Acrylic spinal fusion. A 20-year clinical series and technical note.
Methyl methacrylate (acrylic) was used in fusion techniques in 82 patients, most of whom had metastatic disease, between 1959 and 1979. In all cases the acrylic was used to supplement stabilization with Meurig-Williams stainless steel plates or with wire. In cases involving a decompressive laminectomy and excisional biopsy (radical resection of a tumor mass) that required posterior stabilization, acrylic helped to achieve rapid fusion with excellent results. The series included one anterior fusion with acrylic and nine atlantoaxial fusions in patients without tumors. Strict guidelines for selection of patients are outlined. The advantage of acrylic over bone fusion in selected patients is discussed. Careful follow-up studies including autopsy examinations are included. The technique of the use of acrylic is outlined. There was no case of late instability. There was one instance of infection in a patient who was immunodeficient and in whom a combination acrylic and bone fusion was performed. Tissue reaction to the acrylic in autopsy specimens is discussed.


Diet overlap among flatfish species in the southern North Sea.
The diets of two non-commercial flatfish species (solenette Buglossidium luteum and scaldfish Arnoglossus laterna) and two commercial flatfish species (dab Limanda limanda and plaice Pleuronectes platessa) were compared in a study area in the German Bight (southern North Sea) to investigate prey-resource partitioning between these species. The diets of A. laterna and B. luteum mainly comprised crustaceans (harpacticoids, amphipods, cumaceans and decapods), whereas the diet of L. limanda and P. platessa consisted mainly of polychaetes. The Schoener index, calculated for different fish size classes between these flatfish species, showed a biologically significant diet overlap between small-sized L. limanda and P. platessa and B. luteum and A. laterna, using similar prey resources of smaller prey (e.g. amphipods, harpacticoids and juvenile bivalves). In contrast, with increasing body size, a change in the diet of L. limanda and P. platessa towards larger prey occurred (e.g. polychaetes and decapods), resulting in low diet overlap values with B. luteum and A. laterna. Due to these size-related differences in resource use, it is assumed that there is reduced interspecific competition for prey between larger L. limanda and P. platessa and both non-commercial flatfishes, probably facilitating resource partitioning within the same area. In contrast, smaller L. limanda and P. platessa may compete directly for the same prey resources with B. luteum and A. laterna. Furthermore, prey availability of most important prey items of the studied flatfishes was relatively low in the study area. Therefore, increasing abundances of B. luteum and A. laterna in the southern North Sea since the late 1980s, owing to fishing effects and climate change, might affect the population dynamics of L. limanda and P. platessa.


The NAC proton treatment planning system.
A three-dimensional proton treatment planning system called PROXELPLAN has been used at the National Accelerator Centre (NAC) since October 1994. This system is entirely based on the VOXELPLAN planning system, developed at the Deutches Krebsforschungszentrum (DKFZ), Heidelberg, Germany. The VOXELPLAN system provides the treatment planning infrastructure while the proton dose distributions are calculated using a software module that was initially developed at the Royal Marsden Hospital, UK. The proton module has been extensively modified and refined. It uses a rayline-tracing algorithm which is suitable for planning current treatments but is not sufficiently dynamic to accommodate the use of compensators. A sophisticated pencil beam algorithm is currently under development.


Health care access for rural youth on equal terms? A mixed methods study protocol in northern Sweden.
The purpose of this paper is to propose a protocol for researching the impact of rural youth health service strategies on health care access. There has been no published comprehensive assessment of the effectiveness of youth health strategies in rural areas, and there is no clearly articulated model of how such assessments might be conducted. The protocol described here aims to gather information to; i) Assess rural youth access to health care according to their needs, ii) Identify and understand the strategies developed in rural areas to promote youth access to health care, and iii) Propose actions for further improvement. The protocol is described with particular reference to research being undertaken in the four northernmost counties of Sweden, which contain a widely dispersed and diverse youth population. The protocol proposes qualitative and quantitative methodologies sequentially in four phases. First, to map youth access to health care according to their health care needs, including assessing horizontal equity (equal use of health care for equivalent health needs,) and vertical equity (people with greater health needs should receive more health care than those with lesser needs). Second, a multiple case study design investigates strategies developed across the region (youth clinics, internet applications, public health programs) to improve youth access to health care. Third, qualitative comparative analysis of the 24 rural municipalities in the region identifies the best combination of conditions leading to high youth access to health care. Fourth, a concept mapping study involving rural stakeholders, care providers and youth provides recommended actions to improve rural youth access to health care. The implementation of this research protocol will contribute to 1) generating knowledge that could contribute to strengthening rural youth access to health care, as well as to 2) advancing the application of mixed methods to explore access to health care.


A global database of lake surface temperatures collected by in situ and satellite methods from 1985-2009.
Global environmental change has influenced lake surface temperatures, a key driver of ecosystem structure and function. Recent studies have suggested significant warming of water temperatures in individual lakes across many different regions around the world. However, the spatial and temporal coherence associated with the magnitude of these trends remains unclear. Thus, a global data set of water temperature is required to understand and synthesize global, long-term trends in surface water temperatures of inland bodies of water. We assembled a database of summer lake surface temperatures for 291 lakes collected in situ and/or by satellites for the period 1985-2009. In addition, corresponding climatic drivers (air temperatures, solar radiation, and cloud cover) and geomorphometric characteristics (latitude, longitude, elevation, lake surface area, maximum depth, mean depth, and volume) that influence lake surface temperatures were compiled for each lake. This unique dataset offers an invaluable baseline perspective on global-scale lake thermal conditions as environmental change continues.


The Role of Vitamin E in Thermal Burn Injuries, Infection, and Sepsis: A Review.
Thermal burn injuries are still a serious public health concern in the United States, due to the initial insult and resulting comorbidities. Burned patients are increasingly susceptible to colonization by endogenous and exogenous microorganisms after having lost skin, which acts as the primary protective barrier to environmental contaminants. Furthermore, the onset of additional pathophysiologies, specifically sepsis, becomes more likely in burned patients compared to other injuries. Despite improvements in the early care of burn patients, infections, and sepsis, these pathophysiologies remain major causes of morbidity and mortality and warrant further investigation of potential therapies. Vitamin E may be one such therapy. We aimed to identify publications of studies that evaluated the effectiveness of vitamin E as it pertains to thermal burn injuries, infection, and sepsis. Several investigations ranging from in vitro bench work to clinical studies have examined the impact on, or influence of, vitamin E in vitro, in vivo, and in the clinical setting. To the benefit of subjects it has been shown that enteral or parenteral vitamin E supplementation can prevent, mitigate, and even reverse the effects of thermal burn injuries, infection, and sepsis. Therefore, a large-scale prospective observational study to assess the potential benefits of vitamin E supplementation in patients is warranted and could result in clinical care practice paradigm changes.


Nonsteroidal Anti-inflammatory Drugs for Sciatica: An Updated Cochrane Review.
Systematic review and meta-analysis. To determine the efficacy of nonsteroidal anti-inflammatory drugs (NSAIDs) on pain reduction, overall improvement, and reported adverse effects in people with sciatica. NSAIDs are one of the most frequently prescribed drugs for sciatica. We updated a 2008 Cochrane Review through June 2015. Randomized controlled trials that compared NSAIDs with placebo, with other NSAIDs, or with other medication were included. Outcomes included pain using mean difference (MD, 95% confidence intervals [95% CI]). For global improvement and adverse effects risk ratios (RR, 95% CI) were used. We assessed level of evidence using the Grades of Recommendation, Assessment, Development and Evaluation approach. Ten trials were included (N = 1651). Nine out of 10 trials were assessed at high risk of bias. For pain reduction (visual analog scale, 0 to 100) NSAIDs were no more effective than placebo (MD -4.56, 95% CI -11.11 to 1.99, quality of evidence: very low). For global improvement NSAIDs were more effective than placebo (RR 1.14 [95% CI 1.03 to 1.27], low quality of evidence). One trial reported the effect of NSAIDs on disability with very low-quality evidence that NSAIDs are no more effective than placebo. There was low-quality evidence that the risk for adverse effects is higher for NSAID than placebo (RR 1.40, 95% CI 1.02 to 1.93). Our findings show very low-quality evidence that the efficacy of NSAIDs for pain reduction is comparable with that of placebo, low-quality evidence that NSAIDs is better than placebo for global improvement and low-quality evidence for higher risk of adverse effects using NSAIDs compared with placebo. The findings must be interpreted with caution, due to small study samples, inconsistent results, and a high risk of bias in the included trials. 1.


A phase 2 study incorporating sorafenib into the chemotherapy for older adults with FLT3-mutated acute myeloid leukemia: CALGB 11001.
The Cancer and Leukemia Group B (CALGB), now part of the Alliance for Clinical Trials in Oncology, conducted a multicenter, single-arm, phase 2 study in patients ≥60 years with FMS-like tyrosine kinase 3 (FLT3)-mutated acute myeloid leukemia (AML). In this study, sorafenib was added to daunorubicin and cytarabine-based induction and consolidation chemotherapy and was also continued for 12 months of maintenance therapy. The primary end point of the study was overall survival (OS) at 1 year in the FLT3 internal tandem duplication (FLT3-ITD) cohort. Fifty-four patients with a median age of 67 years (range, 60.3-82.7 years) were enrolled; 39 were FLT3-ITD patients (71%) and 15 were FLT3-TKD (29%) patients. The observed 1-year OS (95% confidence interval [CI]) was 62% (45%-78%) for the FLT3-ITD patients (meeting the primary end point 62% vs 30% for a historical control group, P < .0001) and 71% (42%-92%) for the FLT3-TKD patients. The median disease-free survival and OS were 12.2 months (95% CI, 5-16.9) and 15.0 months (95% CI, 10.4-20.1), respectively, in the FLT3-ITD group and 9.6 (95% CI, 1.9 to not available [NA]) and 16.2 months (95% CI, 5.0 to NA) for the FLT3-TKD group. This study suggests that the addition of sorafenib to chemotherapy for FLT3-ITD AML is feasible and may improve the survival of older adults with FLT3-mutated AML. This trial was registered at www.clinicaltrials.gov as #NCT01253070.


