant pattern was tobramycin-levofloxacin-erythromycin (44%), followed tobramycin-erythromycin-clindamycin (20%). No linezolid, daptomycin and tigecycline resistant strains were observed, but 42 % of the MRSA strains showed decreased susceptibility vancomycin (DSV). PFGE analysis reported 27 genotypes, with 3 major genotypes: E8a (25%), E7b (17%) and E7a (12%). The post-hoc statistical analysis did not reveal significant differences in the distribution of genotypes between different areas. However it revealed some trends that should be considered.


Dual T cell receptor T cells with two defined specificities mediate tumor suppression via both receptors.
Grafting T cells with new antigen specificity by T cell receptor (TCR) gene transfer could greatly facilitate adoptive T cell immunotherapy. Little is known about how two TCR on one T cell influence each other. Among other reasons, this is often due to the fact that only one TCR specificity is known. We have genetically generated murine dual TCR T cells (OT-I/P14), specific for ovalbumin(ova257) and lymphocyte choriomeningitis virus glycoprotein (gp33). These cells retain both specificities and can be stimulated by either antigenic peptide to proliferate and produce IFN-gamma. Even though one TCR (P14) is expressed at reduced levels on dual TCR T cells, the peptide sensitivity of these cells is similar to that of single TCR T cells of the same specificity. TCR down-modulation on dual TCR T cells depends primarily on binding of the specific ligand. Adoptively transferred dual TCR T cells suppress the growth of both B16-ova and B16-gp33 melanoma cells, regardless of the peptide used for in vitro activation. Taken together, despite a certain dominance of expression between two TCR on the same T cell, this need not necessarily have functional consequences.


Greenspace in urban neighbourhoods and residents' health: adding quality to quantity.
Previous research shows a positive link between the amount of green area in one's residential neighbourhood and self-reported health. However, little research has been done on the quality of the green area, as well as on quantity and quality of smaller natural elements in the streetscape. This study investigates the link between the objectively assessed quantity and quality of (1) green areas and (2) streetscape greenery on the one hand and three self-reported health indicators on the other. 80 Dutch urban neighbourhoods were selected, varying in the amount of nearby green area per dwelling, as determined by Geographic Information System analysis. The quality of green areas, as well as the quantity and quality of streetscape greenery, was assessed by observers using an audit tool. Residents of each neighbourhood were asked to complete a questionnaire on their own health (N=1641). In multilevel regression analyses, we examined the relationship between greenspace indicators and three health indicators, controlling for socio-demographic and socioeconomic characteristics. Both indicators for the quantity of greenspace were positively related to all three health indicators. Quantity and quality indicators were substantially correlated in the case of streetscape greenery. Nevertheless, the quality indicators tended to have added predictive value for the health indicators, given that the quantity information was already included in the model. The quantity and also the quality of greenspace in one's neighbourhood seem relevant with regard to health. Furthermore, streetscape greenery is at least as strongly related to self-reported health as green areas.


Age at menarche and risk of asthma: systematic review and meta-analysis.
Several studies have suggested a relationship between the age at menarche and risk of asthma development. To conduct a systematic review and meta-analysis of the relationship between the age at menarche and the risk of asthma. This systematic review and meta-analysis was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA). A pre specified literature search strategy was used to identify studies of potential relevance and independent reviews were carried out by two authors. Raw data was pooled using the software package RevMan to calculate summary odds ratios. The risk of publication bias was assessed graphically by using a funnel plot and the robustness of the overall estimate obtained was assessed by using sensitivity analyses. The searches identified 61 potentially relevant articles of which seven articles, with a total of 22,859 subjects, matched the inclusion criteria for the meta-analysis. Pooling of the seven studies showed that girls with early menarche (<12 years) had an increased risk of asthma relative to girls with late menarche; random effects odds ratio = 1.37 (1.15-1.64), (p = 0.0005). Substantial heterogeneity was revealed (I(2) = 55%). Sensitivity analysis showed that the risk estimate was not markedly changed when excluding any of the studies. The funnel plot did not indicate publication bias. Early menarche appears to be associated with increased risk of asthma. Hormonal, immunological, genetic and environmental factors may act in a developmental context to explain this relationship. Future studies are warranted to further determine the mechanisms responsible for this observation.


Assisting couples to develop healthy relationships: effects of couples relationship education on cortisol.
Couple conflict in unhappy marriages is suggested to impair individual health via chronic psychophysiological stress reactions in couples' everyday lives. As a consequence, we hypothesized that standard couples relationship education (CRE) would decrease psychophysiological stress, namely salivary cortisol levels, during couple conflict in the laboratory as compared to a standard psychological stress paradigm. We considered cortisol to be of particular interest in this context, as it mediates endocrine and immune responses to stress, and thus might influence couples' health. Salivary cortisol was repeatedly investigated in 61 couples during (a) a standard psychological stress test with no relevance for the couples, and (b) a standard couple conflict discussion in the laboratory before and after CRE. In addition, increases in self-evaluated relationship quality were analyzed with regard to their influence on salivary cortisol. Data were analyzed using multilevel modeling. Cortisol responses to the couple-external psychological stress test were unaffected by CRE, but specifically cortisol responses during the couple conflict discussion were significantly reduced following CRE compared to pre-intervention levels. Moreover, cortisol decreases during conflict were partially mediated by increases in self-reported relationship quality following CRE. These data suggest that CRE might buffer the harmful effects of repeated conflict in close relationships. Rather than ameliorating overall stress resilience, CRE might thus specifically improve individual health through increased relationship quality and reduced HPA axis activity during couple conflict.


Cognitive reserve as a moderator of the negative association between mood and cognition: evidence from a population-representative cohort.
Cognitive reserve (CR) has been associated with better cognitive function and lower risk of depression in older people, yet it remains unclear whether CR moderates the association between mood and cognition. This study aimed to investigate whether a comprehensive indicator of CR, including education, occupation and engagement in cognitive and social activities, acts as a moderator of this association. This was a cross-sectional study utilising baseline data from the Cognitive Function and Ageing Study II (CFAS II), a large population-based cohort of people aged 65+ in England. Complete data on the measures of CR, mood and cognition were available for 6565 dementia-free individuals. Linear regression models were used to investigate the potential modifying effect of CR on the association between cognition and mood with adjustment for age, sex and missing data. Levels of CR did moderate the negative association between mood and cognition; the difference in cognition between those with and without a clinical level mood disorder was significantly smaller in the middle (-2.28; 95% confidence interval (CI) -3.65 to -0.90) and higher (-1.30; 95% CI -2.46 to -0.15) CR groups compared with the lower CR group (-4.01; 95% CI -5.53 to -2.49). The individual components of CR did not significantly moderate the negative association between mood and cognition. These results demonstrate that CR, indexed by a composite score based on multiple indicators, can moderate the negative association between lowered mood and cognition, emphasising the importance of continuing to build CR across the lifespan in order to maintain cognitive health.