A full genome search in multiple sclerosis.
The aetiology of multiple sclerosis (MS) is uncertain. There is strong circumstantial evidence to indicate it is an autoimmune complex trait. Risks for first degree relatives are increased some 20 fold over the general population. Twin studies have shown monozygotic concordance rates of 25-30% compared to 4% for dizygotic twins and siblings. Studies of adoptees and half sibs show that familial risk is determined by genes, but environmental factors strongly influence observed geographic differences. Studies of candidate genes have been largely unrewarding. We report a genome search using 257 microsatellite markers with average spacing of 15.2 cM in 100 sibling pairs (Table 1, data set 1 - DS1). A locus of lambda>3 was excluded from 88% of the genome. Five loci with maximum lod scores (MLS) of >1 were identified on chromosomes 2, 3, 5, 11 and X. Two additional data sets containing 44 (Table 1, DS2) and 78 sib pairs (Table 1, DS3) respectively, were used to further evaluate the HLA region on 6p21 and a locus on chromosome 5 with an MLS of 4.24. Markers within 6p21 gave MLS of 0.65 (non-significant, NS). However, D6S461, just outside the HLA region, showed significant evidence for linkage disequilibrium by the transmission disequilibrium test (TDT), in all three data sets (for DS1 chi2 = 10.8, adjusted P < 0.01)(DS2 and DS3 chi2 = 10.9, P < 0.0005), suggesting a modest susceptibility locus in this region. On chromosome 5p results from all three data sets (222 sib pairs) yielded a multipoint MLS of 1.6. The results support genetic epidemiological evidence that several genes interact epistatically to determine heritable susceptibility.


Modifiable lifestyle factors that could reduce the incidence of colorectal cancer in New Zealand.
To estimate population attributable fractions for modifiable lifestyle factors and colorectal cancer in New Zealand. Relative risks for lifestyle risk factors for colorectal cancer, and population data on the prevalence of exposure in New Zealand, were used to estimate the population attributable fraction (PAF) for each risk factor. Six modifiable lifestyle risk factors were identified. The PAFs for these risk factors were 9% for obesity, 7% for alcohol, 4% for physical inactivity, 3% for smoking, 5% for consumption of red meat and 3% for processed meat. PAFs differed by ethnic group and sex. In women, the highest PAFs were 19% for obesity in Pacific women, 14% for obesity in Māori women, 7% for physical inactivity in Asian women, and 8% for obesity in European/other women. In men, the highest PAFs were 17% for obesity in Pacific men, 14% for high alcohol consumption in Māori men, 5% for physical inactivity in Asian men and 9% for high alcohol consumption in European/other men. If obesity, alcohol consumption, smoking and consumption of red and processed meats could be reduced, and physical activity could be increased among New Zealanders, it would reduce the risk of colorectal cancer considerably.


Cross-species comparison of genes related to nutrient sensing mechanisms expressed along the intestine.
Intestinal chemosensory receptors and transporters are able to detect food-derived molecules and are involved in the modulation of gut hormone release. Gut hormones play an important role in the regulation of food intake and the control of gastrointestinal functioning. This mechanism is often referred to as "nutrient sensing". Knowledge of the distribution of chemosensors along the intestinal tract is important to gain insight in nutrient detection and sensing, both pivotal processes for the regulation of food intake. However, most knowledge is derived from rodents, whereas studies in man and pig are limited, and cross-species comparisons are lacking. To characterize and compare intestinal expression patterns of genes related to nutrient sensing in mice, pigs and humans. Mucosal biopsy samples taken at six locations in human intestine (n = 40) were analyzed by qPCR. Intestinal scrapings from 14 locations in pigs (n = 6) and from 10 locations in mice (n = 4) were analyzed by qPCR and microarray, respectively. The gene expression of glucagon, cholecystokinin, peptide YY, glucagon-like peptide-1 receptor, taste receptor T1R3, sodium/glucose cotransporter, peptide transporter-1, GPR120, taste receptor T1R1, GPR119 and GPR93 was investigated. Partial least squares (PLS) modeling was used to compare the intestinal expression pattern between the three species. The studied genes were found to display specific expression patterns along the intestinal tract. PLS analysis showed a high similarity between human, pig and mouse in the expression of genes related to nutrient sensing in the distal ileum, and between human and pig in the colon. The gene expression pattern was most deviating between the species in the proximal intestine. Our results give new insights in interspecies similarities and provide new leads for translational research and models aiming to modulate food intake processes in man.


Need for dental care in older veterans: assessment of patient-based measures.
There is a need for brief and accurate identification of older patients in need of dental care. This study examines the sensitivity and specificity of two screening instruments. Cross-sectional study conducted in older community-dwelling male veterans. Four Department of Veterans Affairs (VA) clinics in greater Boston and the VA Dental Longitudinal Study (DLS). Two hundred thirty-two participants from the Veterans Health Study (VHS) who were outpatients in one of four Department of Veterans Affairs clinics in greater Boston and 206 participants from the VA DLS, community-dwelling veterans who do not use VA for their health care. Self-report measures included a single-item global self-report of oral health (OH-1) and a six-item dental screening measure called the D-E-N-T-A-L. The D-E-N-T-A-L queries whether participants have Dry mouth, Eating or swallowing problems, Not had a dental examination in the last 2 years, Tooth or mouth problems, Altered eating habits because of teeth or mouth, or Lesions or sores in the mouth. The criterion standard for need for treatment was determined by a clinical examination. Sensitivities and specificities were calculated and receiver operating characteristic curves plotted to identify the best cutpoints for each measure. Need for care was nearly universal (97%) in the VHS and present in 64% of the DLS participants. The single-item self-report of oral health performed as well as the D-E-N-T-A-L in identifying persons in need of care. Compared with the clinical criterion, the OH-1 had a sensitivity of 0.75 and a specificity of 0.67 in identifying persons with severe need for denture care, whereas the D-E-N-T-A-L had a sensitivity of 0.80 and a specificity of 0.62 in identifying persons with severe periodontal need. Self-reports of fair or poor oral health are useful in identifying veterans in need of dental care, especially in populations with a large number of persons who do not usually use dental care. The D-E-N-T-A-L may also be useful as a self-screening measure and community education device to encourage older persons to seek regular dental care.


Time-resolved X-ray spectroscopies of chemical systems: New perspectives.
The past 3-5 years have witnessed a dramatic increase in the number of time-resolved X-ray spectroscopic studies, mainly driven by novel technical and methodological developments. The latter include (i) the high repetition rate optical pump/X-ray probe studies, which have greatly boosted the signal-to-noise ratio for picosecond (ps) X-ray absorption spectroscopy studies, while enabling ps X-ray emission spectroscopy (XES) at synchrotrons; (ii) the X-ray free electron lasers (XFELs) are a game changer and have allowed the first femtosecond (fs) XES and resonant inelastic X-ray scattering experiments to be carried out; (iii) XFELs are also opening the road to the development of non-linear X-ray methods. In this perspective, I will mainly focus on the most recent technical developments and briefly address some examples of scientific questions that have been addressed thanks to them. I will look at the novel opportunities in the horizon.


Aspirin inhibits vascular plasminogen activator activity in vivo. Studies utilizing a new assay to quantify plasminogen activator activity.
Vascular or tissue-type plasminogen activator (TPA) is a key enzyme in physiologic fibrinolysis. To study the role of prostaglandins in modulating the synthesis and release of TPA in vivo, we prospectively studied the effect of aspirin (650 mg/d X 2) on TPA activity in 13 human subjects before and after 10 min of forearm venous occlusion. TPA activity was quantified by a newly developed enzyme-linked immunosorbent assay that both measures and differentiates between TPA and urokinase (UK)-like plasminogen activator activity. This assay is based on the observation that the concentration of alpha 2-plasmin inhibitor-plasmin complexes in Reptilase-clotted plasma increases linearly in proportion to the amount of activator added. Resting TPA activity was higher in women than in men (0.56 +/- 0.59 vs. 0.15 +/- 0.11 U/ml, P = 0.049). Venous occlusion induced an eightfold rise in TPA activity in women (to 4.5 U/ml, P = 0.006) and a 15-fold rise in men (to 2.28 U/ml, P = 0.004), whereas UK activity was not detected. Aspirin inhibited the rise in TPA activity after venous occlusion by 69% in men (P = 0.004) and 70% in women (P = 0.014). In contrast, aspirin had no effect on pre- or post-occlusion hematocrits or Factor VIII-related antigen levels. There was no correlation between plasma salicylate level and percentage inhibition of TPA. Neither exogenous aspirin (0-1 microgram/ml) nor salicylate (0-70 micrograms/ml) inhibited the generation of alpha 2-plasmin inhibitor-plasmin complexes by exogenous TPA or interfered with the assay system. We conclude that aspirin may have an antifibrinolytic effect in man that has not been previously described.


Improved postprandial glycemic control with insulin aspart. A randomized double-blind cross-over trial in type 1 diabetes.
Insulin aspart is a novel rapid-acting insulin analog. This study was performed to compare the postprandial serum glucose control after administration of insulin aspart with that of unmodified human insulin. The trial was a double-blind double-dummy injection three-way cross-over study in 22 subjects with type 1 diabetes. Insulin aspart was injected subcutaneously immediately before the meal, and human insulin was injected subcutaneously 30 min before the meal or immediately before the meal. The postprandial glucose control as assessed by the excursion of serum glucose was superior with insulin aspart as compared with that with human insulin injected immediately before or 30 min before a meal (891 +/- 521 vs. 1,311 +/- 512 vs. 1,106 +/- 571 mmol.l-1.min-1, P < 0.0001 and P < 0.02). This was accompanied by a significantly lower glucose maximum concentration [Cmax(SG)] for insulin aspart than for human insulin injected immediately before the meal (13.5 +/- 3.5 vs. 16.4 +/- 3.4 mmol/l, P < 0.001). Insulin aspart was, on average, absorbed twice as fast as human insulin, with median time to insulin aspart Cmax(ins) on the order of 40 min, and the maximum concentration was approximately twice as high for insulin aspart. The relative bioavailability of the insulins indicated a similar extent of absorption. Insulin aspart was well tolerated. This study demonstrates the ability of insulin aspart to improve postprandial glucose control when compared with human insulin.