Cervical cancer screening uptake and challenges in Malawi from 2011 to 2015: retrospective cohort study.
Malawi has the highest cervical cancer incidence and mortality in the world with age-standardized rate (ASR) of 75.9 and 49.8 per 100,000 population respectively. In response, Ministry of Health established a cervical cancer screening programme using visual inspection with acetic acid (VIA) and treatment of precancerous lesions with cryotherapy. This paper highlights the roll out, integration with family planning services and HIV ART Programme, uptake and challenges of VIA and Cryotherapy programme. We analyzed program data, supportive supervision, quarterly and annual reports from the National Cervical Cancer Control Program. We evaluated the uptake and challenges of screening services by age, HIV serostatus and trends over a five year period (2011-2015). Between 2011 and 2015, number of cervical cancer screening sites, number of women screened and coverage per annum increased from 75 to 130, 15,331 to 49,301 and 9.3 % to 26.5 % respectively. In this five year period, a total of 145,015 women were screened. Of these, 7,349 (5.1 %) and 6,289 (4.3 %) were VIA positive and suspect cancer respectively. Overall 13,638 (9.4 %) were detected to be VIA positive or had suspect cancer. Of the 48,588 women with known age screened in 2015; 13,642 (28.1 %), 27,275 (56.1 %) and 7,671 (15.8 %) were aged 29 or less, 30-45, 46 years or more. Among 39,101 women with data on HIV serostatus; 21,546 (55.1 %) were HIV negative, 6,209 (15.9 %) were HIV positive and 11, 346 (29.0 %) status was unknown. VIA positivity rate and prevalence of suspect cancer were significantly higher in HIV positive than HIV negative women (8.8 % vs 5.0 %, 6.4 % vs 3.0 %); in women aged 30-45 years than women aged 29 years or less (5.6 % vs 2.3 %, 2.6 % vs 1.2 %) respectively, all p <0.05). The main challenge of the programme was failure to treat VIA positive women eligible for cryotherapy. Over the five year period, the programme only treated 1,001 (43.3 %) out of 2,311 eligible women and only 266 (31.8 %) of the 836 women with large lesion or suspect cancer who were referred, received the health care at the referral centre. The reasons for failure to provide cryotherapy treatment were stock out of gas, faulty/broken cryotherapy machine (usually connectors or probes) or no cryotherapy machine at all in the whole district. For women with large lesion or suspect cancer; lack of loop electrosurgical excision procedure (LEEP) machine or inadequate gynaecologists at the referral centre, were the major reasons. Cancer radiotherapy services were not available in Malawi. This study provided data on VIA positivity rate, prevalence of suspect cancer, failure rate of cryotherapy and challenges in the provision of cryotherapy and LEEP treatment in Malawi. These data could be used as baseline for monitoring and evaluation of Human Papillomavirus (HPV) vaccination programme which the country introduced in 2013, the linkage of cervical cancer screening and women on HIV ART and the long term effect of ART, voluntary male medical circumcision on the prevalence and incidence of cervical cancer.


Suppression of the intrinsic apoptosis pathway by synaptic activity.
Synaptic activity promotes resistance to diverse apoptotic insults, the mechanism behind which is incompletely understood. We show here that a coordinated downregulation of core components of the intrinsic apoptosis pathway by neuronal activity forms a key part of the underlying mechanism. Activity-dependent protection against apoptotic insults is associated with inhibition of cytochrome c release in most but not all neurons, indicative of anti-apoptotic signaling both upstream and downstream of this step. We find that enhanced firing activity suppresses expression of the proapoptotic BH3-only member gene Puma in a NMDA receptor-dependent, p53-independent manner. Puma expression is sufficient to induce cytochrome c loss and neuronal apoptosis. Puma deficiency protects neurons against apoptosis and also occludes the protective effect of synaptic activity, while blockade of physiological NMDA receptor activity in the developing mouse brain induces neuronal apoptosis that is preceded by upregulation of Puma. However, enhanced activity can also confer resistance to Puma-induced apoptosis, acting downstream of cytochrome c release. This mechanism is mediated by transcriptional suppression of apoptosome components Apaf-1 and procaspase-9, and limiting caspase-9 activity, since overexpression of procaspase-9 accelerates the rate of apoptosis in active neurons back to control levels. Synaptic activity does not exert further significant anti-apoptotic effects downstream of caspase-9 activation, since an inducible form of caspase-9 overrides the protective effect of synaptic activity, despite activity-induced transcriptional suppression of caspase-3. Thus, suppression of apoptotic gene expression may synergize with other activity-dependent events such as enhancement of antioxidant defenses to promote neuronal survival.


Plasma and cerebrospinal fluid pharmacokinetic study of topotecan in nonhuman primates.
Topotecan, a water soluble semisynthetic analogue of camptothecin, is a topoisomerase I inhibitor that has recently entered phase II clinical trials. Topotecan has shown significant preclinical activity in refractory murine tumors and in human tumor xenograft models. In addition, objective antineoplastic activity has been observed in recent adult phase I clinical trials. Topotecan is unstable in solution and is rapidly and spontaneously converted to a less active open ring form which predominates at physiological pH. This study was undertaken to better define the pharmacokinetic behavior of this highly unstable compound in both plasma and cerebrospinal fluid (CSF) and to measure the degree of CSF penetration of this novel antineoplastic agent. Three nonhuman primates with indwelling Ommaya reservoirs received 10 mg/m2 i.v. topotecan administered as a 10-min infusion. Frequent plasma and CSF samples were obtained and immediately extracted and assayed with a reverse phase high performance liquid chromatography assay to quantitate the concentration of topotecan (lactone). Samples were then acidified and reinjected to quantitate total drug (lactone ring plus open ring). Peak plasma concentrations of topotecan ranged from 0.27 to 0.45 microM. Plasma disappearance of the lactone ring was biexponential with a distribution half-life (t1/2 alpha) of 22 +/- 5 min and an elimination half-life (t1/2 beta) of 1.3 +/- 0.1 h. Total body clearance of topotecan was 72.1 +/- 15.8 liters/h/m2. The volume of distribution at steady state was 88.6 +/- 33.2 liters/m2. Peak CSF concentrations of topotecan occurred at 30 min following drug administration and ranged from 0.044 to 0.074 microM. CSF disappearance paralleled that in plasma. The mean ratio of the area under the CSF concentration-time curve to that in plasma was 0.32 (range, 0.29 to 0.37). The mean CSF penetration of topotecan exceeds 30%, which is significantly greater than the penetration of most structurally similar chemotherapeutic agents. The impact of chemotherapy on the survival of patients with primary or metastatic central nervous system malignancies is very limited. Therefore, this novel antineoplastic agent is an excellent candidate for further study in patients with high risk or refractory central nervous system tumors.


Mechanism of biphasic contractions in strontium-treated ventricular muscle.
Biphasic contractions were produced in dog trabeculae by replacing 90-95% of the calcium in the bathing solution with strontium. These conditions produced prolonged action potentials accompanied by contractions with two distinct phasic components. The early component disappeared slowly when the remaining Ca++ was removed, whereas the late component was eliminated quickly when Sr++ was removed. Manganese ion (0.25 mM) preferentially decreased the late component without changing the action potential, whereas caffeine and ryanodine decreased or eliminated the early component. Ryanodine did not alter the action potential. Isoproterenol rapidly increased the early component and, more slowly and to a lesser degree, increased the late component. The results suggest that the early component is caused by intracellular release of activator cation, probably from the sarcoplasmic reticulum, whereas the late component is the result of Sr++ entry across the sarcolemma, possibly by way of the slow inward current.


Symptom severity, self-reported adherence, and electronic pill monitoring in poorly adherent patients with bipolar disorder.
This analysis of screening and baseline data from an ongoing trial examined self-report versus automated adherence monitoring and assessed the relationship between bipolar disorder (BD) symptoms and adherence in 104 poorly adherent individuals. Adherence was measured with the Tablets Routine Questionnaire (TRQ) and the Medication Event Monitoring System (MEMS). Symptoms were measured with the Montgomery-Åsberg Depression Rating Scale (MADRS), the Young Mania Rating Scale (YMRS), and the Brief Psychiatric Rating Scale (BPRS). The mean age of the sample was 46.3 years [standard deviation (SD) = 9.41 years], with 72% (n = 75) women and 71% (n = 74) African American subjects. Adherence improved from screening to baseline, with a mean missed drug proportion measured by TRQ of 61.43% (SD = 26.48%) versus a baseline mean of 46.61% (SD = 30.55%). The mean proportion of missed medication using MEMS at baseline was 66.43% (SD = 30.40%). The correlation between TRQ and MEMS was 0.47. The correlation between a single index drug and all BD medications was 0.95. Symptoms were generally positively correlated with TRQ (worse adherence = more severe symptoms), but in most instances was only at a trend level (p > 0.05), with the exception of the correlations between baseline TRQ and MADRS and BPRS, which were positive (r = 0.20 and r = 0.21, respectively) and significant (p ≤ 0.05). In patients with BD, monitoring increased adherence by 15%. MEMS identified 20% more non-adherence than self-report. Using a standard procedure to identify a single index drug for adherence monitoring may be one way to assess global adherence in patients with BD receiving polypharmacy treatment. Greater BD symptom severity may be a clinical indicator to assess for adherence problems.


Nutrition, immune function and health of dairy cattle.
The large increase in milk yield and the structural changes in the dairy industry have caused major changes in the housing, feeding and management of the dairy cow. However, while large improvements have occurred in production and efficiency, the disease incidence, based on veterinary records, does not seem to be improved. Earlier reviews have covered critical periods such as the transition period in the cow and its influence on health and immune function, the interplay between the endocrine system and the immune system and nutrition and immune function. Knowledge on these topics is crucial for our understanding of disease risk and our effort to develop health and welfare improving strategies, including proactive management for preventing diseases and reducing the severity of diseases. To build onto this the main purpose of this review will therefore be on the effect of physiological imbalance (PI) on immune function, and to give perspectives for prevention of diseases in the dairy cow through nutrition. To a large extent, the health problems during the periparturient period relate to cows having difficulty in adapting to the nutrient needs for lactation. This may result in PI, a situation where the regulatory mechanisms are insufficient for the animals to function optimally leading to a high risk of a complex of digestive, metabolic and infectious problems. The risk of infectious diseases will be increased if the immune competence is reduced. Nutrition plays a pivotal role in the immune response and the effect of nutrition may be directly through nutrients or indirectly by metabolites, for example, in situations with PI. This review discusses the complex relationships between metabolic status and immune function and how these complex interactions increase the risk of disease during early lactation. A special focus will be placed on the major energetic fuels currently known to be used by immune cells (i.e. glucose, non-esterified fatty acids, beta-hydroxybutyrate and glutamine) and how certain metabolic states, such as degree of negative energy balance and risk of PI, contribute to immunosuppression during the periparturient period. Finally, we will address some issues on disease prevention through nutrition.


