EUFOREA Rhinology Research Forum 2016: report of the brainstorming sessions on needs and priorities in rhinitis and rhinosinusitis.
The first European Rhinology Research Forum organized by the European Forum for Research and Education in Allergy and Airway Diseases (EUFOREA) was held in the Royal Academy of Medicine in Brussels on 17th and 18th November 2016, in collaboration with the European Rhinologic Society (ERS) and the Global Allergy and Asthma European Network (GA2LEN). One hundred and thirty participants (medical doctors from different specialties, researchers, as well as patients and industry representatives) from 27 countries took part in the multiple perspective discussions including brainstorming sessions on care pathways and research needs in rhinitis and rhinosinusitis. The debates started with an overview of the current state of the art, including weaknesses and strengths of the current practices, followed by the identification of essential research needs, thoroughly integrated in the context of Precision Medicine (PM), with personalized care, prediction of success of treatment, participation of the patient and prevention of disease as key principles for improving current clinical practices. This report provides a concise summary of the outcomes of the brainstorming sessions of the European Rhinology Research Forum 2016.


Multichannel scanning probe microscopy and spectroscopy of graphene moiré structures.
The graphene moiré structures on 4d and 5d metals, as they demonstrate both long (moiré) and short (atomic) scale ordered structures, are the ideal systems for the application of scanning probe methods. Taking graphene-Ir(111) as an example, we present the complex studies of this graphene-metal moiré-structure system by means of 3D scanning tunnelling and atomic force microscopy/spectroscopy as well as Kelvin-probe force microscopy. The results clearly demonstrate variation of the moiré and atomic scale contrast as a function of the bias voltage as well as the distance between the scanning probe and the sample, allowing one to discriminate between topographic and electronic contributions in the imaging of a graphene layer on metals. The presented results are compared with the state-of-the-art density functional theory calculations demonstrating excellent agreement between theoretical and experimental data.


Why do states privatize mental health services? Six state experiences. The MEDSTAT Group.
State governments fund more than one-half of public mental health service system costs through mental health departments, other state agencies, and the Medicaid program. They use some of these resources to finance community-based mental health services through purchase-of-service contracts. I explored the reasons why states privatize mental health services and focused on political, economic, and organizational theories as possible frameworks for contracting. I gathered data during site visits to Massachusetts, Michigan, New York, Oregon, Tennessee, and Texas, where I interviewed more than one hundred individual stakeholders about mental health purchase-of-service contracting. I also examined relevant documents about contracting practices for mental health services in each state. My results suggest that state policy makers can use mental health contracting to effect multiple goals. Contracting helps states achieve political, economic, and organizational objectives, such as avoiding the influence of interest groups and leveraging state resources, while avoiding conflict. With contracting, state policy makers can also continue the ongoing mental health policy paradigm shift begun during deinstitutionalization, in which persons with serious and persistent mental illnesses receive services from community-based providers rather than in state hospitals. Finally, my results suggest that contracting will continue to be an important state policy tool in further development of state-supported mental health systems.


Small vulnerable newborns-big potential for impact.
Despite major achievements in child survival, the burden of neonatal mortality has remained high and even increased in some countries since 1990. Currently, most neonatal deaths are attributable to being born preterm, small for gestational age (SGA), or with low birthweight (LBW). Besides neonatal mortality, these conditions are associated with stillbirth and multiple morbidities, with short-term and long-term adverse consequences for the newborn, their families, and society, resulting in a major loss of human capital. Prevention of preterm birth, SGA, and LBW is thus critical for global child health and broader societal development. Progress has, however, been slow, largely because of the global community's failure to agree on the definition and magnitude of newborn vulnerability and best ways to address it, to frame the problem attractively, and to build a broad coalition of actors and a suitable governance structure to implement a change. We propose a new definition and a conceptual framework, bringing preterm birth, SGA, and LBW together under a broader umbrella term of the small vulnerable newborn (SVN). Adoption of the framework and the unified definition can facilitate improved problem definition and improved programming for SVN prevention. Interventions aiming at SVN prevention would result in a healthier start for live-born infants, while also reducing the number of stillbirths, improving maternal health, and contributing to a positive economic and social development in the society.


Is Serum Bicarbonate Level Associated With Negative Outcomes in Pediatric Patients?: A Retrospective Cohort Study.
Early identification of children at risk for adverse outcomes is important. Serum bicarbonate is easily collected and widely available. We described the relationship between bicarbonate and adverse outcomes in children presenting to the emergency department (ED). We conducted a retrospective cohort study of children aged 0 to 17 years from January 1, 2007, to December 31, 2011, who had a serum bicarbonate measured in the ED. Primary outcome was the predictive ability of bicarbonate for the individual components of the composite outcome that included at least one of the following: intensive care unit admission, assisted ventilation, inotropic support, cardiopulmonary resuscitation, or death. Secondary outcome was the relationship between bicarbonate level of greater and less than 13 mEq/L and the composite outcome. We reviewed 16,989 charts, of which 432 had an adverse outcome. Receiver operating characteristic curve analysis showed that a bicarbonate level of less than 18.5 mEq/L predicted inotropic support with an area under the curve of 0.69 (95% confidence interval [CI], 0.60-0.77; P < 0.001) and death with an area under the curve of 0.75 (CI, 0.66-0.85; P < 0.001). Significantly more patients with bicarbonate level of less than 13 mEq/L had at least 1 adverse outcome compared with those with bicarbonate level of greater than 13 mEq/L (4.4% vs 2.5%, P = 0.001), odds ratio 1.96 (95% CI, 1.3-2.97). Among children presenting to the ED, bicarbonate level of 18.5 mEq/L had fair specificity in predicting inotropic support and death. Negative outcomes are significantly associated with bicarbonate level of less than 13 mEq/L. Bicarbonate should routinely be measured in children at risk of clinical deterioration.


Injury prevention and risk communication: a mental models approach.
Individuals' decisions and behaviour can play a critical role in determining both the probability and severity of injury. Behavioural decision research studies peoples' decision-making processes in terms comparable to scientific models of optimal choices, providing a basis for focusing interventions on the most critical opportunities to reduce risks. That research often seeks to identify the 'mental models' that underlie individuals' interpretations of their circumstances and the outcomes of possible actions. In the context of injury prevention, a mental models approach would ask why people fail to see risks, do not make use of available protective interventions or misjudge the effectiveness of protective measures. If these misunderstandings can be reduced through context-appropriate risk communications, then their improved mental models may help people to engage more effectively in behaviours that they judge to be in their own best interest. If that proves impossible, then people may need specific instructions, not trusting to intuition or even paternalistic protection against situations that they cannot sufficiently control. The method entails working with domain specialists to elicit and create an expert model of the risk situation, interviewing lay people to elicit their comparable mental models, and developing and evaluating communication interventions designed to close the gaps between lay people and experts. This paper reviews the theory and method behind this research stream and uses examples to discuss how the approach can be used to develop scientifically validated context-sensitive injury risk communications.


Moral People or Moral Projects? Worker Altruism in Youth Residential Treatment.
Paraprofessional youth care workers in residential treatment centers (RTCs) are responsible for the everyday care, supervision, and treatment of youth with serious behavioral and mental health challenges. Turnover rates among this poorly paid workforce are high, and it is not known why individuals seek and maintain youth care work despite its significant challenges. Following anthropologists who study morality as situated practice, we investigate the role of altruism in recruiting and retaining workers in RTCs. We ask: How do managers and youth care workers understand altruism and its role in youth care work and what are the consequences of those understandings? Through organizational ethnography of an RTC, we show that workers and management understood altruism differently. Managers viewed altruism as an inherent trait of some and attributed turnover to its lack. Although workers sometimes enacted this script, they understood themselves as engaged in far more complex situated moral projects in which altruism was only one part. We demonstrate political effects of these differing understandings of altruism, namely, that management deflected institutional critique by viewing it as a sign of workers' immorality. We offer modest recommendations for RTCs seeking to recruit and retain competent youth care workers and address potential new directions for moral anthropology of organizations.


Is there a Link between Vitamin B and Multiple Sclerosis?
Damage to the myelin sheath (demyelination) is one of the main manifestations of multiple sclerosis (MS). Interestingly, both MS and vitamin B deficiencies result in severe myelin degeneration, leading to loss in neuronal signal transmission. Deficiency in vitamin B complex vary, although common symptoms include fatigue, increased oxidative stress, inflammation and demyelination. In particular, vitamin B12 (cobalamin) has had increased attention for its role in the methylation process, involvement in myelination and remyelination, and reversal of MS symptoms. Here, we discuss the role of vitamin B complex (B1, B2, B3, B4, B5, B6, B7, B9, B12) in MS. The anti-inflammatory and re-myelinating attributes of vitamin B complex members are promising, despite limited clinical studies. There is an urgent need for larger studies to determine the role of vitamin B supplementation alone, or in combination with other therapeutic agents, in prevention or reversal of MS, and aid in improved quality of life of MS patients.


Repurposing isoxazoline veterinary drugs for control of vector-borne human diseases.
Isoxazolines are oral insecticidal drugs currently licensed for ectoparasite control in companion animals. Here we propose their use in humans for the reduction of vector-borne disease incidence. Fluralaner and afoxolaner rapidly killed Anopheles, Aedes, and Culex mosquitoes and Phlebotomus sand flies after feeding on a drug-supplemented blood meal, with IC50 values ranging from 33 to 575 nM, and were fully active against strains with preexisting resistance to common insecticides. Based on allometric scaling of preclinical pharmacokinetics data, we predict that a single human median dose of 260 mg (IQR, 177-407 mg) for afoxolaner, or 410 mg (IQR, 278-648 mg) for fluralaner, could provide an insecticidal effect lasting 50-90 days against mosquitoes and Phlebotomus sand flies. Computational modeling showed that seasonal mass drug administration of such a single dose to a fraction of a regional population would dramatically reduce clinical cases of Zika and malaria in endemic settings. Isoxazolines therefore represent a promising new component of drug-based vector control.