Geriatric Rehabilitation: Elderly Clients' Experiences of a Pre-discharge Occupational Therapy Group Programme.
This study describes how elderly people, temporarily living in a pre-discharge community rehabilitation centre, may experience participation in an in-patient occupational therapy programme built around group activities. The group activity programme was comprised of five sessions, each focusing on a theme chosen to encourage reflection and mutual sharing of experiences and support. Data were collected through interviews with each of the three participants immediately after each of the five group sessions. The resultant 15 interviews were analysed by adopting a Grounded Theory approach. The results show that the ways in which the participants experienced participating in the group activity programme can be described from two distinct core categories: experiences of activation and experiences of transformation . The category of activation emerged from their experiences of a creative force whilst engaged in performing the activities and from their discovery that the group was a good place for learning . Engagement in the group activities also seemed to bring about a transformation in the participants in that their experiences triggered reflection and adaptation , which contributed to a change in attitude and a personal synthesis where their new discoveries were internalized. The study shows the potential a group activity programme in occupational therapy has in triggering an adaptational and reflective process within elderly people facing discharge from hospital. Hence, group activity interventions in occupational therapy are suggested as one possible way to support the elderly person in the discharge process from hospital to the home.


Correction for spatial averaging in laser speckle contrast analysis.
Practical laser speckle contrast analysis systems face a problem of spatial averaging of speckles, due to the pixel size in the cameras used. Existing practice is to use a system factor in speckle contrast analysis to account for spatial averaging. The linearity of the system factor correction has not previously been confirmed. The problem of spatial averaging is illustrated using computer simulation of time-integrated dynamic speckle, and the linearity of the correction confirmed using both computer simulation and experimental results. The valid linear correction allows various useful compromises in the system design.


Relative contributions of late dry-season and early rains pasture contaminations with trichostrongyle eggs to the wet-season herbage infestation in eastern Nigeria.
Two worm-free grass paddocks, P1 and P2, were artificially contaminated in March and April-May, respectively, with bovine faeces containing known numbers of trichostrongyle (mainly Cooperia, Haemonchus and Trichostrongylus spp.) eggs in order to determine the relative contributions of late dry-season and early rains pasture contaminations to the wet-season herbage larval infestation in Nsukka, eastern Nigeria. The resulting herbage infestation was assessed by means of larval counts and tracer studies. A sudden rise in herbage infestation occurred simultaneously in both paddocks in late April, this apparently being determined by the onset of the first substantial rainfall of the wet season. Peak infestations in both paddocks also occurred simultaneously in May. The infestation in P1 was much larger, and the larval population persisted longer, than that in P2 and later gave rise to a second smaller peak in June. No L3 were recovered in herbage samples from either of the paddocks after the third week of July. Both paddocks were infective to goats in May-June, while P2 was also infective in July-August. The results suggest that in the Nigerian derived savanna the initial wet-season herbage infestation in pastures grazed by infected cattle during the dry and wet seasons will consist of L3 from late dry-season and early rains pasture contaminations, the former being the major contributor to the infestation. Consequently, pastures contaminated during the late dry season may not be safe for susceptible animals to graze at the start of the succeeding rainy season.


Molecular cloning of a novel non-receptor tyrosine kinase, HYL (hematopoietic consensus tyrosine-lacking kinase).
We identified a novel non-receptor tyrosine kinase from a human megakaryoblastic cell line, UT-7, by means of a PCR-based cloning method. The HYL gene contained a SH2 and SH3 domain and a tyrosine kinase catalytic domain. The deduced amino acid sequence of the protein encoded by this gene was most homologous to CSK (c-src kinase). This gene and CSK shared some unique structural properties such as the absence of a myristylation signal and phosphorylation sites of tyrosine residues corresponding to tyrosines 416 and 527 of chicken p60c-src. Unlike CSK, the SH3 domain of HYL was unique since the ALYDY motif was absent. Northern blot analysis revealed a 2.2 kb transcript in various myeloid cell lines but not in adult tissues except for the brain and the lung, whereas CSK mRNA was ubiquitously expressed. The expression of HYL was upregulated when these myeloid cells were differentiated by induction with phorbol myristate acetate. We named this gene, hematopoietic consensus tyrosine-lacking kinase, HYL. The HYL gene was assigned to chromosome 19 at band p13. It is suggested that HYL plays a significant role in the signal transduction of hematopoietic cells.


Temporal variation of Ixodes ricinus intensity on the rodent host Apodemus flavicollis in relation to local climate and host dynamics.
The risk to humans of contracting tick-borne zoonotic diseases depends on the risk of a bite from an infected tick, which can be broken down into its component parts as the number of host-seeking ticks in the environment, in particular nymphs, and the prevalence of tick-borne pathogens they are carrying. In turn, the prevalence of tick-borne pathogens is dependent upon tick biting intensity on hosts that support transmission between ticks; namely rodents. These ticks once fed moult into the next life stage and search for the next blood meal, thus posing a zoonotic risk. Here, we analyse tick biting intensity on rodents in a known tick-borne encephalitis (TBE) focus in Trentino (northern Italy). We examine patterns of tick demography and the influence of host densities and climate on ticks' generation time, development rates, tick density and intensity. During the period 2000-2004, a population of the yellow-necked mouse, Apodemus flavicollis, the most important TBE transmission host, was intensively monitored. Ticks feeding on individual rodents were counted, distinguishing between the larval and nymph life-stages. Local temperature and relative humidity was calculated using both data-loggers in the field site and regional weather stations. We investigated which factors had a predictive value both on feeding tick intensity and on the overall density of larvae or nymphs feeding on rodents in a year. We observed a negative effect of rodent density on tick intensity, while temperature influenced positively both larvae and nymph intensity. Overall larval density was higher in the years and trapping grids where rodent density was higher, while for nymphs no such effect was observed. The best explanatory variable for nymph density was the larval density in the previous year, confirming the discrete nature of tick demography. This provides important information in terms of monitoring the risk to humans of acquiring pathogen-infected ticks.


Membrane nanotube pearling restricted by confined polymers.
Increasing evidence showed that membrane nanotubes readily undergo pearling in response to external stimuli, while long tubular membrane structures have been observed connecting cells and functioning as channels for intercellular transport, raising a fundamental question of how the stability of membrane nanotubes is maintained in the cellular environment. Here, combining dissipative particle dynamics simulations, free energy calculations, and a force analysis, we propose and demonstrate that nanotube pearling can be restricted by confined polymers, which can be DNA and protein chains transported through the nanotubes, or actin filaments participating in tube formation and elongation. Thermodynamically, nanotube pearling releases the membrane surface energy, but costs bending energies of both the membrane and the confined polymers. Following the mechanism, the pearling of nanotubes confining longer and stiffer polymers is more difficult as it costs larger polymer bending energies. In dynamics, nanotube pearling occurs by repelling polymers from the region of nanotube shrinking to that of swelling. Shorter polymers can be readily repelled owing to the unbalanced force exerted by the shrinking tube region, whereas longer polymers tend to be trapped at the shrinking region to retard the nanotube pearling. Besides the low surface tension maintained by lipid reservoirs kept in living cells, our results supplement the explanation for the stability of membrane nanotubes, and open up a new avenue to manipulate the shape deformation of tubular membrane structures for study of many biological processes.


A Systematic Review of Interventions to Change Staff Care Practices in Order to Improve Resident Outcomes in Nursing Homes.
We systematically reviewed interventions that attempted to change staff practice to improve long-term care resident outcomes. Studies met criteria if they used a control group, included 6 or more nursing home units and quantitatively assessed staff behavior or resident outcomes. Intervention components were coded as including education material, training, audit and feedback, monitoring, champions, team meetings, policy or procedures and organizational restructure. Sixty-three unique studies were broadly grouped according to clinical domain-oral health (3 studies), hygiene and infection control (3 studies), nutrition (2 studies), nursing home acquired pneumonia (2 studies), depression (2 studies) appropriate prescribing (7 studies), reduction of physical restraints (3 studies), management of behavioral and psychological symptoms of dementia (6 studies), falls reduction and prevention (11 studies), quality improvement (9 studies), philosophy of care (10 studies) and other (5 studies). No single intervention component, combination of, or increased number of components was associated with greater likelihood of positive outcomes. Studies with positive outcomes for residents also tended to change staff behavior, however changing staff behavior did not necessarily improve resident outcomes. Studies targeting specific care tasks (e.g. oral care, physical restraints) were more likely to produce positive outcomes than those requiring global practice changes (e.g. care philosophy). Studies using intervention theories were more likely to be successful. Program logic was rarely articulated, so it was often unclear whether there was a coherent connection between the intervention components and measured outcomes. Many studies reported barriers relating to staff (e.g. turnover, high workload, attitudes) or organizational factors (e.g. funding, resources, logistics). Changing staff practice in nursing homes is possible but complex. Interventionists should consider barriers and feasibility of program components to impact on each intended outcome.


A phase II study of intrapleural immuno-chemotherapy, pleurectomy/decortication, radiotherapy, systemic chemotherapy and long-term sub-cutaneous IL-2 in stage II-III malignant pleural mesothelioma.
From therapeutic nihilism to extremely aggressive management, there is a wide range of possibilities in the treatment of malignant pleural mesothelioma (MPM). Unfortunately, there is little evidence as regards the best treatment to offer to the MPM patients. In 1999, we started a phase II study based on the multimodality treatment of stage II-III MPM, the results of which have been analysed and reported. From 1999 to 2004, 49 patients with IMIG stage II-III MPM underwent a multimodality treatment including: intrapleural pre-operative interleukin 2 (IL-2, 18x10(6) UI/day per 3 days), pleurectomy/decortication, intrapleural post-operative epidoxorubicin (25mg/m2 per 3 days), IL-2 (18x10(6) UI/day per 3 days), adjuvant radiotherapy (30Gy), systemic chemotherapy (cisplatin 80 mg/m2 day 1, gemcitabine 1250 mg/m2 day 1 and 8 up to 6 courses) and long-term sub-cutaneous IL-2 (3x10(6) UI/day 3 days per week). There were 41 males and 8 females with a median age of 61 years (range 41-77). All the patients had a diagnosis of MPM by thoracoscopy before inclusion. We did not experience any post-operative mortality. The histology was: 39 epitheliomorf, 6 bifasic and 4 sarcomatous. According to the IMIG the post-operative staging was III in 40 cases and II in 9 cases. With a median follow-up of 59 months (range 14-81) 13 patients are still alive and the median actuarial survival is 26 months (31 and 21 months for stage II and III, respectively). Only the Performance Status at the diagnosis affected survival significantly. The multimodality treatment we adopted for stage II-III MPM was feasible, well tolerated by most of the patients and produced a favourable outcome. New targeted therapies are awaited for further improvements in the treatment of this disease.