Troubled sleep: Night waking, breastfeeding and parent-offspring conflict.
Disrupted sleep is probably the most common complaint of parents with a new baby. Night waking increases in the second half of the first year of infant life and is more pronounced for breastfed infants. Sleep-related phenotypes of infants with Prader-Willi and Angelman syndromes suggest that imprinted genes of paternal origin promote greater wakefulness whereas imprinted genes of maternal origin favor more consolidated sleep. All these observations are consistent with a hypothesis that waking at night to suckle is an adaptation of infants to extend their mothers' lactational amenorrhea, thus delaying the birth of a younger sib and enhancing infant survival.


Detection of Vibrio cholerae O1 in the aquatic environment by fluorescent-monoclonal antibody and culture methods.
Vibrio cholerae O1 in plankton samples collected from ponds and rivers between February 1987 and January 1990 in Matlab, Bangladesh, was detected by the fluorescent-monoclonal antibody (FA) technique. Samples were collected at sites which were monitored fortnightly (fixed sites) as well as at sites that were part of a case-control study. FA results were compared with those obtained by conventional culture methods (CM). A total of 876 samples were collected; V. cholerae O1 was detected in 563 samples (64.27%) by the FA method and in 3 samples (0.34%) by CM. Of the fixed-site plankton samples, 439 (63.62%) were positive by FA and none were positive by CM. Of the 93 case sites sampled on the day after the occurrence of a case of cholera, 73 (78.49%) were positive for V. cholerae O1 by FA and 3 (3.2%) were positive by CM. In comparison, of the 93 first-day sample collections at control sites at the time a case of cholera occurred, only 51 (54.83%) were positive by FA and none were positive by CM. From the data, it is concluded that V. cholerae O1 is present throughout the year in the ponds and rivers of Bangladesh that were examined in this study and that V. cholerae can be detected by FA but not always by CM. The FA procedure was found to be very useful in detecting V. cholerae in plankton, with which it was associated and often occurred in large numbers in the nonculturable stage. Thus, studies investigating the significance of the role of environmental factors in the epidemiology of cholera can be performed effectively by using FA. Such studies are in progress.


Intrinsic resistance of Mycobacterium smegmatis to fluoroquinolones may be influenced by new pentapeptide protein MfpA.
The fluoroquinolones (FQ) are used in the treatment of Mycobacterium tuberculosis, but the development of resistance could limit their effectiveness. FQ resistance (FQ(R)) is a multistep process involving alterations in the type II topoisomerases and perhaps in the regulation of efflux pumps, but several of the steps remain unidentified. Recombinant plasmid pGADIV was selected from a genomic library of wild-type (WT), FQ-sensitive M. smegmatis by its ability to confer low-level resistance to sparfloxacin (SPX). In WT M. smegmatis, pGADIV increased the MICs of ciprofloxacin (CIP) by fourfold and of SPX by eightfold, and in M. bovis BCG it increased the MICs of both CIP and SPX by fourfold. It had no effect on the accumulation of (14)C-labeled CIP or SPX. The open reading frame responsible for the increase in FQ(R), mfpA, encodes a putative protein belonging to the family of pentapeptides, in which almost every fifth amino acid is either leucine or phenylalanine. Very similar proteins are also present in M. tuberculosis and M. avium. The MICs of CIP and SPX were lower for an M. smegmatis mutant strain lacking an intact mfpA gene than for the WT strain, suggesting that, by some unknown mechanism, the gene product plays a role in determining the innate level of FQ(R) in M. smegmatis.


Application of HPLC combined with laser induced fluorescence for protein profile analysis of tissue homogenates in cervical cancer.
A highly objective method, High Performance Liquid Chromatography with Laser Induced Fluorescence (HPLC-LIF) technique was used to study the protein profiles of normal and cervical cancer tissue homogenates. A total of 44 samples including normal cervical biopsy samples from the hysterectomy patients and the patients suffering from different stages of the cervical cancer were recorded by HPLC-LIF and analysed by Principle Component Analysis (PCA) to get statistical information on different tissue components. Discrimination of different stages of the samples was carried out by considering three parameters--scores of factor, spectral residual, and Mahalanobis Distance. Diagnostic accuracy of the method was evaluated using Receiver Operating Characteristic (ROC) analysis, and Youden's index (J) plots. The PCA results showed high sensitivity and specificity (~100) for cervical cancer diagnosis. ROC and Youden's index curves for both normal and malignant standard sets show good diagnostic accuracy with high AUC values. The statistical analysis has shown that the differences in protein profiles can be used to diagnose biochemical changes in the tissue, and thus can be readily applied for the detection of cervical cancer, even in situations where a histopathology examination is not easy because of nonavailability of experienced pathologists.


Henoch-Schönlein purpura: recurrence and chronicity.
To describe a group of patients treated at our service for Henoch-Schönlein purpura, with emphasis on recurrent and chronic cases, and to compare clinical and demographic characteristics of patients with monocyclic and recurrent disease. Data on 67 patients who had been treated since disease onset were analyzed. Twelve patients were excluded because they failed to return for follow-up consultations after less than 3 months, leaving a total of 55 children in the study sample. Recurrence was defined as the presence of a fresh episode after a period of at least 3 months without symptoms, and cases were defined as chronic when cutaneous, abdominal and renal manifestations persisted for a period of 12 months or more. Recurrence was observed in 8/55 patients (14.4%) and four cases were chronic (7.2%). In 29/55 patients (52.7%), infection was identified as the trigger factor. A monocyclic clinical course was observed in 43 patients (26 of whom were girls, with a mean age of 5.4 years). Gastrointestinal and renal involvement was observed in 55.8 and 20.9% of patients, respectively. Among the 12 patients with recurrent or chronic Henoch-Schönlein purpura, three had arthritis, four exhibited signs and symptoms of abdominal involvement and seven of kidney disease: microscopic hematuria in five, macroscopic hematuria in one and hematuria with proteinuria in one other. Late onset was the only variable related to recurrence (p < 0.05). As is observed in medical literature, monocyclic cases are more common among children with early onset disease. Patients with Henoch-Schönlein purpura should be followed over the long term, since recurrent and chronic cases account for more than 20% of the total.


The Silent Threat: Bartonella quintana Endocarditis Unveiling Heart Failure and Severe Pulmonary Hypertension.
BACKGROUND Bartonella quintana is a slow-growing gram-negative bacterium that can cause severe culture-negative endocarditis. In many cases, its insidious onset can be difficult to diagnose given the variable symptoms in the early phases of the disease. This delay in detection and thus treatment can cause advanced consequences of the disease, including heart failure and severe pulmonary hypertension. CASE REPORT A 51-year-old man presented to the Emergency Department with signs and symptoms indicating an acute stroke. Further investigation showed that the source was cardioembolic, and despite negative blood cultures, endocarditis was suspected due to echocardiogram findings. Bartonella endocarditis was diagnosed based on serology results. Further testing indicated severe pulmonary hypertension, a sequelae of chronic heart failure in the setting of endocarditis. This caused a significant delay in valvular repair surgery. This case illustrates the progression from acute to chronic infection, the sequelae of this disease process, and the considerations involved in management. CONCLUSIONS Bartonella is an under-appreciated cause of endocarditis and can evolve into chronic disease with clinical consequences requiring nuanced management. We described a case of chronic culture-negative endocarditis that presented with acute embolic stroke and the sequelae of severe multi-valvular disease in a patient with recent incarceration and unstable housing. This case provides clinicians with valuable insight into the recognition of Bartonella endocarditis, the variable clinical presentations of this pathology, the nuanced and multifactorial approaches to medical management, and the indications for surgery.


Intrinsic 5'-deoxyribose-5-phosphate lyase activity in Saccharomyces cerevisiae Trf4 protein with a possible role in base excision DNA repair.
In Saccharomyces cerevisiae, the base excision DNA repair (BER) pathway has been thought to involve only a multinucleotide (long-patch) mechanism (LP-BER), in contrast to most known cases that include a major single-nucleotide pathway (SN-BER). The key step in mammalian SN-BER, removal of the 5'-terminal abasic residue generated by AP endonuclease incision, is effected by DNA polymerase beta (Polbeta). Computational analysis indicates that yeast Trf4 protein, with roles in sister chromatin cohesion and RNA quality control, is a new member of the X family of DNA polymerases that includes Polbeta. Previous studies of yeast trf4Delta mutants revealed hypersensitivity to methylmethane sulfonate (MMS) but not UV light, a characteristic of BER mutants in other organisms. We found that, like mammalian Polbeta, Trf4 is able to form a Schiff base intermediate with a 5'-deoxyribose-5-phosphate substrate and to excise the abasic residue through a dRP lyase activity. Also like Polbeta, Trf4 forms stable cross-links in vitro to 5'-incised 2-deoxyribonolactone residues in DNA. We determined the sensitivity to MMS of strains with a trf4Delta mutation in a rad27Delta background, in an AP lyase-deficient background (ogg1 ntg1 ntg2), or in a pol4Delta background. Only a RAD27 genetic interaction was detected: there was higher sensitivity for strains mutated in both TRF4 and RAD27 than either single mutant, and overexpression of Trf4 in a rad27Delta background partially suppressed MMS sensitivity. The data strongly suggest a role for Trf4 in a pathway parallel to the Rad27-dependent LP-BER in yeast. Finally, we demonstrate that Trf5 significantly affects MMS sensitivity and thus probably BER efficiency in cells expressing either wild-type Trf4 or a C-terminus-deleted form.


Identification of heart rate-associated loci and their effects on cardiac conduction and rhythm disorders.
Elevated resting heart rate is associated with greater risk of cardiovascular disease and mortality. In a 2-stage meta-analysis of genome-wide association studies in up to 181,171 individuals, we identified 14 new loci associated with heart rate and confirmed associations with all 7 previously established loci. Experimental downregulation of gene expression in Drosophila melanogaster and Danio rerio identified 20 genes at 11 loci that are relevant for heart rate regulation and highlight a role for genes involved in signal transmission, embryonic cardiac development and the pathophysiology of dilated cardiomyopathy, congenital heart failure and/or sudden cardiac death. In addition, genetic susceptibility to increased heart rate is associated with altered cardiac conduction and reduced risk of sick sinus syndrome, and both heart rate-increasing and heart rate-decreasing variants associate with risk of atrial fibrillation. Our findings provide fresh insights into the mechanisms regulating heart rate and identify new therapeutic targets.