A cluster randomised trial of a Needs Assessment Tool for adult Cancer patients and their carers (NAT-C) in primary care: A feasibility study.
People with cancer often have unidentified symptoms and social care needs. The Needs Assessment Tool-Cancer (NAT-C) is a validated, structured method of assessing patient/carer concerns and prompting action, to address unmet need. Assess feasibility and acceptability of a definitive two-armed cluster randomised trial of NAT-C in primary care by evaluating: recruitment of GP practices, patients and carers; most effective approach of ensuring NAT-C appointments, acceptability of study measures and follow-up. Non-blinded, feasibility study in four General Practices, with cluster randomisation to method of NAT-C appointment delivery, and process evaluation. Adults with active cancer were invited to participate with or without carer. Practices cluster randomised (1:1) to Arm I: promotion and use of NAT-C with a NAT-C trained clinician or Arm II: clinician of choice irrespective of training status. Participants completed study questionnaires at: baseline, 1, 3 and 6 months. Patients booked a 20 minute needs-assessment appointment post-baseline. Patients, carers and GP practice staff views regarding the study sought through interviews/focus groups. Quantitative data were analysed descriptively. Qualitative data were analysed thematically, informed by Normalisation Process Theory. Progression to a definitive trial was assessed against feasibility outcomes, relating to: recruitment rate, uptake and delivery of the NAT-C, data collection and quality. Five GP practices approached, four recruited and trained to use the NAT-C. Forty-seven participants and 17 carers recruited. At baseline, 34/47 (72%) participants reported at least one moderate-severe unmet need, confirming study rationale. 32/47 (68%) participants received a NAT-C-guided consultation, 19 of which on Arm I. Study attrition at one month (n = 44 (94%), n = 16 (94%)), three months (n = 38 (81%), n = 14 (82%)) and six months (n = 32 (68%), n = 10 (59%)). Fifteen patient interviews conducted across the whole study and one focus group at each GP practice. Participants supported a definitive study and found measures acceptable. The feasibility trial indicated that recruitment rate, intervention uptake and data collection were appropriate, with refinements, for a definitive multi-centre cluster randomised controlled trial. Feasibility outcomes informed the design of a 2-armed cluster randomised controlled trial to test the effectiveness and cost-effectiveness of the NAT-C compared with usual care.


Polyfunctional analysis of human cytomegalovirus (HCMV)-specific CD4(+) and CD8 (+) memory T-cells in HCMV-seropositive healthy subjects following different stimuli.
Following primary human cytomegalovirus (HCMV) infection, both humoral and T-cell-mediated immune responses develop in immunocompetent subjects. However, while antibodies may be measured by different methodologies, the T-cell-mediated response remains to be analyzed in its polyfunctional aspects, in view of defining (following different stimuli) the optimal assay to monitor the HCMV-specific T-cell response in HCMV-seropositive subjects. In a group of 30 HCMV-seropositive adults, T-cell response revealed by the HCMV-infected dendritic cell (iDC) stimulus was compared with those given by the HCMV-infected cell lysate (iCL), and by a 34-peptide pool (PP). All HCMV-seropositive subjects showed presence of both HCMV-specific CD4(+) and CD8(+) T-cells in peripheral blood following iDC stimulation. One subject did not respond to PP. As compared to iDC, the number of HCMV-specific stimulated T-cells/μl blood was slightly lower for iCL (P = 0.195) and significantly lower for PP (P = 0.001). Polyfunctional analysis of the T-cell response indicated that the lower number of CD4(+) T-cells stimulated by iCL was due to the bifunctional (IFN-γ(+) TNF-α(+)) and CD40L-negative T-cell reduction, while the reduction in specific PP-stimulated CD8(+) T-cells was attributable to the reduction in tri-(IFN-γ(+) TNF-α(+) IL2(+)), bi-(IFN-γ(+) TNF-α(+)) and mono-(IFN-γ(+)) functional T-cells. In addition, 15/30 (50 %) subjects showed a CD4(+) cross-response to PP, and 11/30 (37 %) a CD8(+) cross-response to iCL. HCMV-specific stimulus given by iDC is not significantly different from that of iCL on CD4(+) and is significantly superior to that of PP on CD8+ T-cells. However, iCL may contribute significantly to CD8(+), and PP to CD4(+) T-cell stimulation.


Gallery Game: Smartphone-based assessment of long-term memory in adults at risk of Alzheimer's disease.
Introduction: Gallery Game, deployed within the Mezurio smartphone app, targets the processes of episodic memory hypothesized to be first vulnerable to neurofibrillary tau-related degeneration in Alzheimer's Disease, prioritizing both perirhinal and entorhinal cortex/hippocampal demands.Methods: Thirty-five healthy adults (aged 40-59 years), biased toward those at elevated familial risk of dementia, completed daily Gallery Game tasks for a month. Assessments consisted of cross-modal paired-associate learning, with subsequent tests of recognition and free recall following delays ranging from one to 13 days.Results: Retention intervals of at least three days were needed to evidence significant forgetting at both recognition and paired-associate recall test. The association between Gallery Game outcomes and established in-clinic memory assessments were small but numerically in the anticipated direction. In addition, there was preliminary support for utilizing the perirhinal-dependent pattern of semantic false alarms during object recognition as a marker of early impairment.Conclusions: These results support the need for tests of longer-term memory to sensitively record behavioral differences in adults with no diagnosis of cognitive impairment. Aggregate behavioral outcomes promote Gallery Game's utility as a digital assessment of episodic memory, aligning with established theoretical models of object memory and showing small yet uniform associations with existing in-clinic tests. Initial support for the discriminatory value of perirhinal-targeted outcomes justifies ongoing large-sample validation against traditional biomarkers of Alzheimer's disease.


Connexin defects underlie arrhythmogenic right ventricular cardiomyopathy in a novel mouse model.
Arrhythmogenic right ventricular cardiomyopathy (ARVC) termed a 'disease of the desmosome' is an inherited cardiomyopathy that recently underwent reclassification owing to the identification of left-dominant and biventricular disease forms. Homozygous loss-of-function mutations in the desmosomal component, desmoplakin, are found in patients exhibiting a biventricular form of ARVC; however, no models recapitulate the postnatal hallmarks of the disease as seen in these patients. To gain insights into the homozygous loss-of-function effects of desmoplakin in the heart, we generated cardiomyocyte-specific desmoplakin-deficient mice (DSP-cKO) using ventricular myosin light chain-2-Cre mice. Homozygous DSP-cKO mice are viable but display early ultrastructural defects in desmosomal integrity leading to a cardiomyopathy reminiscent of a biventricular form of ARVC, which includes cell death and fibro-fatty replacement within the ventricle leading to biventricular dysfunction, failure and premature death. DSP-cKO mice also exhibited ventricular arrhythmias that are exacerbated with exercise and catecholamine stimulation. Furthermore, DSP-cKO hearts exhibited right ventricular conduction defects associated with loss of connexin 40 expression and electrical wavefront propagation defects associated with loss of connexin 43 expression. Dose-dependent assessment of the effects of loss of desmoplakin in neonatal ventricular cardiomyocytes revealed primary loss of connexin 43 levels, phosphorylation and function independent of the molecular dissociation of the mechanical junction complex and fibro-fatty manifestation associated with ARVC, suggesting a role for desmoplakin as a primary stabilizer of connexin integrity. In summary, we provide evidence for a novel mouse model, which is reminiscent of the postnatal onset of ARVC while highlighting mechanisms underlying a biventricular form of human ARVC.


The Rate of Age-Related Olfactory Decline Among the General Population of Older U.S. Adults.
Age-related olfactory loss (presbyosmia) is a prevalent sensory impairment with a large public health impact. In cross-sectional analyses, we found striking health disparities in olfactory function among older U.S. adults. Here, we report a 5-year follow-up to determine the magnitude of within-person olfactory decline. The National Social Life, Health, and Aging Project (NSHAP) interviewed a probability sample of home-dwelling older U.S. adults (57-85 years) in 2005-2006 (Wave 1) and reinterviewed them in 2010-2011 (Wave 2), assessing demographics, social life, and health, including olfaction. Odor identification was measured with a 5-item version of the Sniffin' Sticks (0-5 correct). Fourteen hundred and thirty-six respondents provided olfaction data in both waves. Multivariate linear and logistic regression were used to model the association between change in olfactory performance and demographic, health, and psychosocial factors. Odor identification declined most rapidly among older individuals (0.25 additional errors per 5 years for each decade of age, p < .001) and in men (0.17 additional errors per 5 years compared to women, p = .005). Among those with perfect scores in Wave 1, African Americans declined more rapidly than Whites (p = .04). Neither socioeconomic status, health conditions, cognition, mental health, alcohol use nor smoking was associated with change in olfaction (p > .05, all). The rate of olfactory decline increases with age and is greater among men than women despite adjusting for differences in psychosocial and health conditions, indicating physiologic factors as drivers. African Americans are more likely to experience initial olfactory decline, consistent with an earlier onset of aging among this subgroup.


Lesion of cholinergic neurons in nucleus basalis enhances response to general anesthetics.
Acetylcholine in the brain has been associated with consciousness and general anesthesia effects. We tested the hypothesis that the integrity of the nucleus basalis magnocellularis (NBM) affects the response to general anesthetics. Cholinergic neurons in NBM were selectively lesioned by bilateral infusion of 192IgG-saporin in adult, male Long-Evans rats, and control rats were infused with saline. Depletion of choline-acetyltransferase (ChAT)-immunoreactive cells in the NBM and decrease in optical density of acetylcholinesterase (AChE) staining in the frontal and visual cortices confirmed a significant decrease in NBM cholinergic neurons in lesioned as compared to control rats. AChE staining in the hippocampus and ChAT-positive neurons in the medial septum-vertical limb of the diagonal band were not different between lesioned and control rats. When a general anesthetic was administered, lesioned compared to control rats showed significantly longer duration of loss of righting reflex (LORR) after propofol (5 or 10mg/kg i.v.), pentobarbital (20 or 40 mg/kg i.p.) but not halothane (2%). However, the behavioral excitation, as indicated by horizontal movements, induced by halothane was reduced in lesioned as compared to control rats. Reversible inactivation of NBM with GABA(A) receptor agonist muscimol increased slow waves in the neocortex during awake immobility, and prolonged the duration of LORR and loss of tail-pinch response after propofol, pentobarbital and halothane. In summary, lesion of NBM cholinergic neurons or inactivation of the NBM prolonged the LORR response to general anesthetic drugs.