Genetics of type 2 diabetes.
Identification and characterization of genetic variants that either cause or predispose to diabetes are a major focus of biomedical research. As of early 2007, the molecular basis of most forms of monogenic diabetes resulting from beta-cell dysfunction is known and, in particular, there has been recent success in delineating the genetic aetiology of neonatal diabetes. Finding genes predisposing to more common, multifactorial forms of type 2 diabetes represents a far greater challenge, and only a handful of robust, well-replicated examples have been established. Nevertheless, 2006 heralded identification of the most important type 2 diabetes susceptibility gene known so far, TCF7L2, and in 2007 large-scale genome-wide association studies are destined to provide novel insights into the genetic architecture and biology of type 2 diabetes.


Induction Chemotherapy Improved Long Term Outcomes in Stage IV Locoregional Advanced Nasopharyngeal Carcinoma.
Purpose: We aimed to determine whether adding induction chemotherapy (IC) to concurrent chemoradiation (CCRT) improved outcomes in each stage of locally advanced nasopharyngeal carcinoma (LANPC). Methods: From 2007 to 2013, we retrospectively collected 259 histopathologically identified adult LANPC patients from two campuses in south Taiwan. Among the 238 eligibly treated cases, 156 patients received CCRT (CCRT group) upfront and 82 received IC followed by CCRT (IC group). Of these patients, 130 were stage III (92 patients that received CCRT and 38 that received IC adding CCRT) and 108 were stage IV (76 CCRT and 32 IC adding CCRT). Most chemotherapy regimens for IC are composed of cisplatin (P), 5-fluorouracil (F), and ifosfamide (I), while concurrent chemotherapy (CC) was essentially cisplatin-based. For CCRT as the upfront treatment, a P or PF regimen was usually used in CC. Survival outcomes were accessed with a Kaplan-Meier estimate and a p-value by log-rank test to compare the survival distributions of IC added to CCRT or CCRT as the upfront treatment in all LANPC stage III and LANPC IV patients. The failure free survival (FFS), overall survival (OS), local relapse free survival (LRFS), regional recurrence-free survival (RRFS), distant metastasis-free survival (DMFS), first failure site, and other prognostic factors were analyzed. Results: The median follow-up time of all treated LANPC patients was 59 months. For all LANPC patients, there was a significant difference only in the DMFS favoring IC group (91.5% vs 79.4%, p=0.013). In the subgroup study, for the stage III group, there was no significant difference between the groups for overall OS (IC group 71.3% vs CCRT group 78.7%), FFS (71.5% vs 62.4%) and RRFS (91.9% vs 90.9%). However, inferior LRLS (71.7% vs 91.5%; p = 0.03) was noted for the IC group. In contrast, for stage IV, there were significantly longer OS (75.8% vs 52.6%), FFS (66.8% vs 46.8%), and DMFS (86.0% vs 69.6%; p = 0.02, p = 0.04, and p = 0.03, respectively) rates in the IC group. Conclusion: Adding PIF-based IC to CCRT for the LANPC patients resulted in better outcomes for stage IV patients, but not for stage III patients. A future properly designed study should stratify enough LANPC cases under the structure of the AJCC stage grouping system to determine which subgroups truly benefit from adding IC to CCRT.


Improvement and formation of UV-induced damage on LBO crystal surface during long-term high-power third-harmonic generation.
We demonstrate the improvement and formation of UV-induced damage on LBO crystal output surface during long-term (130 h) high-power (20 W) high-repetition-rate (80 kHz) third-harmonic generation. The output surface was super-polished (RMS surface roughness <0.6 nm) to sub-nanometer scale super smooth roughness. The surface lifetime has been improved more than 20-fold compared with the as-polished ones (RMS surface roughness 4.0~8.0 nm). The damage could be attributed to the consequence of thermal effects resulted from impurity absorptions. Simultaneously, it was verified that the impurities originated in part from the UV-induced deposition.


Life and death decisions: ceramide generation and EGF receptor trafficking are modulated by oxidative stress.
Reactive oxidants are associated with the pathogenesis of pulmonary diseases and affect various cell functions, from proliferation to apoptosis. We have shown that oxidants exert growth control on airway epithelial cells by modulating upstream receptor function. Additionally, hydrogen peroxide-mediated oxidative stress modulates ceramide levels to induce apoptosis in lung epithelium. Depletion of glutathione in lung epithelial cells results in ceramide accumulation, suggesting that ceramide elevation, coupled to oxidative stress, initiates apoptosis. While it is desirable to prevent cell death and tissue injury induced by oxidants in diseases such as asthma or acute respiratory distress syndrome, the opposite is sought in cancer. But oxidants may also activate growth factor receptors, enhancing cell proliferation and facilitating tumor promotion. Under oxidative stress, phosphorylation of the epidermal growth factor receptor (EGFR) is abrogated at tyrosine 1,045, the docking site for the ubiquitin ligase c-Cbl, rendering EGFR unable to recruit c-Cbl and be ubiquitylated and degraded. We thus proposed that this deficiency, which confers prolonged receptor signaling at the plasma membrane, links oxidative stress, EGFR, and tumorigenesis. Decoding the molecular interactions between oxidative stress and ceramide pathways and characterizing ubiquitylation control of receptor desensitization should provide new strategies for intervention in diverse pulmonary diseases and in diagnosing and eradicating cancer.


Physical activity, sedentary behaviour and energy balance in the preschool child: opportunities for early obesity prevention.
Prevalence of obesity in preschool children has increased dramatically in recent years. The preschool years (age 3-6 years) have been regarded as critical for the programming of energy balance, via the concept of early 'adiposity rebound'. Children who undergo early adiposity rebound are at increased risk of later obesity. Recent evidence suggests that associations between timing of adiposity rebound and later obesity may not reflect programming, but might denote that 'obesogenic' growth trajectories are often established by the preschool period. Studies of objectively-measured physical activity and sedentary behaviour in preschool children show that levels of physical activity are typically low and sedentary behaviour high. The review of evidence presented here is supportive of the hypothesis that physical activity is protective against obesity in the preschool period, and that sedentary behaviour, particularly television viewing, is obesogenic. Definitive evidence on dose-response relationships between physical activity, sedentary behaviour and obesity remain unclear. Dose-response evidence could be obtained fairly readily by intervention and longitudinal observational studies that use accelerometry in preschool children. The generalisability of much of the evidence base is limited and there is a need for research on the influence of physical activity and sedentary behaviour in the preschool years in the aetiology of obesity in the developing world.


Magnetic induction-induced resistive heating of optical fibers and gratings.
Magnetic induction heating of optical fibers packaged with a steel plate is studied using a fiber Bragg grating. The dependence on the induced wavelength shift with magnetic field is obtained for a commercially available induction heater. More than a 300°C temperature rise is observed within seconds. The potential of magnetic induction as an efficient and rapid means of modulating devices and as a novel approach to potential optical based magnetic field and current sensing is proposed and discussed. The extension of the ideas into micro and nanophotonics is described.


Surface curvature guides early construction activity in mound-building termites.
Termite colonies construct towering, complex mounds, in a classic example of distributed agents coordinating their activity via interaction with a shared environment. The traditional explanation for how this coordination occurs focuses on the idea of a 'cement pheromone', a chemical signal left with deposited soil that triggers further deposition. Recent research has called this idea into question, pointing to a more complicated behavioural response to cues perceived with multiple senses. In this work, we explored the role of topological cues in affecting early construction activity in Macrotermes. We created artificial surfaces with a known range of curvatures, coated them with nest soil, placed groups of major workers on them and evaluated soil displacement as a function of location at the end of 1 h. Each point on the surface has a given curvature, inclination and absolute height; to disambiguate these factors, we conducted experiments with the surface in different orientations. Soil displacement activity is consistently correlated with surface curvature, and not with inclination nor height. Early exploration activity is also correlated with curvature, to a lesser degree. Topographical cues provide a long-term physical memory of building activity in a manner that ephemeral pheromone labelling cannot. Elucidating the roles of these and other cues for group coordination may help provide organizing principles for swarm robotics and other artificial systems. This article is part of the theme issue 'Liquid brains, solid brains: How distributed cognitive architectures process information'.


Efficacy and safety of canagliflozin among patients with type 2 diabetes mellitus: A systematic review and meta-analysis.
To evaluate the efficacy and safety of canagliflozin in combination therapy among patients with type 2 diabetes mellitus with inadequate glycemic control. Two review authors independently searched for the relevant randomized controlled clinical trials from the Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, IndMed, LILACS, and clinical trials registry www.clinicaltrials.gov. Primary outcomes for this review included: change in hemoglobin A1c (HbA1c) levels, fasting plasma glucose (FPG) levels and risk of occurrence of genital mycotic infections at 26 weeks. We combined results using mean difference (MD) for continuous data, and risk ratio (RR) for dichotomous data. Of the 124 identified reports, five RCTs with 3565 participants were eligible for the meta-analysis. All included studies had compared canagliflozin 100 mg and 300 mg once daily with placebo or sitagliptin 100 mg once daily. We judged that most of the studies had low risk of bias or unclear risk of bias in five major domains. Canagliflozin 300 mg once daily led to a significant decrease in HbA1c levels (IV Fixed -0.77, 95% CI [-0.90, -0.64] P < 0.00001) and FPG levels (IV Fixed -2.08; 95% CI [-2.32, -1.84], P <0.00001), body weight, systolic blood pressure and triglyceride levels after 26 weeks as compared to placebo. There was a also a significant difference in the efficacy of canagliflozin 300 mg and sitagliptin 100 mg once daily in favour of canagliflozin. Both doses of canagliflozin led to genital mycotic infections among males and females, urinary tract infections, pollakiuria, polyuria and postural dizziness. Canagliflozin significantly decreases HbA1c and FPG levels and body weight as compared to placebo among patients with inadequate glycemic control with an earlier regime of glucose lowering agents. Long term safety studies are required to evaluate the incidence of adverse events.


