Systematic evaluation of "compliance" to prescribed treatment medications and "abstinence" from psychoactive drug abuse in chemical dependence programs: data from the comprehensive analysis of reported drugs.
This is the first quantitative analysis of data from urine drug tests for compliance to treatment medications and abstinence from drug abuse across "levels of care" in six eastern states of America. Comprehensive Analysis of Reported Drugs (CARD) data was used in this post-hoc retrospective observational study from 10,570 patients, filtered to include a total of 2,919 patients prescribed at least one treatment medication during 2010 and 2011. The first and last urine samples (5,838 specimens) were analyzed; compliance to treatment medications and abstinence from drugs of abuse supported treatment effectiveness for many. Compared to non-compliant patients, compliant patients were marginally less likely to abuse opioids, cannabinoids, and ethanol during treatment although more likely to abuse benzodiazepines. Almost 17% of the non-abstinent patients used benzodiazepines, 15% used opiates, and 10% used cocaine during treatment. Compliance was significantly higher in residential than in the non-residential treatment facilities. Independent of level of care, 67.2% of the patients (n = 1963; P<.001) had every treatment medication found in both first and last urine specimens (compliance). In addition, 39.2% of the patients (n = 1143; P<.001) had no substance of abuse detected in either the first or last urine samples (abstinence). Moreover, in 2010, 16.9% of the patients (n = 57) were abstinent at first but not at last urine (deteriorating abstinence), the percentage dropped to 13.3% (n = 174) in 2011; this improvement over years was statistically significant. A longitudinal analysis for abstinence and compliance was studied in a randomized subset from 2011, (n = 511) representing 17.5% of the total cohort. A statistically significant upward trend (p = 2.353×10-8) of abstinence rates as well as a similar but stronger trend for compliance ((p = 2.200×10-16) was found. Being cognizant of the trend toward drug urine testing being linked to medical necessity eliminating abusive screening, the interpretation of these valuable results require further intensive investigation.


Atmospheric radiometry at submillimeter wavelengths.
The paper considers the application of broadband emission radiometry in the submillimeter (very far infrared) spectral region for studies of stratospheric water vapor. The detailed spectroscopy of the region is discussed and the effects of spectral contamination due to emission lines of other constituents, notably O(3) and O(2), and to a lesser extent N(2), are determined quantitatively. The O(3) lines arise through electric dipole transitions, the O(2) lines through magnetic dipole transitions, and the N(2) emission results from collision-induced electric dipole effects. Under certain circumstances, emission from these other species can represent a significant fraction of that due to H(2)O itself; it must either be corrected for rather carefully or eliminated in the design of the instrument.


Vortex gas lens.
A vortex gas lens concept is presented. Such a lens has a potential power density capability of 10(9)-10(10) w/cm(2). An experimental prototype was constructed and the divergence half angle of the exiting beam was measured as a function of the lens operating parameters. Reasonably good agreement is found between the experimental results and theoretical calculations. The expanded beam was observed to be steady, and no strong, potentially beam-degrading jets were found to issue from the ends of the lens. Estimates of random beam deflection angles to be expected due to boundary layer noise are presented; these angles are very small.


Proteomics Pipeline for Identifying Variant Proteins in Plasmodium falciparum Parasites Isolated from Children Presenting with Malaria.
Plasmodium falciparum variant antigens named erythrocyte membrane protein 1 (PfEMP1) are important targets for developing a protective immunity to malaria caused by P. falciparum. One of the major challenges in P. falciparum proteomics studies is identifying PfEMP1s at the protein level due to antigenic variation. To identify these PfEMP1s using shotgun proteomics, we developed a pipeline that searches high-resolution mass spectrometry spectra against a custom protein sequence database. A local alignment algorithm, LAX, was developed as a part of the pipeline that matches peptide sequences to the most similar PfEMP1 and calculates a weight value based on peptide's uniqueness used for PfEMP1 protein inference. The pipeline was first validated in the analysis of a laboratory strain with a known PfEMP1, then it was implemented on the analysis of parasite isolates from malaria-infected pregnant women and finally on the analysis of parasite isolates from malaria-infected children where there was an increase of PfEMP1s identified in 27 out of 31 isolates using the expanded database.