Effects of long-term administration of recombinant bovine tumor necrosis factor-alpha on glucose metabolism and growth hormone secretion in steers.
To investigate the effects of long-term administration of recombinant bovine tumor necrosis factor-alpha (rbTNF) on plasma glucose and growth hormone concentrations, and to determine whether treatment with rbTNF causes insulin resistance in steers. 5 steers treated with rbTNF and 5 steers treated with saline (0.9% NaCl) solution (control). In experiment 1, rbTNF (5.0 microg/kg of body weight) or saline solution (5 ml) was administered SC daily for 12 days. Blood samples were obtained before treatment, and plasma was harvested for determination of glucose, insulin, and growth hormone (GH) concentrations. In experiment 2, insulin, glucose, or growth hormone-releasing hormone (GHRH) was administered IV on days 7, 9, and 11, respectively, after initiation of rbTNF or saline treatment in experiment 1. Plasma glucose and insulin concentrations were measured before and at various times for 4 hours after insulin or glucose administration. Plasma GH concentrations were measured at various times for 3 hours after GHRH administration. In experiment 1, administration of rbTNF resulted in hyperinsulinemia without hypoglycemia and decreased plasma GH concentrations. In experiment 2, plasma glucose concentrations were higher in steers treated with rbTNF and insulin than in controls. Plasma GH concentrations were lower in steers treated with rbTNF and GHRH than in controls. Prolonged treatment with rbTNF induced insulin resistance and inhibited GHRH-stimulated release of GH in steers. Results indicate that rbTNF is a proximal mediator of insulin resistance and inhibits release of GH during periods of endotoxemia or infection.


[Positive experiences in Scandinavian patient insurance].
Voluntary insurance for the compensation of patients for damage sustained in health care was introduced in Sweden 20 years ago and similar systems exist in Finland, Denmark and Norway. This type of insurance is, or is in the process of becoming, statutory. The basic principle is that the apportioning of blame to any individual(s) is not a prerequisite for compensation to be paid out for injury sustained by a patient. Owing to hospital proprietors and care givers having taken out patient insurance policies with approved insurance companies, it has been possible for damages to be compensated in accordance with current insurance norms and the frequency of lawsuits arising from injury sustained in health care has been minimised. This type of insurance is universally accepted, and has often enabled unfortunate confrontations between doctors and patients to be avoided.


Heparin bonding increases patency of long microvascular prostheses.
The high thrombogenicity of synthetic biomaterials has limited their use for reconstructive microsurgery. Prime factors in the thrombogenicity of synthetic materials in contact with blood include gas nuclei at the blood gas interface as well as the inherent thrombogenicity of the materials themselves. Expanded polytetrafluoroethylene (ePTFE) vascular prostheses were denucleated by placement in acetone and ethanol followed by degassed saline or by placement in degassed saline subjected to hydrostatic pressure. Heparinized grafts were prepared by coating with tridodecylmethylammonium chloride (TDMAC), followed by immersion in heparin. Grafts were installed to reconstruct the femoral artery (1 x 10 mm) or as renal-iliac bypasses (1 x 50 mm) in rats. In the femoral artery reconstruction model, control grafts thrombosed within 10 minutes of implantation. All acetone denucleated femoral grafts remained patent for 60 minutes but were occluded at day 1. All pressure denucleated femoral grafts remained patent for 60 minutes, whereas six were patent at 1 month. In contrast, 11 of 15 heparinized femoral grafts were patent at 1 month. In the renal iliac bypass model, all control grafts were thrombosed within 10 minutes, whereas all heparin bonded grafts remained patent at 1 month. This finding confirms that removal of air from small diameter ePTFE grafts decreases acute thrombogenicity and that heparin bonding further decreases thrombogenicity, suggesting that clinically useful lengths of microvascular prostheses may be possible.


Electronic cigarettes for smoking cessation.
Electronic cigarettes (ECs) are handheld electronic vaping devices which produce an aerosol formed by heating an e-liquid. Some people who smoke use ECs to stop or reduce smoking, but some organizations, advocacy groups and policymakers have discouraged this, citing lack of evidence of efficacy and safety. People who smoke, healthcare providers and regulators want to know if ECs can help people quit and if they are safe to use for this purpose. This is an update conducted as part of a living systematic review. To examine the effectiveness, tolerability, and safety of using electronic cigarettes (ECs) to help people who smoke tobacco achieve long-term smoking abstinence. We searched the Cochrane Tobacco Addiction Group's Specialized Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, and PsycINFO to 1 May 2021, and reference-checked and contacted study authors. We screened abstracts from the Society for Research on Nicotine and Tobacco (SRNT) 2021 Annual Meeting. SELECTION CRITERIA: We included randomized controlled trials (RCTs) and randomized cross-over trials, in which people who smoke were randomized to an EC or control condition. We also included uncontrolled intervention studies in which all participants received an EC intervention. Studies had to report abstinence from cigarettes at six months or longer or data on safety markers at one week or longer, or both. We followed standard Cochrane methods for screening and data extraction. Our primary outcome measures were abstinence from smoking after at least six months follow-up, adverse events (AEs), and serious adverse events (SAEs). Secondary outcomes included the proportion of people still using study product (EC or pharmacotherapy) at six or more months after randomization or starting EC use, changes in carbon monoxide (CO), blood pressure (BP), heart rate, arterial oxygen saturation, lung function, and levels of carcinogens or toxicants or both. We used a fixed-effect Mantel-Haenszel model to calculate risk ratios (RRs) with a 95% confidence interval (CI) for dichotomous outcomes. For continuous outcomes, we calculated mean differences. Where appropriate, we pooled data in meta-analyses. We included 61 completed studies, representing 16,759 participants, of which 34 were RCTs. Five of the 61 included studies were new to this review update. Of the included studies, we rated seven (all contributing to our main comparisons) at low risk of bias overall, 42 at high risk overall (including all non-randomized studies), and the remainder at unclear risk. There was moderate-certainty evidence, limited by imprecision, that quit rates were higher in people randomized to nicotine EC than in those randomized to nicotine replacement therapy (NRT) (risk ratio (RR) 1.53, 95% confidence interval (CI) 1.21 to 1.93; I2 = 0%; 4 studies, 1924 participants). In absolute terms, this might translate to an additional three quitters per 100 (95% CI 1 to 6). There was low-certainty evidence (limited by very serious imprecision) that the rate of occurrence of AEs was similar (RR 0.98, 95% CI 0.80 to 1.19; I2 = 0%; 2 studies, 485 participants). SAEs were rare, but there was insufficient evidence to determine whether rates differed between groups due to very serious imprecision (RR 1.30, 95% CI 0.89 to 1.90: I2 = 0; 4 studies, 1424 participants). There was moderate-certainty evidence, again limited by imprecision, that quit rates were higher in people randomized to nicotine EC than to non-nicotine EC (RR 1.94, 95% CI 1.21 to 3.13; I2 = 0%; 5 studies, 1447 participants). In absolute terms, this might lead to an additional seven quitters per 100 (95% CI 2 to 16). There was moderate-certainty evidence of no difference in the rate of AEs between these groups (RR 1.01, 95% CI 0.91 to 1.11; I2 = 0%; 3 studies, 601 participants). There was insufficient evidence to determine whether rates of SAEs differed between groups, due to very serious imprecision (RR 1.06, 95% CI 0.47 to 2.38; I2 = 0; 5 studies, 792 participants). Compared to behavioural support only/no support, quit rates were higher for participants randomized to nicotine EC (RR 2.61, 95% CI 1.44 to 4.74; I2 = 0%; 6 studies, 2886 participants). In absolute terms this represents an additional six quitters per 100 (95% CI 2 to 15). However, this finding was of very low certainty, due to issues with imprecision and risk of bias. There was some evidence that non-serious AEs were more common in people randomized to nicotine EC (RR 1.22, 95% CI 1.12 to 1.32; I2 = 41%, low certainty; 4 studies, 765 participants), and again, insufficient evidence to determine whether rates of SAEs differed between groups (RR 1.51, 95% CI 0.70 to 3.24; I2 = 0%; 7 studies, 1303 participants). Data from non-randomized studies were consistent with RCT data. The most commonly reported AEs were throat/mouth irritation, headache, cough, and nausea, which tended to dissipate with continued use. Very few studies reported data on other outcomes or comparisons, hence evidence for these is limited, with CIs often encompassing clinically significant harm and benefit. There is moderate-certainty evidence that ECs with nicotine increase quit rates compared to NRT and compared to ECs without nicotine. Evidence comparing nicotine EC with usual care/no treatment also suggests benefit, but is less certain. More studies are needed to confirm the effect size. Confidence intervals were for the most part wide for data on AEs, SAEs and other safety markers, with no difference in AEs between nicotine and non-nicotine ECs. Overall incidence of SAEs was low across all study arms. We did not detect evidence of harm from nicotine EC, but longest follow-up was two years and the number of studies was small. The main limitation of the evidence base remains imprecision due to the small number of RCTs, often with low event rates, but further RCTs are underway. To ensure the review continues to provide up-to-date information to decision-makers, this review is now a living systematic review. We run searches monthly, with the review updated when relevant new evidence becomes available. Please refer to the Cochrane Database of Systematic Reviews for the review's current status.


Genetic disruption of calpain-1 and calpain-2 attenuates tumorigenesis in mouse models of HER2+ breast cancer and sensitizes cancer cells to doxorubicin and lapatinib.
Calpains are a family of calcium activated cysteine proteases which participate in a wide range of cellular functions including migration, invasion, autophagy, programmed cell death, and gene expression. Calpain-1 and calpain-2 isoforms are ubiquitously expressed heterodimers composed of isoform specific catalytic subunits coupled with an obligate common regulatory subunit encoded by capns1. Here, we report that conditional deletion of capns1 disrupted calpain-1 and calpain-2 expression and activity, and this was associated with delayed tumorigenesis and altered signaling in a transgenic mouse model of spontaneous HER2+ breast cancer and effectively blocked tumorigenesis in an orthotopic engraftment model. Furthermore, capns1 knockout in a tumor derived cell line correlated with enhanced sensitivity to the chemotherapeutic doxorubicin and the HER2/EGFR tyrosine kinase inhibitor lapatinib. Collectively, these results indicate pro-tumorigenic roles for calpains-1/2 in HER2+ breast cancer and provide evidence that calpain-1/2 inhibitors could have anti-tumor effects if used either alone or in combination with chemotherapeutics and targeted agents.