Comparative mapping in intraspecific populations uncovers a high degree of macrosynteny between A- and B-genome diploid species of peanut.
Cultivated peanut or groundnut (Arachis hypogaea L.) is an important oilseed crop with an allotetraploid genome (AABB, 2n = 4x = 40). Both the low level of genetic variation within the cultivated gene pool and its polyploid nature limit the utilization of molecular markers to explore genome structure and facilitate genetic improvement. Nevertheless, a wealth of genetic diversity exists in diploid Arachis species (2n = 2x = 20), which represent a valuable gene pool for cultivated peanut improvement. Interspecific populations have been used widely for genetic mapping in diploid species of Arachis. However, an intraspecific mapping strategy was essential to detect chromosomal rearrangements among species that could be obscured by mapping in interspecific populations. To develop intraspecific reference linkage maps and gain insights into karyotypic evolution within the genus, we comparatively mapped the A- and B-genome diploid species using intraspecific F2 populations. Exploring genome organization among diploid peanut species by comparative mapping will enhance our understanding of the cultivated tetraploid peanut genome. Moreover, new sources of molecular markers that are highly transferable between species and developed from expressed genes will be required to construct saturated genetic maps for peanut. A total of 2,138 EST-SSR (expressed sequence tag-simple sequence repeat) markers were developed by mining a tetraploid peanut EST assembly including 101,132 unigenes (37,916 contigs and 63,216 singletons) derived from 70,771 long-read (Sanger) and 270,957 short-read (454) sequences. A set of 97 SSR markers were also developed by mining 9,517 genomic survey sequences of Arachis. An SSR-based intraspecific linkage map was constructed using an F2 population derived from a cross between K 9484 (PI 298639) and GKBSPSc 30081 (PI 468327) in the B-genome species A. batizocoi. A high degree of macrosynteny was observed when comparing the homoeologous linkage groups between A (A. duranensis) and B (A. batizocoi) genomes. Comparison of the A- and B-genome genetic linkage maps also showed a total of five inversions and one major reciprocal translocation between two pairs of chromosomes under our current mapping resolution. Our findings will contribute to understanding tetraploid peanut genome origin and evolution and eventually promote its genetic improvement. The newly developed EST-SSR markers will enrich current molecular marker resources in peanut.


Novel circular single-stranded DNA viruses identified in marine invertebrates reveal high sequence diversity and consistent predicted intrinsic disorder patterns within putative structural proteins.
Viral metagenomics has recently revealed the ubiquitous and diverse nature of single-stranded DNA (ssDNA) viruses that encode a conserved replication initiator protein (Rep) in the marine environment. Although eukaryotic circular Rep-encoding ssDNA (CRESS-DNA) viruses were originally thought to only infect plants and vertebrates, recent studies have identified these viruses in a number of invertebrates. To further explore CRESS-DNA viruses in the marine environment, this study surveyed CRESS-DNA viruses in various marine invertebrate species. A total of 27 novel CRESS-DNA genomes, with Reps that share less than 60.1% identity with previously reported viruses, were recovered from 21 invertebrate species, mainly crustaceans. Phylogenetic analysis based on the Rep revealed a novel clade of CRESS-DNA viruses that included approximately one third of the marine invertebrate associated viruses identified here and whose members may represent a novel family. Investigation of putative capsid proteins (Cap) encoded within the eukaryotic CRESS-DNA viral genomes from this study and those in GenBank demonstrated conserved patterns of predicted intrinsically disordered regions (IDRs), which can be used to complement similarity-based searches to identify divergent structural proteins within novel genomes. Overall, this study expands our knowledge of CRESS-DNA viruses associated with invertebrates and explores a new tool to evaluate divergent structural proteins encoded by these viruses.


Incidence of hospitalized rhabdomyolysis in patients treated with lipid-lowering drugs.
Lipid-lowering agents are widely prescribed in the United States. Reliable estimates of rhabdomyolysis risk with various lipid-lowering agents are not available. To estimate the incidence of rhabdomyolysis in patients treated with different statins and fibrates, alone and in combination, in the ambulatory setting. Drug-specific inception cohorts of statin and fibrate users were established using claims data from 11 managed care health plans across the United States. Patients with at least 180 days of prior health plan enrollment were entered into the cohorts between January 1, 1998, and June 30, 2001. Person-time was classified as monotherapy or combined statin-fibrate therapy. Incidence rates of rhabdomyolysis per 10,000 person-years of treatment, number needed to treat, and relative risk of rhabdomyolysis. In 252,460 patients treated with lipid-lowering agents, 24 cases of hospitalized rhabdomyolysis occurred during treatment. Average incidence per 10,000 person-years for monotherapy with atorvastatin, pravastatin, or simvastatin was 0.44 (95% confidence interval [CI], 0.20-0.84); for cerivastatin, 5.34 (95% CI, 1.46-13.68); and for fibrate, 2.82 (95% CI, 0.58-8.24). By comparison, the incidence during unexposed person-time was 0 (95% CI, 0-0.48; P = .056). The incidence increased to 5.98 (95% CI, 0.72-216.0) for combined therapy of atorvastatin, pravastatin, or simvastatin with a fibrate, and to 1035 (95% CI, 389-2117) for combined cerivastatin-fibrate use. Per year of therapy, the number needed to treat to observe 1 case of rhabdomyolysis was 22,727 for statin monotherapy, 484 for older patients with diabetes mellitus who were treated with both a statin and fibrate, and ranged from 9.7 to 12.7 for patients who were treated with cerivastatin plus fibrate. Rhabdomyolysis risk was similar and low for monotherapy with atorvastatin, pravastatin, and simvastatin; combined statin-fibrate use increased risk, especially in older patients with diabetes mellitus. Cerivastatin combined with fibrate conferred a risk of approximately 1 in 10 treated patients per year.


Organ damage in high-risk patients with systemic and incomplete lupus syndromes.
The objective of this study was to characterize organ damage in lupus patients enrolled in Dallas Regional Autoimmune Disease Registry (DRADR). Retrospective chart review was carried out on 99 patients with four or more diagnostic criteria for systemic lupus erythematosus (SLE) and 15 with less than four of these criteria, who were designated as having incomplete lupus erythematosus (ILE). The majority of patients (84 %) were African American or Hispanic/Latino; mean disease duration was 9.5 years. The mean damage score was 1.57 (range 0-8), and a damage score greater than 0 was present in 64 % of the patients. The ILE group had lower mean damage scores (0.67) than the SLE group (1.67; P = 0.04), explained in part by the shorter disease duration in the ILE patients (4.33 vs. 10.24 years; P = 0.003). The most prevalent damage category was renal, present in 24 % of patients. Malignancies occurred in individuals who were significantly older than those who had renal or peripheral vascular damage (P = 0.0007). The findings confirm clinical impressions that DRADR includes a high-risk lupus population. The ILE patients have less damage but also shorter disease duration, suggesting that this might represent an earlier disease stage. These results are consistent with the hypothesis that ILE patients include a subset that is likely to experience progressive organ damage. Longitudinal study of these patients has significant likelihood of tracking the changes that are correlated with disease progression to SLE.


Momordica charantia, a Nutraceutical Approach for Inflammatory Related Diseases.
Momordica charantia, commonly called bitter melon, is a plant belonging to Cucurbitaceae family known for centuries for its pharmacological activities, and nutritional properties. Due to the presence of many bioactive compounds, some of which possess potent biological actions, this plant is used in folk medicine all over the world for the treatment of different pathologies, mainly diabetes, but also cancer, and other inflammation-associated diseases. It is widely demonstrated that M. charantia extracts contribute in lowering glycaemia in patients affected by type 2 diabetes. However, the majority of existing studies on M. charantia bioactive compounds were performed only on cell lines and in animal models. Therefore, because the real impact of bitter melon on human health has not been thoroughly demonstrated, systematic clinical studies are needed to establish its efficacy and safety in patients. Besides, both in vitro and in vivo studies have demonstrated that bitter melon may also elicit toxic or adverse effects under different conditions. The aim of this review is to provide an overview of anti-inflammatory and anti-neoplastic properties of bitter melon, discussing its pharmacological activity as well as the potential adverse effects. Even if a lot of literature is available about bitter melon as antidiabetic drug, few papers discuss the anti-inflammatory and anti-cancer properties of this plant.


The retinoblastoma tumor suppressor modulates DNA repair and radioresponsiveness.
Perturbations in the retinoblastoma pathway are over-represented in advanced prostate cancer; retinoblastoma loss promotes bypass of first-line hormone therapy. Conversely, preliminary studies suggested that retinoblastoma-deficient tumors may become sensitized to a subset of DNA-damaging agents. Here, the molecular and in vivo consequence of retinoblastoma status was analyzed in models of clinical relevance. Experimental work was performed with multiple isogenic prostate cancer cell lines (hormone sensitive: LNCaP and LAPC4 cells and hormone resistant C42, 22Rv1 cells; stable knockdown of retinoblastoma using shRNA). Multiple mechanisms were interrogated including cell cycle, apoptosis, and DNA damage repair. Transcriptome analysis was performed, validated, and mechanisms discerned. Cell survival was measured using clonogenic cell survival assay and in vivo analysis was performed in nude mice with human derived tumor xenografts. Loss of retinoblastoma enhanced the radioresponsiveness of both hormone-sensitive and castrate-resistant prostate cancer. Hypersensitivity to ionizing radiation was not mediated by cell cycle or p53. Retinoblastoma loss led to alteration in DNA damage repair and activation of the NF-κB pathway and subsequent cellular apoptosis through PLK3. In vivo xenografts of retinoblastoma-deficient tumors exhibited diminished tumor mass, lower PSA kinetics, and decreased tumor growth after treatment with ionizing radiation (P < 0.05). Loss of retinoblastoma confers increased radiosensitivity in prostate cancer. This hypersensitization was mediated by alterations in apoptotic signaling. Combined, these not only provide insight into the molecular consequence of retinoblastoma loss, but also credential retinoblastoma status as a putative biomarker for predicting response to radiotherapy.