Developing and Evaluating a School-Based Tobacco and E-Cigarette Prevention Program for Deaf and Hard-of-Hearing Youth.
School-based programs are an important tobacco prevention tool. Yet, existing programs are not suitable for Deaf and Hard-of-Hearing (DHH) youth. Moreover, little research has examined the use of the full range of tobacco products and related knowledge in this group. To address this gap and inform development of a school-based tobacco prevention program for this population, we conducted a pilot study among DHH middle school (MS) and high school (HS) students attending Schools for the Deaf and mainstream schools in California (n = 114). American Sign Language (ASL) administered surveys, before and after receipt of a draft curriculum delivered by health or physical education teachers, assessed product use and tobacco knowledge. Thirty-five percent of students reported exposure to tobacco products at home, including cigarettes (19%) and e-cigarettes (15%). Tobacco knowledge at baseline was limited; 35% of students knew e-cigarettes contain nicotine, and 56% were aware vaping is prohibited on school grounds. Current product use was reported by 16% of students, most commonly e-cigarettes (12%) and cigarettes (10%); overall, 7% of students reported dual use. Use was greater among HS versus MS students. Changes in student knowledge following program delivery included increased understanding of harmful chemicals in tobacco products, including nicotine in e-cigarettes. Post-program debriefings with teachers yielded specific recommendations for modifications to better meet the educational needs of DHH students. Findings based on student and teacher feedback will guide curriculum development and inform next steps in our program of research aimed to prevent tobacco use in this vulnerable and heretofore understudied population group.


Rates of referable eye disease in the Scottish National Diabetic Retinopathy Screening Programme.
Diabetic retinopathy screening aims to detect people at risk of visual loss due to proliferative diabetic retinopathy, but also refers cases of suspected macular oedema (maculopathy). At the introduction of screening, ophthalmology was concerned that referral rates would be unmanageable. We report yield of referable disease by referral reason for the first 5 years of the programme. We extracted screening results from a nationwide clinical diabetes database to calculate annual referral rates to ophthalmic clinics. We used logistic regression to examine associations between clinical measures and referable disease. 182 397 people underwent ≥ 1successful retinal screening between 2006 and 2010. The yield of referable eye disease was highest in the first 2 years of screening (7.0% and 6.0%) before stabilising at ∼4.3%. The majority of referrals are due to maculopathy with 73% of referrals in 2010 based on a finding of maculopathy. The commonest cause for referral is for suspected macular oedema (maculopathy). Referral rates for retinopathy have stabilised, as predicted, at relatively low rates. However, ophthalmology workload continues to rise as new treatment options (ie, monthly intraocular injections) have unexpectedly increased the impact on ophthalmology. A review of the screening referral path for maculopathy may be timely.


Reepithelialization of the human cornea is regulated by endogenous opioids.
To determine the influence of endogenous opioid modulation on reepithelialization of the human cornea. Eight-millimeter-diameter epithelial defects were created with a trephine and mechanical scraping in the center of human corneas. Resurfacing was studied in organ culture. The size of the defect, the number of specimens with complete reepithelialization, and rate of closure were evaluated using topical fluorescein and morphometric analysis. The influence of opioid receptor blockade was studied using the potent and long-acting opioid antagonist, naltrexone (NTX; 10(-6) M), and the effects of excess (10(-6) M) opioid growth factor (OGF), [Met5]enkephalin, also were determined. The modulatory activity of NTX and OGF on DNA synthesis was evaluated by monitoring the labeling index (LI) using radioactive thymidine. The presence and location of OGF and its receptor (OGFr) were ascertained by immunocytochemistry 1 hour and 24 hours after abrasion. NTX accelerated the wound-healing process, with 21% to 89% less defect than controls observed from 24 to 96 hours. At 72 hours, 62% of the subjects in the NTX group had complete closure of the corneal defects, in contrast to only 19% of the control specimens. All epithelial abrasions were resurfaced in the NTX group between 96 and 120 hours, whereas all controls were not closed until 168 hours. The rate of healing in the NTX group was 1.06 mm2/h compared to a rate of 0.68 mm2/h in the control group. OGF delayed corneal wound healing, with 24% to 260% more defect recorded than in control specimens at day 7. The healing rate of the OGF group was 0.42 mm2/h compared to 0.82 mm2/h for control subjects. The corneal epithelium adjacent to the wound had an LI that was 152% greater than control specimens, whereas OGF decreased the LI of this region by 75%. OGF and OGFr were detected in the epithelium bordering the damaged region at 1 hour, and both peptide and receptor were noted in the regenerating epithelium at 24 hours. These results indicate that an endogenous opioid is present and functions as a tonically active, receptor-mediated, negative growth factor during reepithelialization of the abraded human cornea.


Functional image-guided surgery of intracranial tumors located in or near the sensorimotor cortex.
The purpose of this study was to evaluate the efficacy of noninvasive preoperative functional imaging data used in an interactive fashion in the operating room. The authors describe a method of registering preoperative functional magnetic resonance (fMR) imaging localization of sensorimotor cortex with a frameless stereotactic surgical navigation device. The day before surgery, patients underwent blood oxygen level-dependent fMR imaging while performing a finger-tapping motor paradigm. Immediately afterward an anatomical stereotactic MR image was acquired. Raw fMR imaging data were analyzed offline at a separate workstation, and the resulting functional maps were registered to a high-resolution anatomical scan. The fused functional-anatomical images were then downloaded onto a surgical navigation computer via an ethernet connection. At surgery, the brain was exposed in the standard fashion, and the sensorimotor cortex was identified by direct cortical stimulation, the use of somatosensory evoked potentials, or both. This localization was then compared with that predicted by the registered fMR study. Thirteen procedures were performed in 12 patients. The mean registration error was 2.2 mm. The predicted location of motor and/or sensory cortex matched that found on intraoperative mapping in all 12 patients tested. Maximal tumor resection was accomplished in each case and no new permanent neurological deficits resulted. Compared with conventional brain mapping techniques, fMR image-guided surgery may allow for smaller brain exposures, localization of the language cortex with the patient under general anesthesia, and the mapping of multiple functional sites. The scanning equipment used in this method may be more readily available than for other functional imaging techniques such as positron emission tomography or magnetoencephalography.


Uncaria tomentosa improves insulin sensitivity and inflammation in experimental NAFLD.
We investigated the effect of the crude herbal extract from Uncaria tomentosa (UT) on non-alcoholic fatty liver disease (NAFLD) in two models of obesity: high fat diet (HFD) and genetically obese (ob/ob) mice. Both obese mouse models were insulin resistant and exhibited an abundance of lipid droplets in the hepatocytes and inflammatory cell infiltration in the liver, while only the HFD group had collagen deposition in the perivascular space of the liver. UT treatment significantly reduced liver steatosis and inflammation in both obese mouse models. Furthermore, serine phosphorylation of IRS-1 was reduced by 25% in the HFD mice treated with UT. Overall, UT treated animals exhibited higher insulin sensitivity as compared to vehicle administration. In conclusion, Uncaria tomentosa extract improved glucose homeostasis and reverted NAFLD to a benign hepatic steatosis condition and these effects were associated with the attenuation of liver inflammation in obese mice.


Facial fractures from dog bite injuries.
Dog bites are commonly associated with soft-tissue injury to the face but rarely result in facial fractures. This article reports six new cases of facial fractures associated with dog bites and reviews additional cases reported in the literature. The demographics of the patients attacked, the location of facial fractures, and the characteristics of associated soft-tissue injuries or complications developing from the dog bite are described. With six new cases and 10 from the literature, this article reviewed a total of 16 cases involving 27 facial fractures. Eighty-seven percent of the cases involved children less than 16 years of age. The periorbital or nasal bones were involved in 69 percent of the cases. Lacerations were the most frequently associated soft-tissue injury. Additional injuries included facial nerve damage, lacrimal duct damage requiring stenting and reconstruction, ptosis from levator transection, and blood loss requiring transfusion. Although facial fractures are not commonly considered to be associated with dog bite injuries, the index of suspicion for a fracture should be raised when the injury occurs in a child, particularly when injury occurs near the orbit, nose, and cheek.


Associations between expression levels of nucleotide excision repair proteins in lymphoblastoid cells and risk of squamous cell carcinoma of the head and neck.
Squamous cell carcinoma of head and neck (SCCHN) is one of the most common malignancies worldwide, and nucleotide excision repair (NER) is involved in SCCHN susceptibility. In this analysis of 349 newly diagnosed SCCHN patients and 295 cancer-free controls, we investigated whether expression levels of eight core NER proteins were associated with risk of SCCHN. We quantified NER protein expression levels in cultured peripheral lymphocytes using a reverse-phase protein microarray. Compared with the controls, SCCHN patients had statistically significantly lower expression levels of ERCC3 and XPA (P = 0.001 and 0.001, respectively). After dividing the subjects by controls' median values of expression levels, we found a dose-dependent association between an increased risk of SCCHN and low expression levels of ERCC3 (adjusted OR, 1.75, and 95% CI: 1.26-2.42; Ptrend = 0.008) and XPA (adjusted OR, 1.88; 95% CI, 1.35-2.60; Ptrend = 0.001). We also identified a significant multiplicative interaction between smoking status and ERCC3 expression levels (P = 0.014). Finally, after integrating demographic and clinical variables, we found that the addition of ERCC3 and XPA expression levels to the model significantly improved the sensitivity of the expanded model on SCCHN risk. In conclusion, reduced protein expression levels of ERCC3 and XPA were associated with an increased risk of SCCHN. However, these results need to be confirmed in additional large studies.


Microalbuminuria in salt-sensitive patients. A marker for renal and cardiovascular risk factors.
We previously showed that a high salt diet increases glomerular capillary pressure in salt-sensitive hypertensive patients and suggested that this may underlie the greater propensity of these patients to develop renal failure. Because microalbuminuria is considered an initial sign of renal damage, we have tested whether salt-sensitive patients display greater urinary albumin excretion than salt-resistant hypertensive patients. Twenty-two patients were placed on a low sodium intake (20 mEq/d) for 7 days followed by a high sodium diet (250 mEq/d) for 7 more days. Twelve patients were classified as salt sensitive and 10 as salt resistant. Urinary albumin excretion was greater in salt-sensitive than salt-resistant patients (54 +/- 11 versus 22 +/- 5 mg/24 h, P < .01). During the low sodium diet, glomerular filtration rate, renal plasma flow, and filtration fraction were similar between the two groups. During the high sodium intake, glomerular filtration, renal plasma flow, filtration fraction, and calculated intraglomerular pressure did not change in salt-resistant patients; in salt-sensitive patients, however, renal plasma flow decreased, and filtration fraction and intraglomerular pressure increased, whereas glomerular filtration rate did not change. Urinary albumin excretion was significantly correlated with glomerular capillary pressure. Salt-sensitive patients displayed higher serum levels of low-density lipoprotein cholesterol and lipoprotein(a) and lower levels of high-density lipoprotein cholesterol than salt-resistant patients. These studies have shown greater urinary albumin excretion and serum concentrations of atherogenic lipoproteins in salt-sensitive than in salt-resistant hypertensive patients, suggesting that salt sensitivity may be a marker for greater risk of renal and cardiovascular complications.