A Genome-wide Combinatorial Strategy Dissects Complex Genetic Architecture of Seed Coat Color in Chickpea.
The study identified 9045 high-quality SNPs employing both genome-wide GBS- and candidate gene-based SNP genotyping assays in 172, including 93 cultivated (desi and kabuli) and 79 wild chickpea accessions. The GWAS in a structured population of 93 sequenced accessions detected 15 major genomic loci exhibiting significant association with seed coat color. Five seed color-associated major genomic loci underlying robust QTLs mapped on a high-density intra-specific genetic linkage map were validated by QTL mapping. The integration of association and QTL mapping with gene haplotype-specific LD mapping and transcript profiling identified novel allelic variants (non-synonymous SNPs) and haplotypes in a MATE secondary transporter gene regulating light/yellow brown and beige seed coat color differentiation in chickpea. The down-regulation and decreased transcript expression of beige seed coat color-associated MATE gene haplotype was correlated with reduced proanthocyanidins accumulation in the mature seed coats of beige than light/yellow brown seed colored desi and kabuli accessions for their coloration/pigmentation. This seed color-regulating MATE gene revealed strong purifying selection pressure primarily in LB/YB seed colored desi and wild Cicer reticulatum accessions compared with the BE seed colored kabuli accessions. The functionally relevant molecular tags identified have potential to decipher the complex transcriptional regulatory gene function of seed coat coloration and for understanding the selective sweep-based seed color trait evolutionary pattern in cultivated and wild accessions during chickpea domestication. The genome-wide integrated approach employed will expedite marker-assisted genetic enhancement for developing cultivars with desirable seed coat color types in chickpea.


Attacking Plasmodium vivax.
Discussions beginning in 2012 ultimately led to a landmark document from the World Health Organization (WHO) titled, Control and Elimination of Plasmodium vivax: A Technical Brief, published in July 2015. That body of work represents multiple expert consultations coordinated by the WHO Global Malaria Program, along with technical consensus gathering from national malaria control programs via the WHO regional offices around the globe. That document thus represents thoroughly vetted state-of-the-art recommendations for dealing specifically with P. vivax, the first assembly of such by the WHO. This supplement to the journal was commissioned by the WHO and compiles the very substantial body of evidence and analysis informing those recommendations. This introductory narrative to the supplement provides the historical and technological context of global strategy for combatting P. vivax and reducing the burdens of morbidity and mortality it imposes.


Predictors of treatment failure and clinical stability in patients with community acquired pneumonia.
Community acquired pneumonia (CAP) is the leading infectious cause of mortality worldwide with approximately 10% of patients hospitalized requiring intensive care unit (ICU) admission. The ability to predict clinical stability (CS) and treatment failure (TF) enables the clinician to alter antibiotics appropriately, facilitate a timely ICU admission, or arrange a suitable discharge. The detection of CS and TF can be difficult and changes in clinical signs may be subtle or delayed. Thus clinical scores and biomarkers are routinely used to identify severity and monitor clinical progression. The evidence, however, is vast and the definitive role of these systems is at times difficult to elucidate. The aim of this review is to analyse the current literature and to provide a rational and clinically focused view of the predictive utility of various systems used to identify CS and TF in CAP.


Another link to improving the working environment in acute care hospitals: registered nurses' spirit at work.
Hospitals are situated within historical and socio-political contexts; these influence the provision of patient care and the work of registered nurses (RNs). Since the early 1990s, restructuring and the increasing pressure to save money and improve efficiency have plagued acute care hospitals. These changes have affected both the work environment and the work of nurses. After recognizing this impact, healthcare leaders have dedicated many efforts to improving the work environment in hospitals. Admirable in their intent, these initiatives have made little change for RNs and their work environment, and thus, an opportunity exists for other efforts. Research indicates that spirit at work (SAW) not only improves the work environment but also strengthens the nurse's power to improve patient outcomes and contribute to a high-quality workplace. In this paper, we present findings from our research that suggest SAW be considered an important component in improving the work environment in acute care hospitals.


Development of growth hormone and adrenocorticotropic hormone deficiencies in patients with prenatal or perinatal-onset hypothalamic hypopituitarism having invisible or thin pituitary stalk on magnetic resonance imaging.
A gradual loss of anterior pituitary hormones is suspected in patients treated with irradiation due to brain tumors. Development of growth hormone deficiency (GHD) with age has been documented in patients with idiopathic GHD. A gradual loss of adrenocorticotropic hormone (ACTH) secretion has been also shown in a patient with severe GHD and an invisible pituitary stalk on magnetic resonance imaging (MRI). The purpose of this longitudinal and cross-sectional study was to evaluate the gradual loss of growth hormone (GH) and ACTH in a homogeneous group of patients with hypopituitarism. Twenty-eight patients (23 males, 5 females) from four hospitals were diagnosed as having prenatal or perinatal-onset hypothalamic hypopituitarism. They had an abnormal pituitary stalk on MRI (invisible in 18 patients, thin in 10 patients) without any other organic disease of the brain. Each patient had GHD upon initial evaluation. Height (n=20) was analyzed as standard deviation score (SDS). Longitudinal (n=8) and cross-sectional (n=28) GH secretion capacity was evaluated by GH peaks, in response to insulin tolerance test (ITT) and growth hormone releasing factor test (GRF test). Longitudinal (n=10) and cross-sectional (n=28) ACTH secretion capacity was evaluated by cortisol peaks in response to ITT. Height SDS decreased each year in all the untreated patients after birth. GH peaks decreased gradually with age. Longitudinal data showed decreased GH peaks with age in seven out of eight patients using ITT and in all four patients using GRF tests. Cortisol peaks also decreased gradually together with signs and symptoms for adrenal deficiency such as general fatigue. Cortisol peaks of less than 414 nmol/L (15 microg/dl) in response to ITT were seen in 24% of the tests before age 10 and 56% before age 25. In conclusion, GHD and ACTH deficiency developed gradually in patients with prenatal or perinatal-onset hypothalamic hypopituitarism who had invisible or thin pituitary stalks examined by MRI.


Impact of BRAF mutation status in the prognosis of cutaneous melanoma: an area of ongoing research.
This review is intended to provide an updated role of molecular genetics and various targeted therapies that have been developed to treat advanced stages of melanoma. Because of the declining success in melanoma therapy, the curative treatment for advanced stage melanoma has been a challenge for clinicians. Several mutations such as N-RAS, p53, BRAF including mutant-BRAF that lead to activation of kinase pathway, are implicated in the development of malignant melanoma. However, the current literature depicts that the prognostic role of BRAF mutation in disease progression is still controversial. While its higher level in advanced stage disease is associated with decreased overall survival (OS), some studies show that it failed to confer as an independent prognostic predictor of the disease. This has also led researchers to accomplish newer therapeutic strategies that lead to improved disease-response and grant survival benefits. Vemurafenib, a BRAF inhibitor agent, is one of the few available targeted therapies that is FDA approved and provides promising results in metastatic disease. However, its resistance at an early stage is of great concern. Recent implementation of combinational therapies including "targeted therapy", immunotherapy, and biological agents has appealed many researchers to define the adjunctive role of available therapies and their limitations in advanced stage and metastatic melanoma. This commends the need for future multi-institutional studies to confirm the clinical validity of different therapeutic strategies on a large scale population.


Radioiodine treatment of feline hyperthyroidism in Germany.
Establishment of radioiodine treatment of feline hyperthyroidism in veterinary routine in accordance with German radiation protection regulations. 35 cats with proven hyperthyroidism were treated with 131I in a special ward. Thyroid uptake and effective halflife were determined using gammacamera dosimetry. Patients were released when measured whole body activity was below the limit defined in the German "Strahlenschutzverordnung". 17/20 cats treated with 150 MBq radioiodine and 15/15 cats treated with 250 MBq had normal thyroid function after therapy, normal values for FT3 and FT4 were reached after two and normal TSH levels after three weeks. In 14 cats normal thyroid function was confirmed by controls 3-6 months later. Thyroidal iodine uptake was 24 +/- 10%, effective halflife 2.5 +/- 0.7 days. Whole body activity < 1 MBq was reached 13 +/- 4 days after application of 131I. Radiation exposure of cat owners was estimated as 1.97 microSv/MBq for adults. Radioiodine therapy of feline hyperthyroidism is highly effective and safe. It can easily be performed in accordance with German radiation protection regulations, although this requires hospitalisation for approximately two weeks. Practical considerations on radiation exposure of cat owners do not justify this long interval. Regulations for the veterinary use of radioactive substances similar to existing regulations for medical use in humans are highly desirable.


Lane-Hamilton syndrome - Is it really a needle in a haystack?
The association of pulmonary hemosiderosis with celiac disease (Lane-Hamilton syndrome) is extremely rare. A five-year-old female child presented with fever, cough, breathlessness, and pallor for 20 days, without any previous history of recurrent lower respiratory tract infections, tuberculosis, or cardiac disease. There was no history of pica, chronic diarrhea, bleeding, or personal or family history of repeated blood transfusions. She had tachycardia, tachypnea, severe pallor, stunting, rickets, and bilateral fine lung crepitations. Peripheral smear and blood indices revealed dimorphic anemia. Anti-tissue transglutaminase IgA antibody levels were high (>200 U/mL) and the upper gastrointestinal endoscopy with duodenal biopsy confirmed the diagnosis of celiac disease. The child was discharged on a gluten-free diet (GFD) and oral hematinic, but her dietary compliance was poor. Interestingly, the child had persistent bilateral pulmonary infiltrates, which was initially attributed to congestive cardiac failure (CCF), which persisted even despite treatment. HRCT chest revealed interstitial thickening and bilateral alveolar shadows and bronchoalveolar lavage showed a few inflammatory cells. The child was readmitted four times with similar complaints and was given packed red cell transfusions. In the fourth admission, a lung biopsy was done, which revealed extensive pulmonary hemosiderosis. The patient was given a course of oral steroids for 6 weeks, with a gluten-free diet, following which both the anemia and the pulmonary infiltrates resolved. Pulmonary hemosiderosis is an important cause of anemia in cases of celiac disease and may be misdiagnosed as CCF due to severe anemia. A strict GFD, with or without corticosteroids, can reverse the clinical and radiological picture.


Characterization and activity of visible-light driven TiO2 photocatalyst doped with tungsten.
This research aimed to expand the activity of TiO(2) down to the visible light region by modifying the sol-gel conditions and doping with tungsten. The optimum conditions for calcination temperature, acid type, and heating rate were 200°C, HNO(3), and 1°C/min, respectively. The undoped TiO(2) synthesized under these conditions could significantly absorb the visible light whereas the commercial Degussa P-25 could not. The absorptivity decreased sequentially as the wavelength increased from 400 to 700 nm. Within 6 h of 2-W blue-light illumination, 23% of 0.1 mM 2-chlorophenol was removed. The XRD result showed that the crystalline was anatase phase. The visible-light absorption property of the TiO(2) became even better when doped with tungsten. At the optimum W to TiO(2) ratio of 0.5%, the degradation of 0.1 mM 2-chlorophenol increased to 53% indicating a higher photocatalytic activity. Both crystalline and amorphous TiO(2) could exhibit the photocatalytic activity under the visible light region.