Claudins: emerging targets for cancer therapy.
The claudin (CLDN) family of transmembrane proteins plays a critical role in the maintenance of epithelial and endothelial tight junctions. In addition to their function in preserving the structure of tight junctions, CLDNs might also play a role in the maintenance of the cytoskeleton and in cell signalling. Interestingly, several studies have recently reported specific CLDN family members to be overexpressed in a wide variety of cancer types. Although their functional role in cancer progression remains unclear, the differential expression of these proteins between tumour and normal cells, in addition to their membrane localisation, makes them prime candidates for cancer therapy. Preclinical studies have shown that tumour cells overexpressing CLDNs can be successfully targeted via several approaches, including the use of anti-CLDN antibodies as well as the cytolytic enterotoxin from Clostridium perfringens. Further studies are needed to determine the potential systemic toxicity of this approach considering the ubiquitous expression of CLDNs in the body, but CLDN-targeted therapeutics appear to have promise in the treatment of cancer.


Activation of oxidative stress genes by mutations at the soxQ/cfxB/marA locus of Escherichia coli.
Exposure of Escherichia coli to superoxide-generating drugs, such as menadione or paraquat, uniquely induces approximately 40 proteins, nine of which are under the positive control of the soxR locus (at min 92). We report here that certain mutations at a separate locus that we have named soxQ (at min 34) confer some of the phenotypes seen in soxR-constitutive strains, including resistance to menadione. A previously known mutation called cfxB, identified through antibiotic resistance, is likely an allele of soxQ. The soxQ1 and cfxB mutations cause transcriptional activation of the genes that encode Mn-containing superoxide dismutase, glucose 6-phosphate dehydrogenase, and the soi-17/19::lac and soi-28::lac fusions. These genes are also activated by soxR, but the soxQ1 and cfxB mutations increase the synthesis of seven other proteins not influenced by soxR. Moreover, the soxQ1- and cfxB-dependent phenotypes do not depend on the soxR gene, and gene induction by soxR in response to redox stress does not depend on the soxQ locus. As well as increasing cellular resistance to some oxidants, the soxQ1 and cfxB mutations confer elevated resistance to various antibiotics, probably via diminished expression of outer membrane protein OmpF. The marA1 multiple-antibiotic resistance mutation (also at min 34) behaves like a weak allele of soxQ but probably resides in a nearby gene that, with soxQ, is part of a regulatory complex. We propose that soxQ helps control some oxidative stress proteins as part of another regulon that responds to an unknown environmental signal.


Healing journey: a qualitative analysis of the healing experiences of Americans suffering from trauma and illness.
To elucidate pathways to healing for people having suffered injury to the integrity of their function as a human being. A team of physician-analysts conducted thematic analyses of in-depth interviews of 23 patients who experienced healing, as identified by six primary care physicians purposefully selected as exemplary healers. People in the sample experienced healing journeys that spanned a spectrum from overcoming unspeakable trauma and then becoming healers themselves to everyday heroes functioning well despite ongoing serious health challenges.The degree and quality of suffering experienced by each individual is framed by contextual factors that include personal characteristics, timing of their initial or ongoing wounding in the developmental life cycle and prior and current relationships.In the healing journey, bridges from suffering are developed to healing resources/skills and connections to helpers outside themselves. These bridges often evolve in fits and starts and involve persistence and developing a sense of safety and trust.From the iteration between suffering and developing resources and connections, a new state emerges that involves hope, self-acceptance and helping others. Over time, this leads to healing that includes a sense of integrity and flourishing in the pursuit of meaningful goals and purpose. Moving from being wounded, through suffering to healing, is possible. It is facilitated by developing safe, trusting relationships and by positive reframing that moves through the weight of responsibility to the ability to respond.


Comparison of different regression analyses for identifying risk factors in obese and nonobese patients with coronary artery disease.
This study was designed to assess conventional and novel risk factors in obese and nonobese patients with coronary artery disease (CAD) by using multivariate forward and univariate logistic regression analysis and to find the best model of analysis for identifying these risk factors. The study group consisted of 398 patients who consecutively underwent coronary angiography for the investigation of chest pain, except overweight patients. In univariate logistic regression analysis, high C-reactive protein and cigarette smoking were found to be the strongest variables in obese and nonobese patients with CAD, respectively. In multivariate forward logistic regression analysis, some risk factors were not found as predictors of CAD. Multivariate forward logistic regression analysis with the advantage of a high predictable ratio may be more useful for the analysis of risk factors in patients with CAD.


Shining light on dinitrogen cleavage: structural features, redox chemistry, and photochemistry of the key intermediate bridging dinitrogen complex.
The key intermediate in dinitrogen cleavage by Mo(N[t-Bu]Ar)3, 1 (Ar = 3,5-C6H3Me2), has been characterized by a pair of single crystal X-ray structures. For the first time, the X-ray crystal structure of (mu-N2)[Mo(N[t-Bu]Ar)3]2, 2, and the product of homolytic fragmentation of the NN bond, NMo(N[t-Bu]Ar)3, are reported. The structural features of 2 are compared with previously reported EXAFS data. Moreover, contrasts are drawn between theoretical predictions concerning the structural and magnetic properties of 2 and those reported herein. In particular, it is shown that 2 exists as a triplet (S = 1) at 20 degrees C. Further insight into the bonding across the MoNNMo core of the molecule is obtained by the synthesis and structural characterization of the one- and two-electron oxidized congeners, (mu-N2)[Mo(N[t-Bu]Ar)3]2[B(Ar(F))4], 2[B(Ar(F))4] (Ar(F) = 3,5-C6H3(CF3)2) and (mu-N2)[Mo(N[t-Bu]Ar)3]2[B(Ar(F))4]2, 2[B(Ar(F))4]2, respectively. Bonding in these three molecules is discussed in view of X-ray crystallography, Raman spectroscopy, electronic absorption spectroscopy, and density functional theory. Combining X-ray crystallography data with Raman spectroscopy studies allows the NN bond polarization energy and NN internuclear distance to be correlated in three states of charge across the MoNNMo core. For 2[B(Ar(F))4], bonding is symmetric about the mu-N2 ligand and the NN polarization is Raman active; therefore, 2[B(Ar(F))4] meets the criteria of a Robin-Day class III mixed-valent compound. The redox couples that interrelate 2, 2(+), and 2(2+) are studied by cyclic voltammetry and spectroelectrochemistry. Insights into the electronic structure of 2 led to the discovery of a photochemical reaction that forms NMo(N[t-Bu]Ar)3 and Mo(N[t-Bu]Ar)3 through competing NN bond cleavage and N2 extrusion reaction pathways. The primary quantum yield was determined to be Phi(p) = 0.05, and transient absorption experiments show that the photochemical reaction is complete in less than 10 ns.


Patient and staff experiences of quality in Swedish forensic psychiatric care: a repeated cross-sectional survey with yearly sampling at two clinics.
Systematic efforts to improve the quality, safety and value of health care have increased over the last decades. Even so, it is hard to choose priorities and to know when the desired results are reached, especially in forensic psychiatric care where there can be a discrepancy between patient and staff expectations of what good quality of care is and how it should be reached. The aim of the present study was to describe and compare patient and staff experiences of quality of care in two forensic psychiatric clinics over a period of 4 years. A quantitative design was used and yearly between 2011 and 2014, a total of 105 questionnaires were answered by patients and 598 by staff. The sample consisted of four different groups; patient and staff in Clinic A and Clinic B respectively. The repeated measurements showed that quality of care, as described by the patients, varied over time, with significant changes over the 4 years. The staff evaluations of the quality of care were more stable over time in both clinics compared with the patients. Generally, the staff rated the quality as being better than the patients but these differences tended to decrease when efforts were made to improve the care. It is important to highlight both what staff and patients perceive as both high and low quality care. With regular measurements and sufficient resources, training, support and leadership, the chances of successful improvement work increase. This knowledge is important in forensic nursing practice, for teaching and for management and decision makers in the constant work of improving forensic psychiatric care.


Influence of calorie reduction on DNA repair capacity of human peripheral blood mononuclear cells.
Caloric restrictive feeding prolongs the lifespan of a variety of model organisms like rodents and invertebrates. It has been shown that caloric restriction reduces age-related as well as overall-mortality, reduces oxidative stress and influences DNA repair ability positively. There are numerous studies underlining this, but fewer studies involving humans exist. To contribute to a better understanding of the correlation of calorie reduction and DNA repair in humans, we adapted the host cell reactivation assay to an application with human peripheral blood mononuclear cells. Furthermore, we used this reliable and reproducible assay to research the influence of a special kind of calorie reduction, namely F. X. Mayr therapy, on DNA repair capacity. We found a positive effect in all persons with low pre-existing DNA repair capacity. In individuals with normal pre-existing DNA repair capacity, no effect on DNA repair capacity was detectable. Decline of DNA repair, accumulation of oxidative DNA damages, mitochondrial dysfunction, telomere shortening as well as caloric intake are widely thought to contribute to aging. With regard to that, our results can be considered as a strong indication that calorie reduction may support DNA repair processes and thus contribute to a healthier aging.


Continuous nonequilibrium transition driven by heat flow.
We discovered an out-of-equilibrium transition in the ideal gas between two walls, divided by an inner, adiabatic, movable wall. The system is driven out-of-equilibrium by supplying energy directly into the volume of the gas. At critical heat flux we have found a continuous transition to the state with a low-density, hot gas on one side of the movable wall and a dense, cold gas on the other side. Molecular dynamic simulations of the soft-sphere fluid confirm the existence of the transition in the interacting system. We introduce a stationary state Helmholtz-like function whose minimum determines the stable positions of the internal wall. This transition can be used as a paradigm of transitions in stationary states and the Helmholtz-like function as a paradigm of the thermodynamic description of these states.