A zinc-doped endodontic cement facilitates functional mineralization and stress dissipation at the dentin surface.
The purpose of this study was to evaluate nanohardness and viscoelastic behavior of dentin surfaces treated with two canal sealer cements for dentin remineralization. Dentin surfaces were subjected to: i) 37% phosphoric acid (PA) or ii) 0.5 M ethylenediaminetetraacetic acid (EDTA) conditioning prior to the application of two experimental hydroxyapatite-based cements, containing sodium hydroxide (calcypatite) or zinc oxide (oxipatite), respectively. Samples were stored in simulated body fluid during 24 h or 21 d. The intertubular and peritubular dentin were evaluated using a nanoindenter to assess nanohardness (Hi). The load/displacement responses were used for the nano-dynamic mechanical analysis to estimate complex modulus (E*) and tan delta (δ). The modulus mapping was obtained by imposing a quasistatic force setpoint to which a sinusoidal force was superimposed. AFM imaging and FESEM analysis were performed. After 21 d of storage, dentin surfaces treated with EDTA+calcypatite, PA+calcypatite and EDTA+oxipatite showed viscoelastic discrepancies between peritubular and intertubular dentin, meaning a risk for cracking and breakdown of the surface. At both 24 h and 21 d, tan δ values at intertubular dentin treated with the four treatments performed similar. At 21 d time point, intertubular dentin treated with PA+oxipatite achieved the highest complex modulus and nanohardness, i.e., highest resistance to deformation and functional mineralization, among groups. Intertubular and peritubular dentin treated with PA+oxipatite showed similar values of tan δ after 21 d of storage. This produced a favorable dissipation of energy with minimal energy concentration, preserving the structural integrity at the dentin surface.


Alcohol-Induced Behaviors Require a Subset of Drosophila JmjC-Domain Histone Demethylases in the Nervous System.
Long-lasting transcriptional changes underlie a number of adaptations that contribute to alcohol use disorders (AUD). Chromatin remodeling, including histone methylation, can confer distinct, long-lasting transcriptional changes, and histone methylases are known to play a role in the development of addiction. Conversely, little is known about the relevance of Jumonji (JmjC) domain-containing demethylases in AUDs. We systematically surveyed the alcohol-induced phenotypes of null mutations in all 13 Drosophila JmjC genes. We used a collection of JmjC mutants, the majority of which we generated by homologous recombination, and assayed them in the Booze-o-mat to determine their naïve sensitivity to sedation and their tolerance (change in sensitivity upon repeat exposure). Mutants with reproducible phenotypes had their phenotypes rescued with tagged genomic transgenes, and/or phenocopied by nervous system-specific knockdown using RNA interference (RNAi). Four of the 13 JmjC genes (KDM3, lid, NO66, and HSPBAP1) showed reproducible ethanol (EtOH) sensitivity phenotypes. Some of the phenotypes were observed across doses, for example, the enhanced EtOH sensitivity of KDM3KO and NO66KO , but others were dose dependent, such as the reduced EtOH sensitivity of HSPBAP1KO , or the enhanced EtOH tolerance of NO66KO . These phenotypes were rescued by their respective genomic transgenes in KDM3KO and NO66KO mutants. While we were unable to rescue lidk mutants, knockdown of lid in the nervous system recapitulated the lidk phenotype, as was observed for KDM3KO and NO66KO RNAi-mediated knockdown. Our study reveals that the Drosophila JmjC-domain histone demethylases Lid, KDM3, NO66, and HSPBAP1 are required for normal EtOH-induced sedation and tolerance. Three of 3 tested of those 4 JmjC genes are required in the nervous system for normal alcohol-induced behavioral responses, suggesting that this gene family is an intriguing avenue for future research.


Radial spoke proteins of Chlamydomonas flagella.
The radial spoke is a ubiquitous component of '9+2' cilia and flagella, and plays an essential role in the control of dynein arm activity by relaying signals from the central pair of microtubules to the arms. The Chlamydomonas reinhardtii radial spoke contains at least 23 proteins, only 8 of which have been characterized at the molecular level. Here, we use mass spectrometry to identify 10 additional radial spoke proteins. Many of the newly identified proteins in the spoke stalk are predicted to contain domains associated with signal transduction, including Ca2+-, AKAP- and nucleotide-binding domains. This suggests that the spoke stalk is both a scaffold for signaling molecules and itself a transducer of signals. Moreover, in addition to the recently described HSP40 family member, a second spoke stalk protein is predicted to be a molecular chaperone, implying that there is a sophisticated mechanism for the assembly of this large complex. Among the 18 spoke proteins identified to date, at least 12 have apparent homologs in humans, indicating that the radial spoke has been conserved throughout evolution. The human genes encoding these proteins are candidates for causing primary ciliary dyskinesia, a severe inherited disease involving missing or defective axonemal structures, including the radial spokes.


Diabetes-associated mesenteric vascular hypertrophy is attenuated by angiotensin-converting enzyme inhibition.
In experimental diabetes, the mesenteric vascular tree undergoes hypertrophy, and this is associated with an increase in mesenteric angiotensin-converting enzyme (ACE) levels. The aim of this study was to determine if inhibition of mesenteric ACE by ACE inhibition would influence diabetes-associated mesenteric vascular hypertrophy. Control or streptozocin-induced diabetic rats were randomized to receive no drug or the ACE inhibitor perindopril. In addition, other diabetic rats were randomized to receive either low-dose insulin that does not alter glycemic control or high-dose insulin, administered as a silastic pellet to achieve euglycemia. After 3 weeks, animals were killed for measurement of mesenteric ACE, vessel weight, and wall:lumen ratio. Diabetes was associated with increased mesenteric ACE levels, increased vessel weight, and an increase in the wall:lumen ratio. ACE inhibition, despite no effect on glycemic control, food intake, urinary urea excretion, or gut weight, prevented the increase in mesenteric ACE levels and attenuated mesenteric vascular hypertrophy as assessed by weight or wall:lumen ratio. The increase in staining by an antibody to the endothelial product, von Willebrand factor, in diabetic rats was totally prevented by perindopril treatment. Euglycemia but not low-dose insulin therapy in the diabetic rats normalized mesenteric vessel ACE, weight, and wall:lumen ratio. In conclusion, ACE inhibition may have a specific role in preventing diabetes-associated vascular hypertrophy, an important process in the genesis of micro- and macrovascular diabetic complications.


Predisposing factors of diminished survival in simultaneous liver/kidney transplantation.
Since the adoption of the Model for End-Stage Liver Disease, simultaneous liver/kidney transplants (SLKT) have substantially increased. Recently, unfavorable outcomes have been reported yet contributing factors remain unclear. We retrospectively reviewed 74 consecutive adult SLKT performed at our center from 2000 to 2010 and compared with kidney transplant alone (KTA, N = 544). In SLKT, patient and death-censored kidney graft survival rates were 64 ± 6% and 81 ± 5% at 5 years, respectively (median follow-up, 47 months). Multivariable analyses revealed three independent risk factors affecting patient survival: hepatitis C virus positive (HCV+, hazard ratio [HR] 2.9, 95% confidence interval [CI] 1.1-7.9), panel reactive antibody (PRA) > 20% (HR 2.8, 95% CI 1.1-7.2) and female donor gender (HR 2.9, 95% CI 1.1-7.9). For death-censored kidney graft survival, delayed graft function was the strongest negative predictor (HR 8.3, 95% CI 2.5-27.9), followed by HCV+ and PRA > 20%. The adjusted risk of death-censored kidney graft loss in HCV+ SLKT patients was 5.8 (95% CI 1.6-21.6) compared with HCV+ KTA (p = 0.008). Recurrent HCV within 1 year after SLKT correlated with early kidney graft failure (p = 0.004). Careful donor/recipient selection and innovative approaches for HCV+ SLKT patients are critical to further improve long-term outcomes.


Lessons from UK prospective diabetes study.
Type II diabetes is a major cause of morbidity and mortality, both from an increased risk of developing cardiovascular disease and from specific diabetic complications. At present, patients are often treated to prevent marked hyperglycaemia, that induces symptoms such as thirst. Moderately raised glucose levels are then accepted. At present, it is uncertain whether Type II diabetes should be treated more intensively, with diet, tablet or insulin therapy to maintain near-normal glucose levels, in order to prevent the onset of complications. The Diabetes Control and Complications Trial (DCCT) in insulin-dependent diabetic subjects with a mean age of 27 years has indicated that intensive therapy to achieve a haemoglobin A1c level of 7.1%, compared with 9.0% in a 'standard control group', will retard the progress of diabetic microvascular disease. It is not known whether this is similarly beneficial in Type II diabetic subjects, where the main complication is cardiac disease, or whether the even better control that can be obtained with pharmaceutical therapy in Type II diabetic patients would be worthwhile. It is similarly not known whether treatment with sulphonylurea, metformin or insulin is particularly beneficial or whether any of these therapies is potentially harmful. The UK Prospective Diabetes Study (UKPDS) has randomly allocated 4209 newly diagnosed Type II diabetic patients to different therapies and is determining: (a) whether improved glucose control will delay the onset of clinical complications; and (b) whether any specific therapy has advantages or disadvantages.