[Relationship between phthalates and testicular dysgenesis syndrome].
Recent epidemiological evidence demonstrates that boys born to women exposed to phthalates during pregnancy have an increased incidence of cryptorchidism, hypospadias, testicular cancer and spermatogenic dysfunction, which are collectively referred to as testicular dysgenesis syndrome (TDS). TDS may be attributed to the dysfunction of Leydig cells and Sertoli cells during their differentiation after exposure to phthalates in utero. Fox example, Leydig cell functions are significantly affected by phthalates, leading to the decrease of two Leydig cell products--insulin-like growth factor 3 (INSL3) and testosterone, which are critical factors for testis descent. The disorientation of Leydig cells and Sertoli cells in the adult testis may be the cause of spermatogenic dysfunction.


Pharmacokinetics and ex vivo pharmacodynamics of oral firocoxib administration in New Zealand White rabbits (Oryctolagus cuniculus).
To examine the pharmacokinetics and ex vivo pharmacodynamics of oral firocoxib administration in New Zealand White rabbits (Oryctolagus cuniculus). 6 healthy New Zealand White rabbits. Pharmacokinetics were determined from plasma concentrations measured via ultra performance liquid chromatography-tandem mass spectrometry after oral administration of firocoxib at a dose of 3.74 to 4.20 mg/kg. Pharmacokinetic analysis was performed using non compartmental methods. Pharmacodynamics of firocoxib were evaluated by measuring plasma concentrations of thromboxane and prostaglandin via ELISAs as surrogate markers of cyclooxygenase enzyme isoform inhibition. The terminal rate constant was 0.07 hours (range, 0.05 to 0.11 h). The mean maximum concentration (Cmax) and time to Cmax were 0.16 µg/mL and 3.81 hours (range, 2.0 to 8.0 h), respectively. Mean residence time was 15.02 hours. Mean elimination half-life was 9.12 hours. For the pharmacodynamic analysis, firocoxib administration did not demonstrate a significant difference between any time point for prostaglandin E2 and only a significant difference between 24 and 48 hours for thromboxane B2. Although the pharmacokinetic research supports that plasma firocoxib concentrations that would be therapeutic in dogs are achieved in rabbits, the pharmacodynamic results do not demonstrate a significant difference in levels of cyclooxygenase-2 inhibition, which indirectly reflects the anti-inflammatory effects of the drug. Further pharmacodynamic studies and multidose studies are warranted to determine the efficacy and safety of this drug in rabbits.


Drug checking services for people who use drugs: a systematic review.
Drug checking services provide people who use drugs with chemical analysis results of their drug samples while simultaneously monitoring the unregulated drug market. We sought to identify and synthesize literature on the following domains: (a) the influence of drug checking services on the behaviour of people who use drugs; (b) monitoring of drug markets by drug checking services; and (c) outcomes related to models of drug checking services. Systematic review. A systematic literature search was conducted in MEDLINE, Embase, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, PsycINFO, Scopus, Web of Science and Dissertations and Theses Global. Eligible studies were peer-reviewed articles and conference abstracts or grey literature, published in any language since 1990 and including original data on the domains. We assessed risk of bias for quantitative peer-reviewed articles reporting on behaviour or models of drug checking services using National Institutes of Health tools. We screened 2463 titles and abstracts and 156 full texts, with 90 studies meeting inclusion criteria. Most (n = 65, 72.2%) were from Europe and used cross-sectional designs (n = 79, 87.7%). Monitoring of drug markets by drug checking services (n = 63, 70%) was the most reported domain, followed by the influence of drug checking services on behaviour (n = 31, 34.4%), including intent to use, actual use and disposal of the drug, and outcomes related to models of drug checking services (n = 17, 18.9%). The most common outcome measures were detection of unexpected substances (n = 50, 55.6%), expected substances (n = 44, 48.9%), new psychoactive substances (n = 40, 44.4%) and drugs of concern (n = 32, 36.5%) by drug checking services. Drug checking services appear to influence behavioural intentions and the behaviour of people who use drugs, particularly when results from drug checking services are unexpected or drugs of concern. Monitoring of drug markets by drug checking services is well established in Europe, and increasingly in North America. Concerns about drug contents and negative health consequences facilitate the use of drug checking services; lack of concern; trust in drug sellers; lack of accessibility of drug checking services; and legal and privacy concerns are barriers to use.


Transmission of information and herd Behavior: an application to financial markets.
We propose a model for stochastic formation of opinion clusters, modeled by an evolving network, and herd behavior to account for the observed fat-tail distribution in returns of financial-price data. The only parameter of the model is h, the rate of information dispersion per trade, which is a measure of herding behavior. For h below a critical h(*) the system displays a power-law distribution of the returns with exponential cutoff. However, for h>h(*) an increase in the probability of large returns is found and may be associated with the occurrence of large crashes.


Phylogenomic analysis sheds light on the evolutionary pathways towards acoustic communication in Orthoptera.
Acoustic communication is enabled by the evolution of specialised hearing and sound producing organs. In this study, we performed a large-scale macroevolutionary study to understand how both hearing and sound production evolved and affected diversification in the insect order Orthoptera, which includes many familiar singing insects, such as crickets, katydids, and grasshoppers. Using phylogenomic data, we firmly establish phylogenetic relationships among the major lineages and divergence time estimates within Orthoptera, as well as the lineage-specific and dynamic patterns of evolution for hearing and sound producing organs. In the suborder Ensifera, we infer that forewing-based stridulation and tibial tympanal ears co-evolved, but in the suborder Caelifera, abdominal tympanal ears first evolved in a non-sexual context, and later co-opted for sexual signalling when sound producing organs evolved. However, we find little evidence that the evolution of hearing and sound producing organs increased diversification rates in those lineages with known acoustic communication.


Cytokines in chronic inflammatory arthritis. VI. Analysis of the synovial cells involved in granulocyte-macrophage colony-stimulating factor production and gene expression in rheumatoid arthritis and its regulation by IL-1 and tumor necrosis factor-alpha.
Granulocyte-macrophage CSF (GM-CSF) is a potent stimulator of macrophages and neutrophils and is produced by rheumatoid arthritis (RA) synovium. We now report studies that identify some of the synovial cells and cytokines responsible for local GM-CSF production and gene expression in RA. GM-CSF was assayed by ELISA in supernatants from cultured RA fibroblast-like synoviocytes stimulated with various cytokines (IL-1 beta, TNF-alpha, macrophage-CSF, IFN-gamma, IL-6, and TGF-beta). Immunoreactive GM-CSF was detected in IL-1 beta and TNF-alpha-stimulated cultures, but not in cells cultured in medium or stimulated with any of the other cytokines. IL-1 and TNF-alpha had a synergistic effect on GM-CSF production. GM-CSF gene expression by fibroblast-like synoviocytes was analyzed by ribonuclease protection assay, Northern blot analysis, and in situ hybridization. Both IL-1 beta and TNF-alpha induced GM-CSF mRNA accumulation, with a maximum effect after 4 h of stimulation. We then studied GM-CSF production by macrophage-like synoviocytes (MLS) isolated from fresh synovial specimens by flow microfluorimetry. Fresh MLS spontaneously secreted the cytokine and exogenous IL-1 beta or TNF-alpha had no effect. After 1 wk in culture, additional stimulation with IL-1 beta or TNF-alpha was required for GM-CSF production. Finally, in situ hybridization performed on freshly isolated subpopulations of synovial cells, identified GM-CSF RNA transcripts in MLS.


CENTROIDFOLD: a web server for RNA secondary structure prediction.
The CENTROIDFOLD web server (http://www.ncrna.org/centroidfold/) is a web application for RNA secondary structure prediction powered by one of the most accurate prediction engine. The server accepts two kinds of sequence data: a single RNA sequence and a multiple alignment of RNA sequences. It responses with a prediction result shown as a popular base-pair notation and a graph representation. PDF version of the graph representation is also available. For a multiple alignment sequence, the server predicts a common secondary structure. Usage of the server is quite simple. You can paste a single RNA sequence (FASTA or plain sequence text) or a multiple alignment (CLUSTAL-W format) into the textarea then click on the 'execute CentroidFold' button. The server quickly responses with a prediction result. The major advantage of this server is that it employs our original CentroidFold software as its prediction engine which scores the best accuracy in our benchmark results. Our web server is freely available with no login requirement.


Diammine{N-[2-(hy-droxy-imino)-propion-yl]-N'-[2-(oxidoimino)-propion-yl]propane-1,3-diaminido-κ(4) N,N',N'',N'''}iron(III).
In the title compound, [Fe(C9H13N4O4)(NH3)2], the Fe(III) atom, lying on a mirror plane, is coordinated by four N atoms of a triply deprotonated tetra-dentate N-[2-(hy-droxy-imino)-propion-yl]-N'-[2-(oxidoimino)-propion-yl]propane-1,3-diaminide ligand in the equatorial plane and two N atoms of two ammonia mol-ecules at the axial positions in a distorted octa-hedral geometry. A short intra-molecular O-H⋯O hydrogen bond between the cis-disposed oxime O atoms stabilizes the pseudo-macrocyclic configuration of the ligand. In the crystal, mol-ecules are linked by N-H⋯O hydrogen bonds into a three-dimensional network. The ligand has a mirror-plane symmetry. One of the methyl-ene groups of the propane bridge is disordered over two sets of sites with equal occupancy factors.