Results of a long-term study of vapor intrusion at four large buildings at the NASA Ames Research Center.
Most of the published empirical data on indoor air concentrations resulting from vapor intrusion of contaminants from underlying groundwater are for residential structures. The National Aeronautics and Space Administration (NASA) Research Park site, located in Moffett Field, CA, and comprised of 213 acres, is being planned for redevelopment as a collaborative research and educational campus with associated facilities. Groundwater contaminated with hydrocarbon and halogenated hydrocarbon volatile organic compounds (VOCs) is the primary environmental medium of concern at the site. Over a 15-month period, approximately 1000 indoor, outdoor ambient, and outdoor ambient background samples were collected from four buildings designated as historical landmarks using Summa canisters and analyzed by the U.S. Environmental Protection Agency TO-15 selective ion mode. Both 24-hr and sequential 8-hr samples were collected. Comparison of daily sampling results relative to daily background results indicates that the measured trichloroethylene (TCE) concentrations were primarily due to the subsurface vapor intrusion pathway, although there is likely some contribution due to infiltration of TCE from the outdoor ambient background concentrations. Analysis of the cis-1,2-dichloroethylene concentrations relative to TCE concentrations with respect to indoor air concentrations and the background air support this hypothesis; however, this indicates that relative contributions of the vapor intrusion and infiltration pathways vary with each building. Indoor TCE concentrations were also compared with indoor benzene and background benzene concentrations. These data indicate significant correlation between background benzene concentrations and the concentration of benzene in the indoor air, indicating benzene was present in the indoor air primarily through infiltration of outdoor air into the indoor space. By comparison, measured TCE indoor air concentrations showed a significantly different relationship to background concentrations. Analysis of the results show that indoor air samples can be used to definitively define the source of the TCE present in the indoor air space of large industrial buildings.


Tobacco use and readiness to quit smoking in low-income HIV-infected persons.
The study aim was to identify covariates of smoking status and readiness to quit that encompassed key sociodemographic and health status variables, health-related quality of life, drug use and unprotected sex, and tobacco use variables in a cohort of low-income persons living with HIV. We also examined the impact of HIV diagnosis on smoking cessation. The sample (N = 428) was mostly male (59%) and Black (53%) or Hispanic (30%), and had a high school education or less (87%). Mean age was 40 years. Two-thirds of participants were current smokers, 19% former smokers, and 16% never smokers. Current smokers smoked a mean of 16 cigarettes/day for 22 years; 42% were in the precontemplation stage of readiness to quit smoking, 40% were contemplators, and 18% were in preparation. Most current smokers (81%) reported receiving medical advice to quit smoking. Multivariate logistic regression analyses indicated that current smokers, compared with former smokers, were more likely to use illicit drugs, perceive a lower health risk for continued smoking, and report less pain. Current smokers, compared with nonsmokers (former and never smokers), were more likely to report greater illicit drug use in their lifetime, current illicit drug use, and less pain. A multiple linear regression indicated that greater current illicit drug use, greater emotional distress, and a lower number of quit attempts were associated with lower stage of readiness to quit smoking. These findings confirm a high prevalence of smoking among HIV-infected persons and suggest a complex interplay among drug use, pain, and emotional distress that impact smoking status and, among smokers, readiness to quit. Tobacco control programs for HIV-infected persons should build motivation to quit smoking and address salient barriers to cessation--such as comorbid drug use, emotional distress, pain, and access to and coverage for treatment--and should educate smokers regarding the HIV-specific health benefits of cessation.


CHOPCHOP v3: expanding the CRISPR web toolbox beyond genome editing.
The CRISPR-Cas system is a powerful genome editing tool that functions in a diverse array of organisms and cell types. The technology was initially developed to induce targeted mutations in DNA, but CRISPR-Cas has now been adapted to target nucleic acids for a range of purposes. CHOPCHOP is a web tool for identifying CRISPR-Cas single guide RNA (sgRNA) targets. In this major update of CHOPCHOP, we expand our toolbox beyond knockouts. We introduce functionality for targeting RNA with Cas13, which includes support for alternative transcript isoforms and RNA accessibility predictions. We incorporate new DNA targeting modes, including CRISPR activation/repression, targeted enrichment of loci for long-read sequencing, and prediction of Cas9 repair outcomes. Finally, we expand our results page visualization to reveal alternative isoforms and downstream ATG sites, which will aid users in avoiding the expression of truncated proteins. The CHOPCHOP web tool now supports over 200 genomes and we have released a command-line script for running larger jobs and handling unsupported genomes. CHOPCHOP v3 can be found at https://chopchop.cbu.uib.no.


Infection and co-infection by the amphibian chytrid fungus and ranavirus in wild Costa Rican frogs.
Amphibian populations are globally threatened by emerging infectious diseases, and 2 pathogens in particular are recognized as major threats: the amphibian chytrid fungus Batrachochytrium dendrobatidis (Bd) and ranaviruses. Here, we evaluated the prevalence of infection by Bd and ranavirus in an assemblage of frogs from a lowland wet forest in Costa Rica. We found an overall prevalence of 21.3% for Bd and 16.6% for ranavirus, and detected both pathogens widely among our 20 sampled species. We found a positive association between ranavirus and Bd infection in one of our 4 most commonly sampled species. We also found a positive but non-significant association between infection by ranavirus and infection by Bd among species overall. Our study is among the first detailed evaluations of ranavirus prevalence in the American tropics, and to our knowledge is the first to detect a positive association between Bd and ranavirus in any species. Considerable research attention has focused on the ecology of Bd in tropical regions, yet we argue that greater research focus is necessary to understand the ecology and conservation impact of ranaviruses on amphibian populations already decimated by the emergence of Bd.


The Immunomodulatory Role of Adjuvants in Vaccines Formulated with the Recombinant Antigens Ov-103 and Ov-RAL-2 against Onchocerca volvulus in Mice.
In some regions in Africa, elimination of onchocerciasis may be possible with mass drug administration, although there is concern based on several factors that onchocerciasis cannot be eliminated solely through this approach. A vaccine against Onchocerca volvulus would provide a critical tool for the ultimate elimination of this infection. Previous studies have demonstrated that immunization of mice with Ov-103 and Ov-RAL-2, when formulated with alum, induced protective immunity. It was hypothesized that the levels of protective immunity induced with the two recombinant antigens formulated with alum would be improved by formulation with other adjuvants known to enhance different types of antigen-specific immune responses. Immunizing mice with Ov-103 and Ov-RAL-2 in conjunction with alum, Advax 2 and MF59 induced significant levels of larval killing and host protection. The immune response was biased towards Th2 with all three of the adjuvants, with IgG1 the dominant antibody. Improved larval killing and host protection was observed in mice immunized with co-administered Ov-103 and Ov-RAL-2 in conjunction with each of the three adjuvants as compared to single immunizations. Antigen-specific antibody titers were significantly increased in mice immunized concurrently with the two antigens. Based on chemokine levels, it appears that neutrophils and eosinophils participate in the protective immune response induced by Ov-103, and macrophages and neutrophils participate in immunity induced by Ov-RAL-2. The mechanism of protective immunity induced by Ov-103 and Ov-RAL-2, with the adjuvants alum, Advax 2 and MF59, appears to be multifactorial with roles for cytokines, chemokines, antibody and specific effector cells. The vaccines developed in this study have the potential of reducing the morbidity associated with onchocerciasis in humans.


Efficacy and Safety Assessment of Microbiological Feed Additive for Chicken Broilers in Tolerance Studies.
One aim of the study was to evaluate the impact when added to feed of the two potentially probiotic strains of lactic acid bacteria (LAB) Lactobacillus plantarum K KKP 593/p and Lactobacillus rhamnosus KKP 825 on production performance, health, and the composition of gut microbiota. The complementary aim was to assess the safety of these strains in broiler rearing. A total of 500 one-day-old Ross 308 chicks were divided into four groups. The experimental factor was the admixture of bacterial preparation to the feed at different doses: the recommended maximum dose, a dose ten times higher, the recommended minimum dose, and a zero dose for the control group not receiving bacteria. Addition of bacteria to the diets did not have a significant effect on the final body weight, final body weight gain, nor total feed intake or feed conversion. However, lactic acid bacteria had a positive effect on chicken health. Mortality among chickens fed with LAB was reduced. Moreover, LAB feeding inhibited the growth of Salmonella spp. and Clostridium perfringens in the intestines. There were no significant differences in chicken performance by dose of bacteria in the feed. The group dosed with LAB ten times higher than the recommended maximum did not demonstrate changes in biochemical or haematological parameters of blood compared to the remaining groups. Feeding chicken broilers with two potentially probiotic LAB strains is safe and impacts animal health positively.


Characterization of potential TRPP2 regulating proteins in early Xenopus embryos.
Transient receptor potential cation channel-2 (TRPP2) is a nonspecific Ca2+ -dependent cation channel with versatile functions including control of extracellular calcium entry at the plasma membrane, release of intracellular calcium ([Ca2+ ]i) from internal stores of endoplasmic reticulum, and calcium-dependent mechanosensation in the primary cilium. In early Xenopus embryos, TRPP2 is expressed in cilia of the gastrocoel roof plate (GRP) involved in the establishment of left-right asymmetry, and in nonciliated kidney field (KF) cells, where it plays a central role in early specification of nephron tubule cells dependent on [Ca2+ ]i signaling. Identification of proteins binding to TRPP2 in embryo cells can provide interesting clues about the mechanisms involved in its regulation during these various processes. Using mass spectrometry, we have therefore characterized proteins from late gastrula/early neurula stage embryos coimmunoprecipitating with TRPP2. Binding of three of these proteins, golgin A2, protein kinase-D1, and disheveled-2 has been confirmed by immunoblotting analysis of TRPP2-coprecipitated proteins. Expression analysis of the genes, respectively, encoding these proteins, golga2, prkd1, and dvl2 indicates that they are likely to play a role in these two regions. Golga2 and prkd1 are expressed at later stage in the developing pronephric tubule where golgin A2 and protein kinase-D1 might also interact with TRPP2. Colocalization experiments using exogenously expressed fluorescent versions of TRPP2 and dvl2 in GRP and KF reveal that these two proteins are generally not coexpressed, and only colocalized in discrete region of cells. This was observed in KF cells, but does not appear to occur in the apical ciliated region of GRP cells.


Foods and supplements in the management of migraine headaches.
Although a wide range of acute and preventative medications are now available for the treatment of migraine headaches, many patients will not have a significant improvement in the frequency and severity of their headaches unless lifestyle modifications are made. Also, given the myriad side effects of traditional prescription medications, there is an increasing demand for "natural" treatment like vitamins and supplements for common ailments such as headaches. Here, we discuss the role of food triggers in the management of migraines, and review the evidence for supplements in migraine treatment. A review of the English language literature on preclinical and clinical studies of any type on food triggers, vitamins, supplements, and migraine headaches was conducted. A detailed nutritional history is helpful in identifying food triggers. Although the data surrounding the role of certain foods and substances in triggering headaches is controversial, certain subsets of patients may be sensitive to phenylethylamine, tyramine, aspartame, monosodium glutamate, nitrates, nitrites, alcohol, and caffeine. The available evidence for the efficacy of certain vitamins and supplements in preventing migraines supports the use of these agents in the migraine treatment. The identification of food triggers, with the help of food diaries, is an inexpensive way to reduce migraine headaches. We also recommend the use of the following supplements in the preventative treatment of migraines, in decreasing order of preference: magnesium, Petasites hybridus, feverfew, coenzyme Q10, riboflavin, and alpha lipoic acid.