A genomic mutational constraint map using variation in 76,156 human genomes.
The depletion of disruptive variation caused by purifying natural selection (constraint) has been widely used to investigate protein-coding genes underlying human disorders1-4, but attempts to assess constraint for non-protein-coding regions have proved more difficult. Here we aggregate, process and release a dataset of 76,156 human genomes from the Genome Aggregation Database (gnomAD)-the largest public open-access human genome allele frequency reference dataset-and use it to build a genomic constraint map for the whole genome (genomic non-coding constraint of haploinsufficient variation (Gnocchi)). We present a refined mutational model that incorporates local sequence context and regional genomic features to detect depletions of variation. As expected, the average constraint for protein-coding sequences is stronger than that for non-coding regions. Within the non-coding genome, constrained regions are enriched for known regulatory elements and variants that are implicated in complex human diseases and traits, facilitating the triangulation of biological annotation, disease association and natural selection to non-coding DNA analysis. More constrained regulatory elements tend to regulate more constrained protein-coding genes, which in turn suggests that non-coding constraint can aid the identification of constrained genes that are as yet unrecognized by current gene constraint metrics. We demonstrate that this genome-wide constraint map improves the identification and interpretation of functional human genetic variation.


Retinal microvascular parameters are not significantly associated with mild cognitive impairment in the Northern Ireland Cohort for the Longitudinal Study of Ageing.
The retinal and cerebral microvasculature share similar embryological origins and physiological characteristics. Improved imaging technologies provide opportunistic non-invasive assessment of retinal microvascular parameters (RMPs) against cognitive outcomes. We evaluated baseline measures for associations between RMPs and mild cognitive impairment (MCI) from participants of the Northern Ireland Cohort for the Longitudinal Study of Ageing (NICOLA). RMPs (central retinal arteriolar / venular equivalents, arteriole to venular ratio, fractal dimension and tortuosity) were measured from optic disc centred fundus images and analysed using semi-automated software. Associations between RMPs and MCI were assessed by multivariable logistic regression with adjustment for potential confounders including age, sex, alcohol consumption, smoking status, educational attainment, physical activity, cardiovascular disease (CVD), hypertension, mean arterial blood pressure, triglycerides, diabetes, body mass index, and high density lipoprotein levels. P < 0.05 was considered statistically significant. Data were available for 1431 participants, of which 156 (10.9%) were classified with MCI defined by a Montreal Cognitive Assessment (MoCA) score ≤ 26, with subjective cognitive decline, in the absence of depression or problems with activities of daily living. Participants had a mean age of 62.4 ± 8.5 yrs. and 52% were female. As expected, individuals with MCI had a lower MoCA score than those without (23.5 ± 2.6 versus 26.3 ± 2.7, respectively), were more likely to be female, have a lower level of educational attainment, be less physically active, more likely to have CVD, have higher levels of triglycerides and lower levels of high density lipoprotein. No significant associations between RMPs and MCI were detected in unadjusted, minimally adjusted or fully adjusted regression models or subsequent sensitivity analyses. Previous studies have reported both increased retinal venular calibre and reduced fractal dimension in association with mild cognitive impairment. Our study failed to detect any associations between RMPs and those individuals at an early stage of cognitive loss in an older community-based cohort.


An fMRI Study of the Brain Network Involved in Teeth Tapping in Elderly Adults.
Cortical activity during jaw movement has been analyzed using various non-invasive brain imaging methods, but the contribution of orofacial sensory input to voluntary jaw movements remains unclear. In this study, we used functional magnetic resonance imaging (fMRI) to observe brain activities during a simple teeth tapping task in adult dentulous (AD), older dentulous (OD), and older edentulous subjects who wore dentures (OEd) or did not wear dentures (OE) to analyze their functional network connections. (1) To assess the effect of age on natural activation patterns during teeth tapping, a comparison of groups with natural dentition-AD and OD-was undertaken. A general linear model analysis indicated that the major activated site in the AD group was the primary sensory cortex (SI) and motor cortex (MI) (p < 0.05, family wise error corrected). In the OD group, teeth tapping induced brain activity at various foci (p < 0.05, family wise error corrected), including the SI, MI, insula cortex, supplementary motor cortex (SMC)/premotor cortex (PMA), cerebellum, thalamus, and basal ganglia in each group. (2) Group comparisons between the OD and OEd subjects showed decreased activity in the SI, MI, Brodmann's area 6 (BA6), thalamus (ventral posteromedial nucleus, VPM), basal ganglia, and insular cortex (p ¡ 0.005, uncorrected). This suggested that the decreased S1/M1 activity in the OEd group was related to missing teeth, which led to reduced periodontal afferents. (3) A conjunction analysis in the OD and OEd/OE groups revealed that commonly activated areas were the MI, SI, cerebellum, BA6, thalamus (VPM), and basal ganglia (putamen; p < 0.05, FWE corrected). These areas have been associated with voluntary movements. (4) Psychophysiological interaction analysis (OEd vs OE) showed that subcortical and cortical structures, such as the MI, SI, DLPFC, SMC/PMA, insula cortex, basal ganglia, and cerebellum, likely function as hubs and form an integrated network that participates in the control of teeth tapping. These results suggest that oral sensory inputs are involved in the control of teeth tapping through feedforward control of intended movements, as well as feedback control of ongoing movements.


Impact of temperature on the extrinsic incubation period of Zika virus in Aedes aegypti.
Since Zika virus (ZIKV) emerged as a global human health threat, numerous studies have pointed to Aedes aegypti as the primary vector due to its high competence and propensity to feed on humans. The majority of vector competence studies have been conducted between 26-28°C, but arboviral extrinsic incubation periods (EIPs), and therefore transmission efficiency, are known to be affected strongly by temperature. To better understand the relationship between ZIKV EIPs and temperature, we evaluated the effect of adult mosquito exposure temperature on ZIKV infection, dissemination, and transmission in Ae. aegypti at four temperatures: 18°C, 21°C, 26°C, and 30°C. Mosquitoes were exposed to viremic mice infected with a 2015 Puerto Rican ZIKV strain, and engorged mosquitoes were sorted into the four temperatures with 80% RH and constant access to 10% sucrose. ZIKV infection, dissemination, and transmission rates were assessed via RT-qPCR from individual mosquito bodies, legs and wings, and saliva, respectively, at three to five time points per temperature from three to 31 days, based on expectations from other flavivirus EIPs. The median time from ZIKV ingestion to transmission (median EIP, EIP50) at each temperature was estimated by fitting a generalized linear mixed model for each temperature. EIP50 ranged from 5.1 days at 30°C to 24.2 days at 21°C. At 26°C, EIP50 was 9.6 days. At 18°C, only 15% transmitted by day 31 so EIP50 could not be estimated. This is among the first studies to characterize the effects of temperature on ZIKV EIP in Ae. aegypti, and the first to do so based on feeding of mosquitoes on a live, viremic host. This information is critical for modeling ZIKV transmission dynamics to understand geographic and seasonal limits of ZIKV risk; it is especially relevant for determining risk in subtropical regions with established Ae. aegypti populations and relatively high rates of return travel from the tropics (e.g. California or Florida), as these regions typically experience cooler temperature ranges than tropical regions.


Descriptive epidemiology of salivary gland neoplasms in Nigeria: An AOPRC multicenter tertiary hospital study.
Accurate diagnosis of salivary gland neoplasms (SGN) in many centers in Africa is limited by poor diagnostic resources and ancillary services. Hence, we have carried out a multicenter epidemiological study to understand the true burden of SGN in Nigeria. In this descriptive cross-sectional study, we have deployed resources available to members of the African Oral Pathology Consortium (AOPRC) to examine the burden of salivary gland lesions in Nigeria, using a multicenter approach. Data from seven major tertiary health institutions in northern, western, and southern Nigeria were generated using a standardized data extraction format and analyzed using the Epi-info software (Version 7.0, Atlanta, USA). Of the 497 cases examined across the seven centers, we observed that SGN occurred more in females than males. Overall, pleomorphic salivary adenoma (PA) was found to be the most common. PA was found to be the commonest benign SGN while adenocystic carcinoma (ADCC) was the commonest malignant SGN. Regional variations were observed for age group, diagnosis, and gender distribution. Significant statistical differences were found between males and females for malignant SGNs (p-value=0.037). We found regional variation in the pattern of distribution of SGN in Nigeria. This is the largest multicenter study of SGN in Nigeria, and our findings are robust and representative of the epidemiology of this neoplasm in Nigeria.


Molecular Links Between Diabetes and Osteoarthritis: The Role of Physical Activity.
Diabetes mellitus (DM) and osteoarthritis (OA) are two of the most relevant and common chronic diseases affecting older people. Both DM and OA are considered metabolic diseases due to their high correlation with the capacity of the body to metabolize some nutritive substances such as glucose, fat, vitamins and also the response to oxidative molecules. We searched PubMed, Scopus, Google Scholar, and authors' bibliographies in order to extract articles regarding the relationship between DM and OA. The main purpose of this review is to investigate the molecules involved in the onset and progression of both DM and OA and the beneficial role of physical activity. The main focus is on the importance of glucose metabolism and its derivatives in the pathogenesis of OA and DM. Advanced glycation end-product (AGEs), sorbitol and diacylglycerol (DAG) are glucose derivatives which promote the activation of several pathways, most of them involved in the activation of inflammatory processes. The possible link between DM and OA is represented by the inflammatory process deriving from the increased expression of pro-inflammatory cytokines. Moreover, we investigated the biological mechanisms and the clinical findings that confirm a beneficial effect of physical activity in both DM and OA. Thus a tailored and adapted physical activity can be used in the treatment of both diseases as a part of a correct and healthy lifestyle. For this reason we strongly suggest the scientific community to introduce mild physical activity as part of our lifestyle to prevent metabolism diseases and osteoarthritis.


Protective and Promotive Effects of Latino Early Adolescents' Cultural Assets Against Multiple Types of Discrimination.
Given adversity associated with discrimination, it is important to identify culturally relevant factors that may protect against its harmful effects. Using latent variable interactions, this study examined the moderating effects of cultural assets on the association between multiple types of discrimination and adolescents' adjustment. Participants included 174 seventh- and eighth-grade Latino adolescents (51% girls); majority were of Mexican origin. Peer discrimination was associated with higher internalizing symptoms, whereas cultural assets predicted higher academic motivation above and beyond racial-ethnic discrimination, demonstrating a promotive effect. Adolescents' Latino cultural assets also protected against higher levels of externalizing symptoms in the context of high peer discrimination and foreigner objectification. The discussion focuses on the conceptual and applied implications of these findings.