Epinephrine for bronchiolitis.
Bronchodilators are commonly used for acute bronchiolitis, despite uncertain effectiveness. To examine the efficacy and safety of epinephrine in children less than two with acute viral bronchiolitis. We searched CENTRAL (2010, Issue 3) which contains the Acute Respiratory Infections Group's Specialized Register, MEDLINE (1950 to September Week 2, 2010), EMBASE (1980 to September 2010), Scopus (1823 to September 2010), PubMed (March 2010), LILACS (1985 to September 2010) and Iran MedEx (1998 to September 2010). We included randomized controlled trials comparing epinephrine to placebo or another intervention involving children less than two years with acute viral bronchiolitis. Studies were included if the trials presented data for at least one quantitative outcome of interest.We selected primary outcomes a priori, based on clinical relevance: rate of admission by days one and seven of presentation for outpatients, and length of stay (LOS) for inpatients. Secondary outcomes included clinical severity scores, pulmonary function, symptoms, quality of life and adverse events. Two review authors independently screened the searches, applied inclusion criteria, assessed risk of bias and graded the evidence. We conducted separate analyses for different comparison groups (placebo, non-epinephrine bronchodilators, glucocorticoids) and for clinical setting (inpatient, outpatient). We included 19 studies (2256 participants). Epinephrine versus placebo among outpatients showed a significant reduction in admissions at Day 1 (risk ratio (RR) 0.67; 95% confidence interval (CI) 0.50 to 0.89) but not at Day 7 post-emergency department visit. There was no difference in LOS for inpatients. Epinephrine versus salbutamol showed no differences among outpatients for admissions at Day 1 or 7. Inpatients receiving epinephrine had a significantly shorter LOS compared to salbutamol (mean difference -0.28; 95% CI -0.46 to -0.09). One large RCT showed a significantly shorter admission rate at Day 7 for epinephrine and steroid combined versus placebo (RR 0.65; 95% CI 0.44 to 0.95). There were no important differences in adverse events. This review demonstrates the superiority of epinephrine compared to placebo for short-term outcomes for outpatients, particularly in the first 24 hours of care. Exploratory evidence from a single study suggests benefits of epinephrine and steroid combined for later time points. More research is required to confirm the benefits of combined epinephrine and steroids among outpatients. There is no evidence of effectiveness for repeated dose or prolonged use of epinephrine or epinephrine and dexamethasone combined among inpatients.


Betulinic Acid-Mediated Tuning of PERK/CHOP Signaling by Sp1 Inhibition as a Novel Therapeutic Strategy for Glioblastoma.
Patients with glioblastoma are at high risk of local recurrences after initial treatment with standard therapy, and recurrent tumor cells appear to be resistant to first-line drug temozolomide. Thus, finding an effective second-line agent for treating primary and recurrent glioblastomas is critical. Betulinic acid (BA), a natural product of plant origin, can cross the blood-brain barrier. Here, we investigated the antitumor effects of BA on typical glioblastoma cell lines and primary glioblastoma cells from patients, as well as corresponding temozolomide-resistant cells. Our findings verified that BA significantly reduced growth in all examined cells. Furthermore, gene-expression array analysis showed that the unfolded-protein response was significantly affected by BA. Moreover, BA treatment increased activation of the protein kinase RNA-like endoplasmic reticulum kinase (PERK)/C/EBP homologous protein (CHOP) apoptotic pathway, and reduced specificity protein 1 (Sp1) expression. However, Sp1 overexpression reversed the observed cell-growth inhibition and PERK/CHOP signaling activation induced by BA. Because temozolomide-resistant cells exhibited significantly increased Sp1 expression, we concluded that Sp1-mediated PERK/CHOP signaling inhibition protects glioblastoma against cancer therapies; hence, BA treatment targeting this pathway can be considered as an effective therapeutic strategy to overcome such chemoresistance and tumor relapse.


Management of hypertension by reduction in sympathetic activity.
The sympathetic nervous system may initiate or maintain hypertension, and a range of approaches that reduce sympathetic activity is often of value in management. These may include nonpharmacological methods, such as the various forms of behavioral therapy (e.g., meditation, relaxation, and biofeedback techniques); weight reduction and avoidance of particular foods and agents that stimulate sympathetic activity (including caffeine and alcohol), and regular physical exercise. Pharmacological therapy includes centrally acting drugs such as alpha-methyldopa, clonidine, and reserpine; ganglionic blockers such as hexamethonium; agents acting on sympathetic nerve terminals such as guanethidine and debrisoquine; and drugs that may act at multiple sites, such as the beta-adrenergic blockers. The role of reducing sympathetic activity in the current management of hypertension and its complications is considered in this overview.


Structural constraints and importance of caffeic acid moiety for anti-hyperglycemic effects of caffeoylquinic acids from chicory.
Chicory (Cichorium intybus L.) is a perennial herb often consumed as a vegetable, whereas the ground and roasted roots are blended as a coffee substitute. Caffeoylquinic or chlorogenic acids (CQA), the abundant intermediates of lignin biosynthesis in chicory, have been reported to improve glucose metabolism in humans, but the functional group in their structure responsible for this effect has not been yet characterized. Here, we showed that three di-O-caffeoylquinic acids suppressed hepatic glucose production in H4IIE rat hepatoma cells by reducing expression of glucose-6-phosphatase (G6Pase) and phosphoenolpyruvate carboxykinase (PEPCK), two key enzymes that regulate hepatic gluconeogenesis. Direct comparisons between CQAs and their metabolites (3-caffeoylquinic, caffeic, and quinic acids) revealed the caffeic acid moiety alone was responsible for the observed effects. Further analysis suggested the activation of PI3K and MAPK pathways as a method of controlling gene expression was shared between caffeoylquinic and caffeic acids. These compounds promoted increased mitochondrial respiration and cellular metabolism, in part by inducing oxidative phosphorylation and proton leak. We concluded that the caffeic acid moiety was important for suppression of hepatic gluconeogenesis and hyperglycemia, ultimately strengthening the link between dietary interventions based on caffeic acid-containing plant foods and healthy glucose metabolism.


Post-treatment control or treated controllers? Viral remission in treated and untreated primary HIV infection.
An HIV cure will impose aviraemia that is sustained following the withdrawal of antiretroviral therapy (ART). Understanding the efficacy of novel interventions aimed at curing HIV requires characterization of both natural viral control and the effect of ART on viral control after treatment interruption. Analysis of transient viral control in recent seroconverters in the Short Pulse AntiRetroviral Therapy at Acute Seroconversion trial. We compared untreated and treated HIV seroconverters (n = 292) and identified periods of control (plasma HIV RNA < 400 copies/ml for ≥16 weeks off therapy) in 7.9% of ART-naive participants, and in 12.0% overall. HIV DNA was measured by qPCR, and HIV-specific CD8 responses were measured by enzyme-linked immunosorbent spot assay (ELISpot). T-cell activation and exhaustion were measured by flow cytometry. At baseline, future controllers had lower HIV DNA, lower plasma HIV RNA, higher CD4 : CD8 ratios (all P < 0.001) and higher CD4 cell counts (P < 0.05) than noncontrollers. Among controllers, the only difference between the untreated and those who received ART was higher baseline HIV RNA in the latter (P = 0.003), supporting an added ART effect. Consideration of spontaneous remission in untreated individuals will be critical to avoid overestimating the effect size of new interventions used in HIV cure studies.


Silicates: Reactivity with Sea Water.
Silicate minerals rapidly release silica to sea water. Fine-grained, 1-gram samples were placed in 200 milliliters of sea water, and the silica content of the water was measured intermittently for 6 months. At the end of 10 days and of 6 months the silica concentrations with various minerals, in parts per million, were, respectively: kaolinite, 0.6, 2.2; chlorite, 2.5, 2.4; illite, 1.8, 2.6; muscovite, 1.8, 3.9; montmorillonite A, 7, 10.5; montmorillonite B, 10, 21. Except for ion exchange phenomena, it generally has been assumed that these minerals do not react significantly with sea water, or, if they do, they react at geologically slow rates. The rates observed indicate that the ocean must be looked upon as a chemical system with a rapid response to added detrital silicates.


Profiling antibodies to class II HLA in transplant patient sera.
Immunizing events including pregnancy, transfusions, and transplantation promote strong alloantibody responses to HLA. Such alloantibodies to HLA preclude organ transplantation, foster hyperacute rejection, and contribute to chronic transplant failure. Diagnostic antibody-screening assays detect alloreactive antibodies, yet key attributes including antibody concentration and isotype remain largely unexplored. The goal here was to provide a detailed profile of allogeneic antibodies to class II HLA. Methodologically, alloantibodies were purified from sensitized patient sera using an HLA-DR11 immunoaffinity column and subsequently categorized. Antibodies to DR11 were found to fix complement, exist at a median serum concentration of 2.3μg/mL, consist of all isotypes, and isotypes IgG2, IgM, and IgE were elevated. Because multimeric isotypes can confound diagnostic determinations of antibody concentration, IgM and IgA isotypes were removed and DR11-IgG tested alone. Despite removal of multimeric isotypes, patient-to-patient antibody concentrations did not correlate with MFI values. In conclusion, allogeneic antibody responses to DR11 are comprised of all antibody isotypes at differing proportions, these combined isotypes fix complement at nominal serum concentrations, and enhancements other than the removal of IgM and IgA multimeric isotypes may be required if MFI is to be used as a means of determining anti-HLA serum antibody concentrations in diagnostic clinical assays.


False-belief understanding in frontotemporal dementia and Alzheimer's disease.
The ability to understand other people's behavior in terms of mental states, such as beliefs, desires, and intentions, is central to social interaction. It has been argued that the interpersonal problems of patients with behavioral variant of frontotemporal dementia (FTD-b) are due to a dysfunction of that system. We used first- and second-order false-belief tasks to assess theory-of-mind reasoning in a group of patients with FTD-b and a cognitively matched group of patients with Alzheimer's disease (AD). Both patient groups were equally impaired relative to a healthy elderly group in the cognitively demanding second-order false-belief tasks, revealing that cognitive demands are an important factor in false-belief task performance. Both patient groups reached ceiling performance in the first-order false-belief tasks with minimal cognitive demands, despite the striking difference in their social graces. These results suggest that a conceptual deficit in theory of mind-as measured by the false-belief task-is not at the core of the differences between FTD-b and AD.


Medical day hospital care for the elderly versus alternative forms of care.
The proportion of the world's population aged 60 or over is increasing. This review sets out to examine the effectiveness and resource implications of geriatric medical day hospital attendance for elderly people. This is an update of a Cochrane review first published in 1999. To examine the effectiveness of attendance at a medical day hospital for elderly people in preventing death, disability, and institutionalisation and improving subjective health status. We searched the EPOC group specialist register (March 2008), Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, Issue 1, 2008), MEDLINE (1996 to January 2008), EMBASE (1996 to 2008 week 5), and other databases. Randomised and quasi-randomised studies comparing attendance at a geriatric medical day hospital with alternative forms of care for elderly medical patients (usually > 60 years). Three review authors independently assessed research reports to determine eligibility, categorise trial type and extract data. Thirteen trials involving 3007 participants were included. These compared day hospital with a) comprehensive elderly care (five trials), b) domiciliary care (five trials), or c) no comprehensive elderly care (three trials).There were no significant differences between day hospital attendance and the sub-categories of comparison treatments for the outcomes of death, death or requiring institutional care, death or deterioration in ADL. When death or a 'poor' outcome at follow up was examined there was a significant difference in favour of day hospital attendance when compared to no comprehensive elderly care (odds ratio (OR) 0.73; 95% confidence interval (CI) 0.53 to 1.00; P < 0.05).Dependency was measured in 12 trials using a variety of ADL measures; two described short-term improvement for the day hospital group, one reported improved outcome for the comparison group, while in the remaining trials there was no statistically significant difference. Using the outcome of deterioration in ADL among survivors, day hospital patients showed a reduced odds of deterioration when compared with those receiving no comprehensive elderly care (OR 0.60; 95% CI 0.38 to 0.97; P < 0.05).When resource use was examined the day hospital group showed trends towards reductions in hospital bed use and placement of survivors in institutional care. Medical day hospital care for the elderly appears to be more effective than no intervention but may have no clear advantage over other forms of comprehensive elderly medical services.