Nonlinearities in porous silicon optical waveguides at 1550 nm.
We report an experimental investigation of the nonlinear optical properties of nanoporous silicon optical waveguides measured at 1550 nm. The nonlinear properties including two-photon absorption, self-phase modulation, free-carrier absorption and free-carrier plasma dispersion are characterized and compared with similar measurements conducted on a conventional silicon-on-insulator ridge waveguide. Our study reveals that even waveguides that are 70% porous exhibit two-photon absorption and self-phase modulation coefficients that are comparable to those of crystalline silicon. The free-carrier absorption and dispersion in porous silicon waveguides are found to be significantly faster, and stronger than those reported for crystalline silicon.


Structure-function analysis of the heat shock factor-binding protein reveals a protein composed solely of a highly conserved and dynamic coiled-coil trimerization domain.
Heat shock factor-binding protein (HSBP) 1 is a small, evolutionarily conserved protein originally identified in a yeast two-hybrid screen using the trimerization domain of heat shock factor (HSF) 1 as the bait. Similar in size to HSF1 trimerization domain, human HSBP1 contains two arrays of hydrophobic heptad repeats (designated HR-N and HR-C) characteristic of coiled-coil proteins. Proteins of the HSBP family are relatively small (<100 residues), comprising solely a putative coiled-coil oligomerization domain without any other readily recognizable structural or functional motif. Our biophysical and biochemical characterization of human HSBP1 reveals a cooperatively folded protein with high alpha-helical content and moderate stability. NMR analyses reveal a single continuous helix encompassing both HR-N and HR-C in the highly conserved central region, whereas the less conserved carboxyl terminus is unstructured and accessible to proteases. Unlike previously characterized coiled-coils, backbone 15N relaxation measurements implicate motional processes on the millisecond time scale in the coiled-coil region. Analytical ultracentrifugation and native PAGE studies indicate that HSBP1 is predominantly trimeric over a wide concentration range. NMR analyses suggest a rotationally symmetric trimer. Because the highly conserved hydrophobic heptad repeats extend over 60% of HSBP1, we propose that HSBP most likely regulates the function of other proteins through coiled-coil interactions.


Measuring souls: Psychometry, female instruments, and subjective science, 1840-1910.
This essay focuses on the history of psychometry, the science of soul measuring. For its founder, Dr Joseph Rodes Buchanan, the soul was simultaneously an object for anthropological research and a measuring instrument capable of revealing human character, interpreting natural history, and demonstrating the reality of an immortal soul. Psychometry taught that human souls, especially those of women, were capable of acting as instruments because they could feel the mysterious energies that people and objects radiated. Although orthodox male scientists rejected the visions of sensitive women as the antithesis of reliable data, psychometric researchers believed that the feelings of women were both the instruments and information that made their science possible. Psychometry promised to revolutionize science by insisting that sympathy and subjectivity, not detachment and objectivity, ought to undergird research. Yet as male experimenters worked to prove psychometry's effectiveness, they almost invariably cast themselves as detached observers accurately recording the data provided by their female instruments. Thus, despite pushing for scientific reform, the methods and discourse of male psychometric experimenters eroded their field's core arguments about connectedness and subjectivity and, instead, reinforced the notion that detachment and objectivity were essential to legitimate science. Challenges to objectivity could prove just how thoroughly it dominated scientific discourse and practice. Still, some psychometers, particularly women who practiced at home, were untroubled by the fact that their research was predicated on subjective feelings, and psychometry remained a viable pursuit among spiritualists even as it faded from the realm of science. Psychometry emerged and, ultimately, fractured amid tensions between widespread enthusiasm for sciences that emphasized spiritual connectedness and the mounting pressure to legitimize scientific knowledge through the language and practices of objectivity.


A prospective cohort study of modifiable risk factors for gestational diabetes among Hispanic women: design and baseline characteristics.
Women diagnosed with gestational diabetes mellitus (GDM) are at high risk for future diabetes, with rates of GDM consistently higher in Hispanic than non-Hispanic white women. Currently recognized risk factors for GDM are absent in up to half of affected women, and studies addressing modifiable risk factors for GDM in Hispanic women are sparse. Proyecto Buena Salud is an ongoing prospective cohort study of Hispanic women in Massachusetts designed to assess physical activity, psychosocial stress, and GDM risk. Bilingual interviewers recruit prenatal care patients early in pregnancy and assess activity, trait anxiety, perceived stress, and depressive symptoms using validated questionnaires. Baseline characteristics of the first 632 participants are presented. Women were predominantly young (69% <24 years), were unmarried (87%), and had low levels of education (48% had less than high school). Women with high acculturation were less likely to live with a partner (OR: 0.6, 95% CI 0.4-0.8) than women with low acculturation. Few participants met physical activity guidelines during pregnancy (5.2%). Levels of perceived stress (mean 26.9 +/- 7.1), trait anxiety (mean 41.6 +/- 10.4), and depressive symptoms (33.2%) were high. Proyecto Buena Salud represents a high-risk population of pregnant Hispanic women who are predominantly inactive, with higher levels of perceived stress, trait anxiety, and depressive symptoms compared to predominantly non-Hispanic white cohorts studied earlier. Therefore, Proyecto Buena Salud provides a unique opportunity to prospectively evaluate modifiable risk factors for GDM. Findings will inform prenatal behavioral intervention programs designed to address modifiable GDM risk factors.


Continuous postoperative blood glucose monitoring and control by artificial pancreas in patients having pancreatic resection: a prospective randomized clinical trial.
To evaluate a closed-loop system providing continuous monitoring and strict control of perioperative blood glucose following pancreatic resection. Prospective, randomized clinical trial. Thirty patients who had pancreatic resection for pancreatic neoplasm. Patients were prospectively randomized. Perioperative blood glucose levels were continuously monitored using an artificial endocrine pancreas (STG-22). Glucose levels were controlled using either the sliding scale method (sliding scale group, n = 13) or the artificial pancreas (artificial pancreas group, n = 17). Incidence of severe hypoglycemia (<40 mg/dL) during the intensive care period following pancreatic resection in patients monitored with the artificial pancreas. The secondary outcome measure was the total amount of insulin required for glycemic control in the first 18 hours after pancreatic resection in each patient group. In the sliding scale group, postoperative blood glucose levels rose initially before reaching a plateau of approximately 200 mg/dL between 4 and 6 hours after pancreatectomy. The levels remained high for 18 hours postoperatively. In the artificial pancreas group, blood glucose levels reduced steadily, reaching the target zone (80-110 mg/dL) by 6 hours after surgery. The total insulin dose administered per patient during the first postoperative 18 hours was significantly higher in the artificial pancreas group (mean [SD], 107 [109] IU) than the sliding scale group (8 [6] IU; P < .01). Neither group showed hypoglycemia. Perioperative use of an artificial endocrine pancreas to control pancreatogenic diabetes after pancreatic resection is an easy and effective way to maintain near-normal blood glucose levels. The artificial pancreas shows promise for use as insulin treatment for patients with pancreatogenic diabetes after pancreatic resection.


The association of coffee intake with liver cancer incidence and chronic liver disease mortality in male smokers.
Coffee intake is associated with reduced risk of liver cancer and chronic liver disease as reported in previous studies, including prospective ones conducted in Asian populations where hepatitis B viruses (HBVs) and hepatitis C viruses (HCVs) are the dominant risk factors. Yet, prospective studies in Western populations with lower HBV and HCV prevalence are sparse. Also, although preparation methods affect coffee constituents, it is unknown whether different methods affect disease associations. We evaluated the association of coffee intake with incident liver cancer and chronic liver disease mortality in 27,037 Finnish male smokers, aged 50-69, in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study, who recorded their coffee consumption and were followed up to 24 years for incident liver cancer or chronic liver disease mortality. Multivariate relative risks (RRs) and 95% confidence intervals (CIs) were estimated by Cox proportional hazard models. Coffee intake was inversely associated with incident liver cancer (RR per cup per day=0.82, 95% CI: 0.73-0.93; P-trend across categories=0.0007) and mortality from chronic liver disease (RR=0.55, 95% CI: 0.48-0.63; P-trend<0.0001). Inverse associations persisted in those without diabetes, HBV- and HCV-negative cases, and in analyses stratified by age, body mass index, alcohol and smoking dose. We observed similar associations for those drinking boiled or filtered coffee. These findings suggest that drinking coffee may have benefits for the liver, irrespective of whether coffee was boiled or filtered.


Clinical trial evaluating color change and tooth sensitivity throughout and following in-office bleaching.
The aim of this study was to assess the color alteration and sensitivity of teeth throughout and following in-office bleaching. Twenty-two volunteers participated in this clinical trial of bleaching treatment (35% hydrogen peroxide bleaching gel and placebo) applied on maxillary incisors and canines. According to a split-mouth design, the volunteers' maxillary hemi-arches received either the bleaching or placebo agent, applied four times, at 1-week intervals. Color alteration and tooth sensitivity were assessed throughout and following bleaching. Statistical calculations were performed using gamma distribution and repeated-measures ANOVA. There was a statistically significant difference between teeth submitted to a bleaching agent and placebo (P < .001). At the end of the first, second, third, and fourth sessions, the bleached teeth presented color scores statistically lower than those observed immediately before bleaching. There was no difference in the color scale scores of the bleached teeth between bleaching sessions. The sensitivity data test showed a significant difference among treatments (P < .0001). Color alteration and dental sensitivity were altered by the bleaching agent.