Characterization of CART neurons in the rat and human hypothalamus.
Cocaine- and amphetamine-regulated transcript (CART) is a recently described neuropeptide widely expressed in the rat brain. CART mRNA and peptides are found in hypothalamic sites such as the paraventricular nucleus (PVH), the supraoptic nucleus (SON), the lateral hypothalamic area (LHA), the dorsomedial nucleus of the hypothalamus (DMH), the arcuate nucleus (Arc), the periventricular nucleus (Pe), and the ventral premammillary nucleus (PMV). Intracerebroventricular administration of recombinant CART peptide decreases food intake and CART mRNA levels in the Arc are regulated by leptin. Leptin administration induces Fos expression in hypothalamic CART neurons in the PVH, the DMH, the Arc, and the PMV. In the current study, we used double label in situ hybridization histochemistry to investigate the potential direct action of leptin on hypothalamic CART neurons and to define the chemical identity of the hypothalamic CART neurons in the rat brain. We found that CART neurons in the Arc, DMH, and PMV express long form leptin-receptor mRNA, and the suppressor of cytokine signaling-3 (SOCS-3) mRNA after an acute dose of intravenous leptin. We also found that CART neurons in the parvicellular PVH, in the DMH and in the posterior Pe coexpress thyrotropin-releasing hormone (TRH) mRNA. CART neurons in the magnocellular PVH and in the SON coexpress dynorphin (DYN), and CART cell bodies in the LHA and in the posterior Pe coexpress melanin-concentrating hormone (MCH) and glutamic acid decarboxylase (GAD-67) mRNA. In the Arc, a few CART neurons coexpress neurotensin (NT) mRNA. In addition, we examined the distribution of CART immunoreactivity in the human hypothalamus. We found CART cell bodies in the PVH, in the SON, in the LHA, in the Arc (infundibular nucleus) and in the DMH. We also observed CART fibers throughout the hypothalamus, in the bed nucleus of the stria terminalis, and in the amygdala. Our results indicate that leptin directly acts on CART neurons in distinct nuclei of the rat hypothalamus. Furthermore, hypothalamic CART neurons coexpress neuropeptides involved in energy homeostasis, including MCH, TRH, DYN, and NT. The distribution of CART cell bodies and fibers in the human hypothalamus indicates that CART may also play a role in the regulation of energy homeostasis in humans.


Self- and proxy reports of quality of life among adolescents living in residential youth care compared to adolescents in the general population and mental health services.
Child welfare services are aimed at providing care and protection, fostering well-being and prosocial behaviour. Thus, Quality of Life (QoL) should be an important outcome measure in Residential Youth Care (RYC) institutions. However, the dearth of research in this area gives rise to serious concern. The present study is the first large scale, nationwide study assessing QoL among adolescents living in RYC. To provide a reference frame, adolescent self- and primary contact proxy reports were compared to the general population and to adolescent outpatients in Child and Adolescent Mental Health Service (CAMHS). Also, we investigated the association between self-report of QoL in adolescents living in RYC and proxy reports of their primary contacts at the institution. All residents between the ages of 12-23 years living in RYC in Norway were the inclusion criteria. Eighty-six RYC institutions (with 601 eligible youths) were included, 201 youths/ parents did not give their consent. Finally, 400 youths aged 12-20 years participated, yielding a response rate of 67%. As a reference frame for comparison, a general population (N = 1444) and an outpatient sample of adolescents in CAMHS (N = 68) were available. We used the Questionnaire for Measuring Health-related Quality of Life in Children and Adolescents (KINDL-R). General Linear Model analyses (ANCOVA) were conducted with five KINDL life domains as dependent variables and group as independent variable. Self- and proxy reports of QoL in adolescents living in RYC revealed a significantly (p < 0.001) poorer QoL compared to the general population on the life domains Physical- and Emotional well-being, Self-esteem, and relationship with Friends. Adolescents evaluated their physical well-being as worse compared to adolescents in CAHMS. Self- and proxy reports in RYC differed significantly on two of five life domains, but correlated low to moderate with each other. The results in this study raise major concerns about the poor QoL of the adolescents living in RYC, thereby challenging the child welfare system and decision makers to take action to improve the QoL of this group. The use of QoL as outcome measures is highly recommended.


Patterns of care and outcomes in adolescent and young adult acute lymphoblastic leukemia: a population-based study.
Adolescents and young adults (AYAs, 15-39 years) with acute lymphoblastic leukemia (ALL) represent a heterogeneous population who receive care in pediatric or adult cancer settings. Using the California Cancer Registry, we describe AYA ALL patterns of care and outcomes over the past decade. Sociodemographics, treatment location, and front-line therapies administered to AYAs diagnosed with ALL between 2004 and 2014 were obtained. Cox regression models evaluated associations between ALL setting and regimen and overall survival (OS) and leukemia-specific survival (LSS) for the entire cohort, younger AYA (<25 years), and AYAs treated in the adult cancer setting only. Of 1473 cases, 67.7% were treated in an adult setting; of these, 24.8% received a pediatric ALL regimen and 40.7% were treated at a National Cancer Institute (NCI)-designated center. In multivariable analyses, front-line treatment in a pediatric (vs adult) setting (OS HR = 0.53, 95% confidence interval [CI], 0.37-0.76; LSS HR = 0.51, 95% CI, 0.35-0.74) and at an NCI/Children's Oncology Group (COG) center (OS HR = 0.80, 95% CI, 0.66-0.96; LSS HR = 0.80, 95% CI, 0.65-0.97) were associated with significantly superior survival. Results were similar when analyses were limited to younger AYAs. Outcomes for AYAs treated in an adult setting did not differ following front-line pediatric or adult ALL regimens. Our population-level findings demonstrate that two-thirds of AYAs with newly diagnosed ALL are treated in an adult cancer setting, with the majority receiving care in community settings. Given the potential survival benefits, front-line treatment of AYA ALL at pediatric and/or NCI/COG-designated cancer centers should be considered.


Efficacy of Rituharitaki (seasonal adjuvant of Haritaki) on disorders of Varsha Ritu (monsoon) w.s.r. to quality of life: An open labelled randomized controlled clinical trial.
Monsoon epidemics are always a serious concern in the public health sector. Administration of Haritaki with suitable vehicle as per season (Rituharitaki) is a simple, cost-effective preventive measure which can be used for such conditions. Study objectives were to assess the effect of Rituharitaki in preventing the diseases in Varsha Ritu (monsoon) and its effect on the WHO quality of life BREF (QOL BREF), total leukocyte count (TLC), differential count (DC) and erythrocyte sedimentation rate (ESR) in healthy volunteers. From 82 participants, based on inclusion criteria, 60 participants were selected and randomly allocated into trial and control group of 30 each using a computer generated random number table. Intervention given was Rituharitaki (Terminalia chebula Retz) in tablet form-3 tablets of 1g each and Saindhava (rock salt) 1g with lukewarm water at 6.30 am on empty stomach to the participants of trial group for 60 days in Varsha Ritu in Kerala and were observed during this period. The results were analyzed using Chi-square test and paired t-test. Significant results were obtained in the trial group in reducing the severity and frequency of common cold (p < 0.001), cough (p < 0.05), and fever (p < 0.001). In the WHO QOL BREF domain 1 & 4 showed significant result in the trial group (p < 0.05). Among the haematological parameters - total leukocyte count (TLC), eosinophil count and erythrocyte sedimentation rate (ESR) were statistically significant reduced (p < 0.05) in the trial group. Rituharitaki is found to be effective in reducing severity and frequency of diseases in Varsha Ritu and had effect on quality of life of patients.


[Effectiveness of excimer laser coronary angioplasty in treatment of patients with in-stent restenosis].
In-stent restenosis (ISR), when treated with balloon angioplasty (PTCA) alone, has an angiographic recurrence rate of 30-85%. Ablating the hypertrophic neointimal tissue prior to PTCA is an attractive alternative, however late outcomes of such treatment have not been fully determined. This multicenter case control study assessed angiographic and clinical outcomes of 137 consecutive procedures in 125 patients treated for ISR with either PTCA alone (n = 58) or excimer laser assisted coronary angioplasty (ELCA, n = 67). Demographics were similar. Lesions selected for ELCA compared with those selected for \PTCA were longer (17.1+/-9.9 mm vs. 13.6+/-9.1 mm; p=0,034), more complex (ACC/AHA type C: 36,5% vs. 14,3%; p=0,006), and with reduced antegrade flow (TIMI flow < 3: 18,9% vs. 4,8%; p = 0,025). ELCA- and PTCA treated patients had similar rates of procedural success (98,5 and 98,3%, respectively, p=1,0), major clinical complications (3,0% and 8,6%; respectively, NS), major cardiac events at 1 year (37,3 and 46,6%. respectively, NS), and target lesion revascularization (32,8 and. 34,5%; respectively, NS). These data suggest that ELCA in patients with complex in-stent restenosis is as safe and effective as PTCA. Despite higher lesion complexity in ELCA-treated patients, no increase in event rates was observed.


Defining the mechanism of polymerization in the serpinopathies.
The serpinopathies result from the ordered polymerization of mutants of members of the serine proteinase inhibitor (serpin) superfamily. These polymers are retained within the cell of synthesis where they cause a toxic gain of function. The serpinopathies are exemplified by inclusions that form with the common severe Z mutant of α(1)-antitrypsin that are associated with liver cirrhosis. There is considerable controversy as to the pathway of serpin polymerization and the structure of pathogenic polymers that cause disease. We have used synthetic peptides, limited proteolysis, monoclonal antibodies, and ion mobility-mass spectrometry to characterize the polymerogenic intermediate and pathological polymers formed by Z α(1)-antitrypsin. Our data are best explained by a model in which polymers form through a single intermediate and with a reactive center loop-β-sheet A linkage. Our data are not compatible with the recent model in which polymers are linked by a β-hairpin of the reactive center loop and strand 5A. Understanding the structure of the serpin polymer is essential for rational drug design strategies that aim to block polymerization and so treat α(1)-antitrypsin deficiency and the serpinopathies.


Liver Simulated Allocation Modeling: Were the Predictions Accurate for Share 35?
The liver simulated allocation model (LSAM) can be used to study likely effects of liver transplant allocation policy changes on organ offers, acceptance, waitlist survival, and posttransplant survival. Implementation of Share 35 in June 2013 allowed for testing how well LSAM predicted actual changes. LSAM projections for 1 year of liver transplants before and after the Share 35 policy change were compared with observed data during the same period. Numbers of organs recovered, organ sharing, transplant rates, and waitlist mortality rates (per 100 waitlist years) were evaluated by LSAM and compared with observed data. Candidate, recipient, and donor characteristics in the LSAM cohorts were similar to those in the observed population before and after Share 35. LSAM correctly predicted more accepted organs and fewer discarded organs with Share 35. LSAM also predicted increased regional and national sharing, consistent with observed data, although the magnitude was overestimated. Transplant rates were correctly projected to increase and waitlist death rates to decrease. Although the absolute number of transplants was underestimated and waitlist deaths overestimated, the direction of change was consistent with observed data. LSAM correctly predicted change in discarded organs, regional and national sharing, waitlist mortality, and transplants after Share 35 implementation.