Periodontal Regeneration with Enamel Matrix Derivative in the Management of Generalized Aggressive Periodontitis: A Case Report with 11-Year Follow-up and Literature Review.
Aggressive periodontitis (AgP) represents an uncommon but rapidly advanced inflammatory process, which involves the destruction of periodontal tissues. This study aimed to report a case of generalized AgP (GAgP), where the treatment approach consists of the utilization of the full-mouth disinfection protocol (FMDP) in conjunction with flap curettage and regenerative appliance of enamel matrix derivatives (EMDs). The associated literature was also reviewed. A 19-year-old female patient was diagnosed with GAgP. The treatment was initiated with FMDP and administration of antibiotics. Afterward, open flap debridement was performed, and EMD was selected as the regenerative material for the reconstruction of the periodontal defects. Over an 11-year period and during all the phases of the treatment, the outcomes were regularly evaluated with clinical measurements and radiographic controls. The 11-year results demonstrated no recurrence of disease, and the patient's periodontal health exhibited evident improvement. Overall, the pocket depths presented satisfactory reduction while the clinical attachment loss (CAL) was improved. Both our limited experience and available literature data revealed that the use of EMD in AgP treatment contributes to bone fill of the intrabony defects as well as regeneration of the destructed periodontal apparatus. Although the outcomes of this treatment approach have not been widely evaluated, it seems that the use of EMD may be an effective means of periodontal regeneration in patients with GAgP. Additional prospective studies with adequate number of GAgP patients are essential to thoroughly assess the effectiveness of this approach.


New ages for Middle and Later Stone Age deposits at Mumba rockshelter, Tanzania: optically stimulated luminescence dating of quartz and feldspar grains.
The archaeological deposits at Mumba rockshelter, northern Tanzania, have been excavated for more than 70 years, starting with Margit and Ludwig Köhl-Larsen in the 1930s. The assemblages of Middle Stone Age (MSA) and Later Stone Age (LSA) artefacts collected from this site constitute the type sequences for these cultural phases in East Africa. Despite its archaeological importance, however, the chronology of the site is poorly constrained, despite the application since the 1980s of several dating methods (radiocarbon, uranium-series and amino acid racemisation) to a variety of materials recovered from the deposits. Here, we review these previous chronologies for Mumba and report new ages obtained from optically stimulated luminescence (OSL) and infrared stimulated luminescence (IRSL) measurements on single grains of quartz and multi-grain aliquots of potassium (K) feldspar from the MSA and LSA deposits. Measurements of single grains of quartz allowed the rejection of unrepresentative grains and the application of appropriate statistical models to obtain the most reliable age estimates, while measurements of K-feldspars allowed the chronology to be extended to older deposits. The seven quartz ages and four K-feldspar ages provide improved temporal constraints on the archaeological sequence at Mumba. The deposits associated with the latest Kisele Industry (Bed VI-A) and the earliest Mumba Industry (Bed V) are dated to 63.4 ± 5.7 and 56.9 ± 4.8 ka (thousands of years ago), respectively, thus constraining the time of transition between these two archaeological phases to ~60 ka. An age of 49.1 ± 4.3 ka has been obtained for the latest deposits associated with the Mumba Industry, which show no evidence for post-depositional mixing and contain ostrich eggshell (OES) beads and abundant microlithics. The Nasera Industry deposits (Bed III) contain large quantities of OES beads and date to 36.8 ± 3.4 ka. We compare the luminescence ages with the previous chronologies for Mumba, and briefly discuss how the revised chronology fits in the context of existing archaeological records and palaeoclimatic reconstructions for East Africa.


Increased production of interleukin-10 and inflammatory cytokines in blood monocytes of hemodialysis patients.
Chronic hemodialysis (HD) patients have defects in cell-mediated immunity. To investigate the mechanisms underlying this immunodeficiency, we studied the production of cytokines in peripheral blood mononuclear cells (PBMC) from HD patients. PBMC from 22 HD patients and 20 healthy controls were cultured for 48 h in the presence or absence of phytohemagglutinin (PHA), lipopolysaccharide (LPS), or tuberculin purified protein derivative (PPD). Cytokine levels were measured by enzyme-linked immunosorbent assays. Only 64% of HD patients had a positive tuberculin skin test compared to 90% of normal Japanese controls. HD patients showed a diminished proliferative response to PHA. Compared to healthy controls, stimulated PBMC from HD patients produced similar amounts of T cell-derived cytokines (interleukin-2 (IL-2) and interferon-gamma (IFN-gamma)), but greater amounts of monocyte-derived inflammatory cytokines (IL-1 beta, tumor necrosis factor-alpha (TNF-alpha), and IL-8) and a regulatory cytokine (IL-10). IL-10 production was positively correlated with IL-1 beta and TNF-alpha in healthy controls, whereas no correlation was observed in HD patients. Abnormal cytokine production by monocytes may contribute to the immunodeficiency seen in HD patients.


Lack of the sodium-driven chloride bicarbonate exchanger NCBE impairs visual function in the mouse retina.
Regulation of ion and pH homeostasis is essential for normal neuronal function. The sodium-driven chloride bicarbonate exchanger NCBE (Slc4a10), a member of the SLC4 family of bicarbonate transporters, uses the transmembrane gradient of sodium to drive cellular net uptake of bicarbonate and to extrude chloride, thereby modulating both intracellular pH (pH(i)) and chloride concentration ([Cl(-)](i)) in neurons. Here we show that NCBE is strongly expressed in the retina. As GABA(A) receptors conduct both chloride and bicarbonate, we hypothesized that NCBE may be relevant for GABAergic transmission in the retina. Importantly, we found a differential expression of NCBE in bipolar cells: whereas NCBE was expressed on ON and OFF bipolar cell axon terminals, it only localized to dendrites of OFF bipolar cells. On these compartments, NCBE colocalized with the main neuronal chloride extruder KCC2, which renders GABA hyperpolarizing. NCBE was also expressed in starburst amacrine cells, but was absent from neurons known to depolarize in response to GABA, like horizontal cells. Mice lacking NCBE showed decreased visual acuity and contrast sensitivity in behavioral experiments and smaller b-wave amplitudes and longer latencies in electroretinograms. Ganglion cells from NCBE-deficient mice also showed altered temporal response properties. In summary, our data suggest that NCBE may serve to maintain intracellular chloride and bicarbonate concentration in retinal neurons. Consequently, lack of NCBE in the retina may result in changes in pH(i) regulation and chloride-dependent inhibition, leading to altered signal transmission and impaired visual function.


The rhythm of yeast.
Although yeast are unicellular and comparatively simple organisms, they have a sense of time which is not related to reproduction cycles. The glycolytic pathway exhibits oscillatory behaviour, i.e. the metabolite concentrations oscillate around phosphofructokinase. The frequency of these oscillations is about 1 min when using intact cells. Also a yeast cell extract can oscillate, though with a lower frequency. With intact cells the macroscopic oscillations can only be observed when most of the cells oscillate in concert. Transient oscillations can be observed upon simultaneous induction; sustained oscillations require an active synchronisation mechanism. Such an active synchronisation mechanism, which involves acetaldehyde as a signalling compound, operates under certain conditions. How common these oscillations are in the absence of a synchronisation mechanism is an open question. Under aerobic conditions an oscillatory metabolism can also be observed, but with a much lower frequency than the glycolytic oscillations. The frequency is between one and several hours. These oscillations are partly related to the reproductive cycle, i.e. the budding index also oscillates; however, under some conditions they are unrelated to the reproductive cycle, i.e. the budding index is constant. These oscillations also have an active synchronisation mechanism, which involves hydrogen sulfide as a synchronising agent. Oscillations with a frequency of days can be observed with yeast colonies on plates. Here the oscillations have a synchronisation mechanism which uses ammonia as a synchronising agent.


Localization and functional characterization of the alternative oxidase in Naegleria.
The alternative oxidase (AOX) is a protein involved in supporting enzymatic reactions of the Krebs cycle in instances when the canonical (cytochrome-mediated) respiratory chain has been inhibited, while allowing for the maintenance of cell growth and necessary metabolic processes for survival. Among eukaryotes, alternative oxidases have dispersed distribution and are found in plants, fungi, and protists, including Naegleria ssp. Naegleria species are free-living unicellular amoeboflagellates and include the pathogenic species of N. fowleri, the so-called "brain-eating amoeba." Using a multidisciplinary approach, we aimed to understand the evolution, localization, and function of AOX and the role that plays in Naegleria's biology. Our analyses suggest that AOX was present in last common ancestor of the genus and structure prediction showed that all functional residues are also present in Naegleria species. Using cellular and biochemical techniques, we also functionally characterize N. gruberi's AOX in its mitochondria, and we demonstrate that its inactivation affects its proliferation. Consequently, we discuss the benefits of the presence of this protein in Naegleria species, along with its potential pathogenicity role in N. fowleri. We predict that our findings will spearhead new explorations to understand the cell biology, metabolism, and evolution of Naegleria and other free-living relatives.


Scaffold hopping with virtual screening from IP3 to a drug-like partial agonist of the inositol trisphosphate receptor.
Inositol 1,4,5-trisphosphate (IP3 ) is a universal signalling molecule that releases calcium from stores within cells by activating the IP3 receptor. Although chemical tools that modulate the IP3 receptor exist, none is ideal due to trade offs between potency, selectivity and cell permeability, and their chemical properties make them challenging starting points for optimisation. Therefore, to find new leads, we used virtual screening to scaffold hop from IP3 by using the program ROCS to perform a 3D ligand-based screen of the ZINC database of purchasable compounds. We then used the program FRED to dock the top-ranking hits into the IP3 binding pocket of the receptor. We tested the 12 highest-scoring hits in a calcium-release bioassay and identified SI-9 as a partial agonist. SI-9 competed with [(3) H]IP3 binding, and reduced histamine-induced calcium signalling in HeLa cells. SI-9 has a novel 2D scaffold that represents a tractable lead for designing improved IP3 receptor modulators.