Cabozantinib inhibits prostate cancer growth and prevents tumor-induced bone lesions.
Cabozantinib, an orally available multityrosine kinase inhibitor with activity against mesenchymal epithelial transition factor (MET) and VEGF receptor 2 (VEGFR2), induces resolution of bone scan lesions in men with castration-resistant prostate cancer bone metastases. The purpose of this study was to determine whether cabozantinib elicited a direct antitumor effect, an indirect effect through modulating bone, or both. Using human prostate cancer xenograft studies in mice, we determined the impact of cabozantinib on tumor growth in soft tissue and bone. In vitro studies with cabozantinib were performed using (i) prostate cancer cell lines to evaluate its impact on cell growth, invasive ability, and MET and (ii) osteoblast cell lines to evaluate its impact on viability and differentiation and VEGFR2. Cabozantinib inhibited progression of multiple prostate cancer cell lines (Ace-1, C4-2B, and LuCaP 35) in bone metastatic and soft tissue murine models of prostate cancer, except for PC-3 prostate cancer cells in which it inhibited only subcutaneous growth. Cabozantinib directly inhibited prostate cancer cell viability and induced apoptosis in vitro and in vivo and inhibited cell invasion in vitro. Cabozantinib had a dose-dependent biphasic effect on osteoblast activity and inhibitory effect on osteoclast production in vitro that was reflected in vivo. It blocked MET and VEGFR2 phosphorylation in prostate cancer cells and osteoblast-like cells, respectively. These data indicate that cabozantinib has direct antitumor activity, and that its ability to modulate osteoblast activity may contribute to its antitumor efficacy.


CD59 incorporation protects hepatitis C virus against complement-mediated destruction.
Several enveloped viruses including human immunodeficiency virus type 1 (HIV-1), cytomegalovirus (CMV), herpes simplex virus 1 (HSV-1), Ebola virus, vaccinia virus, and influenza virus have been found to incorporate host regulators of complement activation (RCA) into their viral envelopes and, as a result, escape antibody-dependent complement-mediated lysis (ADCML). Hepatitis C virus (HCV) is an enveloped virus of the family Flaviviridae and incorporates more than 10 host lipoproteins. Patients chronically infected with HCV develop high-titer and crossreactive neutralizing antibodies (nAbs), yet fail to clear the virus, raising the possibility that HCV may also use the similar strategy of RCA incorporation to escape ADCML. The current study was therefore undertaken to determine whether HCV virions incorporate biologically functional CD59, a key member of RCA. Our experiments provided several lines of evidence demonstrating that CD59 was associated with the external membrane of HCV particles derived from either Huh7.5.1 cells or plasma samples from HCV-infected patients. First, HCV particles were captured by CD59-specific Abs. Second, CD59 was detected in purified HCV particles by immunoblot analysis and in the cell-free supernatant from HCV-infected Huh7.5.1 cells, but not from uninfected or adenovirus serotype 5 (Ad5) (a nonenveloped cytolytic virus)-infected Huh7.5.1 cells by enzyme-linked immunosorbent assay. Last, abrogation of CD59 function with its blockers increased the sensitivity of HCV virions to ADCML, resulting in a significant reduction of HCV infectivity. Additionally, direct addition of CD59 blockers into plasma samples from HCV-infected patients increased autologous virolysis. Our study, for the first time, demonstrates that CD59 is incorporated into both cell line-derived and plasma primary HCV virions at levels that protect against ADCML. This is also the first report to show that direct addition of RCA blockers into plasma from HCV-infected patients renders endogenous plasma virions sensitive to ADCML.


Natural history of experimental coronary atherosclerosis and vascular remodeling in relation to endothelial shear stress: a serial, in vivo intravascular ultrasound study.
The natural history of heterogeneous atherosclerotic plaques and the role of local hemodynamic factors throughout their development are unknown. We performed a serial study to assess the role of endothelial shear stress (ESS) and vascular remodeling in the natural history of coronary atherosclerosis. Intravascular ultrasound-based 3-dimensional reconstruction of all major coronary arteries (n=15) was performed serially in vivo in 5 swine 4, 11, 16, 23, and 36 weeks after induction of diabetes mellitus and hyperlipidemia. The reconstructed arteries were divided into 3-mm-long segments (n=304). ESS was calculated in all segments at all time points through the use of computational fluid dynamics. Vascular remodeling was assessed at each time point in all segments containing significant plaque, defined as maximal intima-media thickness >/=0.5 mm, at week 36 (n=220). Plaque started to develop at week 11 and progressively advanced toward heterogeneous, multifocal lesions at all subsequent time points. Low ESS promoted the initiation and subsequent progression of plaques. The local remodeling response changed substantially over time and determined future plaque evolution. Excessive expansive remodeling developed in regions of very low ESS, further exacerbated the low ESS, and was associated with the most marked plaque progression. The combined assessment of ESS, remodeling, and plaque severity enabled the early identification of plaques that evolved to high-risk lesions at week 36. The synergistic effect of local ESS and the remodeling response to plaque formation determine the natural history of individual lesions. Combined in vivo assessment of ESS and remodeling may predict the focal formation of high-risk coronary plaque.


Suicide Typologies in the United States Air Force: A Hierarchical Cluster Analysis.
This study describes characteristics of United States Air Force (USAF) suicide decedents and determines subgroups. Retrospective review of demographic, psychiatric, event-related, and psychosocial variables for USAF suicide decedents in the Suicide Event Surveillance System database was conducted between February 1999 and July 2009 (N = 376). Hierarchical cluster analysis was used to determine initial clusters and cluster centroids. Analyses identified three clusters. Cluster 1 (n = 149) individuals were mostly single or divorced, E-1-E-6 rank, living alone, and less likely to have psychiatric disorder diagnoses or engage with most helping resources. Cluster 2 (n = 126) decedents were mostly married, living with a partner, higher ranking, and least likely to communicate suicide intent. Cluster 3 (n = 101) individuals were mostly E-4-E-6 rank, with the highest rates of most psychiatric diagnoses, previous suicide-related events, engagement with multiple helping resources, communication of intent, and psychosocial precipitants. Clusters differed significantly in marital status, rank, psychiatric diagnoses, precipitants, service utilization, previous suicide-related events, risk factors, communication of intent, location and method of death, and residential status. This study identifies empirically based suicide typologies within a military decedent sample. While further research and replications of findings are needed, these typologies have clinical and policy implications for military suicide prevention.


A revision of the order Pellitida Smirnov et al., 2011 (Amoebozoa, Discosea) based on ultrastructural and molecular evidence, with description of Endostelium crystalliferum n. sp.
We present the results of an ultrastructural re-investigation of two amoebae strains that can be identified morphologically as previously described species of the genus Pellita, as well as the first molecular phylogenetic analysis of these amoebae based on SSU rRNA and actin gene sequences. The results obtained show close relationships between the genera Pellita, Gocevia, and Endostelium. These relationships are further supported by the description of Endostelium crystalliferum n. sp., which shares morphological characters simultaneously with Pellita spp. and Endostelium zonatum. The three genera form a robust clade that branches deeply within Amoebozoa, among either Flabellinia, or Longamoebia, depending on taxon sampling. The results suggest that Gocevia and Endostelium should not be included in the Himatismenida; therefore, we transfer the family Goceviidae into Pellitida. The type of cell organisation that was considered to be typical of Himatismenida (a lens-shaped cell covered dorsally with a flexible layer of organic material) has most probably evolved in some of these amoebae independently of Cochliopodiidae and Parvamoebidae. The robustness of the Pellitida clade in the molecular trees is consistent with the fine structure cytoplasmic evidence for these taxa, in particular, the presence of a centrosphere (a dictyosome-associated lamellar MTOC) in all these genera.


Main sources of infection in 145 cases of epidemic keratoconjunctivitis.
Epidemic keratoconjunctivitis (EKC) is a combination of conjunctivitis and keratitis induced by an adenovirus that is found especially in eye clinics and in eye hospitals. In Bavaria, EKC represents a common eye disease and occurs in epidemics in the spring and early autumn. We report on 145 patients who presented with EKC in our hospital between March 17 and September 12, 1991, and who were evaluated prospectively (67 men and 78 women ranging in age from 4 to 85 years). The recent patient history was noted using a standardized protocol to analyze possible sources and pathways of the infection. Overall, 44 of the EKC patients (30%) remembered having undergone eye treatment during the incubation period of 2 weeks before the onset of symptoms. In all, 18 patients (12%) recalled that a family member had also had conjunctivitis during that time, and 4 patients (3%) reported the infection of a workmate during the 2 weeks prior to the onset of symptoms. In 82 patients (55%), no presumed source of infection was apparent. A total of 24 patients (17%) presumably acquired the infection during examination or treatment in our hospital. The main cause was the removal of foreign body, followed by cataract operation. In all, 20 patients (14%) had been treated in private practice during the incubation period; 14 of these remembered having had tonometry, and 4 patients had undergone contact-lens fitting. In 18 patients, virus isolation and serotyping from a conjunctival smear was conducted. In 12 of these patients an adenovirus could be isolated; in all cases it proved to be serotype 8.(ABSTRACT TRUNCATED AT 250 WORDS)


Systematic review of growth factors and cytokines for the management of oral mucositis in cancer patients and clinical practice guidelines.
To update the clinical practice guidelines for the use of growth factors and cytokines for the prevention and/or treatment of oral mucositis (OM). A systematic review was conducted by the Mucositis Study Group of the Multinational Association of Supportive Care in Cancer/International Society of Oral Oncology (MASCC/ISOO). The body of evidence for each intervention, in each cancer treatment setting, was assigned an evidence level. The findings were added to the database used to develop the 2014 MASCC/ISOO clinical practice guidelines. Based on the evidence level, the following guidelines were determined: recommendation, suggestion, and no guideline possible. A total of 15 new papers were identified within the scope of this section and were merged with 51 papers that were reviewed in the previous guidelines update. Of these, 14, 5, 13, 2, and 1 were randomized controlled trials about KGF-1, G-CSF, GM-CSF, EGF, and erythropoietin, respectively. For the remaining agents there were no new RCTs. The previous recommendation for intravenous KGF-1 in patients undergoing autologous hematopoietic stem cell transplantation (HSCT) conditioned with high-dose chemotherapy and TBI-based regimens is confirmed. The previous suggestion against the use of topical GM-CSF for the prevention of OM in the setting of high-dose chemotherapy followed by autologous or allogeneic stem cell transplantation remains unchanged. Of the growth factors and cytokines studied for the management of OM, the evidence supports a recommendation in favor of KGF-1 and a suggestion against GM-CSF in certain clinical settings.