Assessing whether medical language is a barrier to receiving healthcare services in Bangladesh: an exploratory study.
In many global settings, medical language acts as a barrier to accessing and using health services. However, this issue remained unexplored in Bangladesh, where the non-native English language is commonly used for health care. To examine whether medical language is an obstacle for obtaining health services in Bangladesh and to provide policy recommendations. An exploratory study was undertaken to identify the impact of medical language on general practice. Data were collected online from Bangladeshi people between July-November 2014. A semi-structured questionnaire was developed through Google Forms for data collection. The snowball technique was applied to obtain data purposively from 50 participants. With prior consent, the questionnaire along with the online link was sent to responders by email. When responders clicked on the 'submit' option of the questionnaire, responses were stored online automatically in the pre-built system. Quantitative data were analysed using SPSS (version 22). Textual data analyses (especially of suggestions of the responders) were conducted using a thematic approach. Among study participants, 44% (n = 22) said that English language was the choice for writing prescriptions by health service providers in Bangladesh, and 26% said that a mixture of Bengali and English was used. Around 30% of the study participants could not understand medical language used by doctors (this includes those who were not sure or preferred not to say). Among responders, 78% said that medical language was affecting the treatment process and 48% were of the opinion that it was acting as a barrier in receiving health services. Medical language is acting as a barrier in the health services of Bangladesh. Tailored interventions must be developed and implemented to overcome medical language barriers in health services in order to strengthen the health system.


Radiative transfer code SHARM for atmospheric and terrestrial applications.
An overview of the publicly available radiative transfer Spherical Harmonics code (SHARM) is presented. SHARM is a rigorous code, as accurate as the Discrete Ordinate Radiative Transfer (DISORT) code, yet faster. It performs simultaneous calculations for different solar zenith angles, view zenith angles, and view azimuths and allows the user to make multiwavelength calculations in one run. The Delta-M method is implemented for calculations with highly anisotropic phase functions. Rayleigh scattering is automatically included as a function of wavelength, surface elevation, and the selected vertical profile of one of the standard atmospheric models. The current version of the SHARM code does not explicitly include atmospheric gaseous absorption, which should be provided by the user. The SHARM code has several built-in models of the bidirectional reflectance of land and wind-ruffled water surfaces that are most widely used in research and satellite data processing. A modification of the SHARM code with the built-in Mie algorithm designed for calculations with spherical aerosols is also described.


Device-Associated Healthcare-Associated Infections (DA-HAI) and the caveat of multiresistance in a multidisciplinary intensive care unit.
Device-Associated Healthcare-Associated Infections (DA-HAI), including Ventilator-Associated Pneumonia (VAP), Central-Line-Associated Blood Stream Infection (CLABSI), and Catheter-Related Urinary Tract Infection (CAUTI), are considered as principal contributors to healthcare hazard and threat to patient safety as they can cause prolonged hospital stay, sepsis, and mortality in the ICU. The study intends to characterize DA-HAI in a tertiary care multidisciplinary ICU of a teaching hospital in eastern India. This prospective outcome-surveillance study was conducted among 2157 ICU patients of a 760-bedded teaching hospital in Eastern India. Clinical, laboratory and environmental surveillance, and screening of HCPs were conducted using the US Centers for Disease Control and Prevention (CDC)'s National Healthcare Safety Network (NHSN) definitions and methods. With 8824 patient/bed/ICU days and 14,676 device days, pooled average device utilization ratio was 1.66, total episodes of DA-HAI were 114, and mean monthly rates of DA-HAI, VAP, CLABSI, and CAUTI were 4.75, 2, 1.4, and 1.25/1000 device days. Most common pathogens isolated from DA-HAI patients were Klebsiella pneumoniae (24.6%), Escherichia coli (21.9%), and Pseudomonas aeruginosa (20.2%). All Acinetobacter baumanii, >80% K. pneumoniae and E. coli, and >70% P. aeruginosa were susceptible only to colistin and tigecycline. One P. aeruginosa isolate was panresistant. Mean rates of VAP, CLABSI, and CAUTI were 14.4, 8.1, and 4.5 per 1000 device days, which are comparable with Indian and global ICUs. Patients and HCPs form important reservoirs of infection. Resolute conviction and sustained momentum in Infection Control Initiatives are an essential step toward patient safety.


Mechanisms of insulin resistance in human obesity: evidence for receptor and postreceptor defects.
To assess the mechanisms of the insulin resistance in human obesity, we have determined, using a modification of the euglycemic glucose clamp technique, the shape of the in vivo insulin-glucose disposal dose-response curves in 7 control and 13 obese human subjects. Each subject had at least three euglycemic studies performed at insulin infusion rates of 15, 40, 120, 240, or 1,200 mU/M2/min. The glucose disposal rate was decreased in all obese subjects compared with controls (101 +/- 16 vs. 186 +/- 16 mg/M2/min) during the 40 mU/M2/min insulin infusion. The mean dose-response curve for the obese subjects was displaced to the right, i.e., the half-maximally effective insulin concentration was 270 +/- 27 microU/ml for the obese compared with 130 +/- 10 microU/ml for controls. In nine of the obese subjects, the dose-response curves were shifted to the right, and maximal glucose disposal rates (at a maximally effective insulin concentration) were markedly decreased, indicating both a receptor and a postreceptor defect. On the other hand, four obese patients had right-shifted dose-response curves but reached normal maximal glucose disposal rates, consistent with decreased insulin receptors as the only abnormality. When the individual data were analyzed, it was found that the lease hyperinsulinemic, least insulin-resistant patients displayed only the receptor defect, whereas those with the greatest hyperinsulinemia exhibited the largest post-receptor defect, suggesting a continuous spectrum of defects as one advances from mild to severe insulin resistance. When insulin's ability to suppress hepatic glucose output was assessed, hyperinsulinemia produced total suppresssion in all subjects. The dose-response curve for the obese subjects was shifted to the right, indicating a defect in insulin receptors. Insulin binding to isolated adipocytes obtained from the obese subjects was decreased, and a highly significant inverse linear relationship was demonstrated between insulin binding and the serum insulin concentration required for halfmaximal stimulation of glucose disposal. (a) decreased cellular insulin receptors contribute to the insulin resistance associated with human obesity in all subjects; (b) in the least hyperinsulinemic, insulin-resistant patients, decreased insulin receptors are the sole defect, whereas in the more hyperinsulinemic, insulin-resistant patients, the insulin resistance is the result of a combination of receptor and postreceptor abnormalities; (c) all obese patients were insensitive to insulin's suppressive effects on hepatic glucose output; this was entirely the result of decreased insulin receptors; no postreceptor defect in this insulin effect was demonstrated.


Composite analysis of immunological and metabolic markers defines novel subtypes of triple negative breast cancer.
Cancer biology is influenced by the tumor microenvironment, which impacts disease prognosis and therapeutic interventions. The inter-relationship of tumor-infiltrating lymphocytes, immune response regulators, and a glycolytic tumor environment was evaluated in a cohort of 183 largely consecutive patients with triple negative breast cancer diagnosis. High levels of tumor-infiltrating lymphocytes were associated with improved survival of triple negative breast cancer cases. However, elevated levels of PD-L1, CD163, and FOXP3 were individually associated with significantly decreased overall survival. These three determinants were significantly correlated, and could serve to differentiate the prognostic significance of tumor-infiltrating lymphocytes. Interestingly, a glycolytic tumor environment, as determined by the expression of MCT4 in the tumor stroma, was associated with the immune evasive environment and poor prognosis. Clustering of all markers defined four distinct triple negative breast cancer subtypes that harbored prognostic significance in multivariate analysis. Immune and metabolic markers stratified triple negative breast cancer into subtypes that have prognostic significance and implications for therapies targeting immune checkpoints and tumor metabolism.


Mapping Protein-DNA Interactions Using ChIP-exo and Illumina-Based Sequencing.
Chromatin immunoprecipitation (ChIP) provides a means of enriching DNA associated with transcription factors, histone modifications, and indeed any other proteins for which suitably characterized antibodies are available. Over the years, sequence detection has progressed from quantitative real-time PCR and Southern blotting to microarrays (ChIP-chip) and now high-throughput sequencing (ChIP-seq). This progression has vastly increased the sequence coverage and data volumes generated. This in turn has enabled informaticians to predict the identity of multi-protein complexes on DNA based on the overrepresentation of sequence motifs in DNA enriched by ChIP with a single antibody against a single protein. In the course of the development of high-throughput sequencing, little has changed in the ChIP methodology until recently. In the last three years, a number of modifications have been made to the ChIP protocol with the goal of enhancing the sensitivity of the method and further reducing the levels of nonspecific background sequences in ChIPped samples. In this chapter, we provide a brief commentary on these methodological changes and describe a detailed ChIP-exo method able to generate narrower peaks and greater peak coverage from ChIPped material.


Future research directions in multiple sclerosis therapies.
The success of presently available injectable immunomodulatory therapies in treating multiple sclerosis has led to heightened interest in finding even more efficacious and better tolerated therapies. Several oral agents have shown efficacy in phase-II clinical trials and are now entering phase-III pivotal trials. In addition, monoclonal antibodies targeting surface receptors on various cells of the peripheral immune system have also shown efficacy in early studies and will soon be entering phase III. All of these approaches target immune molecules that are not specific for multiple sclerosis (MS) and carry inherent risk of infection and systemic side effects. Novel immunotherapies in preclinical or phases I to IIa testing are attempting to more selectively target pathogenic effector cells and thereby block abnormal immune cell activation without compromising normal healthy immune responses. The induction of tolerance to self-proteins continues to be a goal of MS immunotherapy, but as yet has not been accomplished outside of the laboratory. There is increasing awareness of the need to understand and modulate nonclassical immune targets as well as central nervous system degenerative processes. The roles of vitamins, antimicrobials, and hormones continue to be studied. The mechanisms of neurodegeneration in MS are likely multifactorial and include direct damage by T cells and humoral immunity as well as oxidative stress, glutamate-mediated excitotoxicity, and neuronal and oligodendrocyte apoptosis. Neuroprotective drugs that were once only considered for classical degenerative diseases, such as amyotrophic lateral sclerosis and Parkinson's disease, are now being considered in MS.