Phenotypic Dimensions of Spirituality: Implications for Mental Health in China, India, and the United States.
While the field of empirical study on religion and spirituality in relation to mental health has rapidly expanded over the past decade, little is known about underlying dimensions of spirituality cross-culturally conceived. We aimed to bridge this gap by inductively deriving potential universal dimensions of spirituality through a large-scale, multi-national data collection, and examining the relationships of these dimensions with common psychiatric conditions. Five-thousand five-hundred and twelve participants from China, India, and the United States completed a two-hour online survey consisting of wide-ranging measures of the lived experience of spirituality, as well as clinical assessments. A series of inductive Exploratory Factor Analysis (EFA) and cross-validating Exploratory Structural Equation Modeling (ESEM) were conducted to derive common underlying dimensions of spirituality. Logistic regression analyses were then conducted with each dimension to predict depression, suicidal ideation, generalized anxiety, and substance-related disorders. Preliminary EFA results were consistently supported by ESEM findings. Analyses of 40 spirituality measures revealed five invariant factors across countries which were interpreted as five dimensions of universal spiritual experience, specifically: love, in the fabric of relationships and as a sacred reality; unifying interconnectedness, as a sense of energetic oneness with other beings in the universe; altruism, as a commitment beyond the self with care and service; contemplative practice, such as meditation, prayer, yoga, or qigong; and religious and spiritual reflection and commitment, as a life well-examined. Love, interconnectedness, and altruism were associated with less risk of psychopathology for all countries. Religious and spiritual reflection and commitment and contemplative practice were associated with less risk in India and the United States but associated with greater risk in China. Education was directly associated with dimensions of spiritual awareness in India and China but inversely associated with dimensions in the United States. Findings support the notion that spirituality is a universal phenomenon with potentially universal dimensions. These aspects of spirituality may each offer protective effects against psychiatric symptoms and disorders and suggest new directions for treatment.


Antibody responses to vaccination among South African HIV-exposed and unexposed uninfected infants during the first 2 years of life.
HIV-exposed but uninfected (HEU) infants born to HIV-infected mothers from areas in the world with a high burden of infectious disease suffer higher infectious morbidity and mortality than their HIV unexposed uninfected (HUU) peers. Vaccination provides protection from infection. The possibility exists that altered response to vaccination contributes to the higher rate of infection in HEU than in HUU infants. While short-term, cross-sectional studies support this notion, it is unclear whether or not HEU infants develop long-term protective immune responses following the WHO extended program on immunization (EPI). Vaccine-specific antibody responses were compared between HEU and HUU infants from 2 weeks until 2 years of age in a longitudinal South African cohort. Total IgG and antibodies specific for Bordetella pertussis, Haemophilus influenzae type b (Hib), tetanus toxoid, hepatitis B virus (HepB), and measles virus were measured at multiple time points throughout the first 2 years of life. Prevaccine antibodies (maternal antibodies passively acquired) specific for tetanus were lower in HEU than in HUU infants, while prevaccine antibodies to HepB were higher in HEU than in HUU infants. Both groups responded similarly to tetanus, Hib, and HepB vaccination. HEU demonstrated stronger pertussis vaccine responses, developing protective titers 1 year earlier than HUU patients, and maintained higher anti-tetanus titers at 24 months of age. Vaccine-induced antibodies to measles virus were similar in both groups at all time points. Our results suggest that the current EPI vaccination program as practiced in South Africa leads to the development of vaccine-specific antibody responses that are equivalent in HEU and HUU infants. However, our data also suggest that a large fraction of both HEU and HUU South African infants have antibody titers for several infectious threats that remain below the level of protection for much of their first 2 years of life.


In vitro inhibition of the bile salt export pump correlates with risk of cholestatic drug-induced liver injury in humans.
Inhibition of the activity of the human bile salt export pump (BSEP: ABCB11) has been proposed to play a role in drug-induced liver injury (DILI). To enhance understanding of the relationship between BSEP inhibition and DILI, inhibition of human BSEP (hBSEP) and its rat ortholog (rBsep) by 85 pharmaceuticals was investigated in vitro. This was explored using assays that quantified inhibition of ATP-dependent [(3)H]taurocholate uptake into inverted plasma membrane vesicles from Sf21 insect cells, which expressed the proteins. Of the pharmaceuticals, 40 exhibited evidence of in vitro transporter inhibition and overall a close correlation was observed between potency values for inhibition of hBSEP and rBsep activity (r(2) = 0.94), although 12 drugs exhibited >2-fold more potent inhibition of hBSEP than rBsep. The median potency of hBSEP inhibition was higher among drugs that caused cholestatic/mixed DILI than among drugs that caused hepatocellular or no DILI, as was the incidence of hBSEP inhibition with IC(50) <300 μM. All drugs with hBSEP IC(50) <300 μM had molecular weight >250, ClogP >1.5, and nonpolar surface area >180Å. A clear distinction was not evident between hBSEP IC(50) or unbound plasma concentration (C(max, u)) of the drugs in humans and whether the drugs caused DILI. However, all 17 of the drugs with hBSEP IC(50) <100 μM and C(max, u) >0.002 μM caused DILI. Overall, these data indicate that inhibition of hBSEP/rBsep correlates with the propensity of numerous pharmaceuticals to cause cholestatic DILI in humans and is associated with several of their physicochemical properties.


The endosomal transcriptional regulator RNF11 integrates degradation and transport of EGFR.
Stimulation of cells with epidermal growth factor (EGF) induces internalization and partial degradation of the EGF receptor (EGFR) by the endo-lysosomal pathway. For continuous cell functioning, EGFR plasma membrane levels are maintained by transporting newly synthesized EGFRs to the cell surface. The regulation of this process is largely unknown. In this study, we find that EGF stimulation specifically increases the transport efficiency of newly synthesized EGFRs from the endoplasmic reticulum to the plasma membrane. This coincides with an up-regulation of the inner coat protein complex II (COPII) components SEC23B, SEC24B, and SEC24D, which we show to be specifically required for EGFR transport. Up-regulation of these COPII components requires the transcriptional regulator RNF11, which localizes to early endosomes and appears additionally in the cell nucleus upon continuous EGF stimulation. Collectively, our work identifies a new regulatory mechanism that integrates the degradation and transport of EGFR in order to maintain its physiological levels at the plasma membrane.


Comparison of the late H1 histone genes of the sea urchins Lytechinus pictus and Strongelocentrotus purpuratus.
We have isolated and sequenced a gene encoding a late H1 histone subtype from the sea urchin species L. pictus. The primary structure of the late H1 subtype encoded by this gene is 209 amino acids in length, and has a net positive charge of 67. This gene is present in a single copy per haploid genome and encodes an mRNA of 752 nucleotides. Late H1 transcripts are detected in the unfertilized egg and are most prevalent in gastrulating embryos. Comparison of 375 bp of 5' flanking sequences of the L. pictus late H1 gene and the H1-gamma gene of a distantly related sea urchin species, S. purpuratus, reveals large blocks of sequences that are identical between the two genes. To determine if these conserved 5' sequences are present in other members of the sea urchin H1 gene family, the analogous region of S. purpuratus H1-alpha, an early H1 gene, was sequenced. The homology between the flanking sequences of the early and late families was limited to consensus sequences which are found upstream of all H1 genes. The possible regulatory implications of these findings are discussed.


Dysgerminoma: the role of conservative surgery.
Twenty-five cases of pure ovarian dysgerminoma treated at UCLA Medical Center between 1958 and 1992 were reviewed retrospectively. Patterns of recurrence and overall survival were analyzed with regard to primary surgery (conservative versus nonconservative), use of adjuvant therapy, and stage of disease. Fourteen patients (56%) underwent conservative surgical therapy defined as preservation of the contralateral ovary, 10 patients (40%) had nonconservative primary surgery, and one patient (4%) had chemotherapy as primary treatment. Three patients (12%) received adjuvant chemotherapy and nine patients (36%) received postoperative radiation therapy. Fifteen patients (60%) had stage I disease, four (16%) stage II, and three each (12%) had stage III and IV disease. Nine patients (36%) experienced recurrence of disease. Seven of these nine patients (78%) had stage I disease and all seven had undergone conservative primary surgery with preservation of the contralateral ovary. Six of the seven had received no adjuvant therapy. Only one of these seven patients experienced recurrence in the preserved ovary. She was found to have a dysgenetic ovary and an XY karyotype. Three patients with recurrent disease had received radiation therapy after primary surgery. Twenty patients (80%) were alive without disease at follow-up, two patients (8%) were alive with disease, and three (12%) had died of disease. There was no statistically significant difference in recurrence rates between those patients treated with conservative surgery and those treated with nonconservative surgery, although the total number of patients with recurrences was greater in the former group. Our data suggest that a conservative surgical approach is the preferred treatment in patients with pure dysgerminoma of the ovary who desire future fertility. Lack of adjuvant chemotherapy or radiation therapy, rather than type of initial surgery, may be associated with a higher risk of recurrence.


Phosphorylation of human DNA polymerase lambda by the cyclin-dependent kinase Cdk2/cyclin A complex is modulated by its association with proliferating cell nuclear antigen.
DNA polymerase (Pol) lambda is a member of the Pol X family and possesses four different enzymatic activities, being DNA polymerase, terminal transferase, deoxyribose phosphate lyase and polynucleotide synthetase, all localized in its C-terminal region. On the basis of its biochemical properties, Pol lambda has been implicated in various DNA repair pathways, such as abasic site translesion DNA synthesis, base excision repair and non-homologous end joining of double strand breaks. However, its role in vivo has not yet been elucidated. In addition, Pol lambda has been shown to interact with the replication clamp proliferating cell nuclear antigen (PCNA) in vitro and in vivo. In this work, we searched by affinity chromatography for novel partners and we identified the cyclin-dependent kinase Cdk2 as novel partner of Pol lambda. Pol lambda is phosphorylated in vitro by several Cdk/cyclin complexes, including Cdk2/cyclin A, in its proline-serine-rich domain. While the polymerase activity of Pol lambda was not affected by Cdk2/cyclin A phosphorylation, phosphorylation of Pol lambda was decreased by its interaction with PCNA. Finally, Pol lambda is also phosphorylated in vivo in human cells and this phosphorylation is modulated during the cell cycle.