Depression in pregnancy and the postpartum period: balancing adverse effects of untreated illness with treatment risks.
The author reviews the risks and benefits of untreated maternal depression during pregnancy and the postnatal period and its effects on the well-being of the mother and infant. She then discusses the significant role psychiatrists can play in detecting and managing maternal depression as a primary measure for preventing future child psychopathology. A literature search was conducted on PubMed to identify both preclinical and clinical studies concerning deleterious effects of maternal depression on offspring. Additional searches focused on available safety data concerning the use of antidepressants during pregnancy and lactation. Key search items included depression during pregnancy, postpartum depression, lactation, and antidepressants. Burgeoning evidence was found concerning the adverse effects of maternal depression on the developing fetus and infant in the perinatal period. No controlled studies on the safety of antidepressant use in pregnancy and lactation were found; therefore, case reports, and some retrospective and prospective case series, must serve as guidelines for the treating clinician. Each case of maternal depression needs to be evaluated on an individual basis and decisions about treatment interventions should involve both the patient and family. Maternal depression during pregnancy and the postnatal period is associated with a significant disease burden in that it affects not only the mother but may also have both short- and long-term effects on offspring. Therefore, early detection and management of maternal depression, of which perinatal screening of mothers is an important component, are warranted.


Drug development in oncology: a regulatory perspective.
The ultimate goal of any drug development, including that in oncology, is to register the new medicinal product. A number of challenges remain in this field, primarily in demonstrating the efficacy of the new oncology products to the satisfaction of the regulatory authorities worldwide. Key aspects of clinical trial design, conduct, and analysis that require careful consideration by the sponsors before initiation of drug development programs in oncology include the choice of primary and secondary end points, the choice of comparators, the necessity for independent radiologic review of a disease-related end point such as progression-free survival and tumor response, and the relative value of the independently reviewed and investigator-assessed clinical end points. Many of these aspects, including the choice of comparators and choice of primary/secondary end points, may have a crucial impact on both the eventual registrability of the new medicine and on the feasibility of conducting the clinical trials in the first place. Although both the industry and the regulators share a common goal of developing promising new oncology products that make a tangible contribution to the care of patients with cancer, more harmonized expectations for "proof of efficacy" and more pragmatic, clinically driven decision-making approaches from regulatory authorities would go a long way in making oncology drug development process less fraught with uncertainties and will result in a more efficient path from clinical trials to the clinic for new medicines. An open dialogue and greater collaboration between the industry and the regulators may help in achieving clarity around these goals and in bringing these to fruition.


Environmental and social benefits of the targeted intraoperative radiotherapy for breast cancer: data from UK TARGIT-A trial centres and two UK NHS hospitals offering TARGIT IORT.
To quantify the journeys and CO2 emissions if women with breast cancer are treated with risk-adapted single-dose targeted intraoperative radiotherapy (TARGIT) rather than several weeks' course of external beam whole breast radiotherapy (EBRT) treatment. (1) TARGIT-A randomised clinical trial (ISRCTN34086741) which compared TARGIT with traditional EBRT and found similar breast cancer control, particularly when TARGIT was given simultaneously with lumpectomy, (2) 2 additional UK centres offering TARGIT. 485 UK patients (249 TARGIT, 236 EBRT) in the prepathology stratum of TARGIT-A trial (where randomisation occurred before lumpectomy and TARGIT was delivered simultaneously with lumpectomy) for whom geographical data were available and 22 patients treated with TARGIT after completion of the TARGIT-A trial in 2 additional UK breast centres. The shortest total journey distance, time and CO2 emissions from home to hospital to receive all the fractions of radiotherapy. Distances, time and CO2 emissions were calculated using Google Maps and assuming a fuel efficiency of 40 mpg. The groups were compared using the Student t test with unequal variance and the non-parametric Wilcoxon rank-sum (Mann-Whitney) test. TARGIT patients travelled significantly fewer miles: TARGIT 21 681, mean 87.1 (SE 19.1) versus EBRT 92 591, mean 392.3 (SE 30.2); had lower CO2 emissions 24.7 kg (SE 5.4) vs 111 kg (SE 8.6) and spent less time travelling: 3 h (SE 0.53) vs 14 h (SE 0.76), all p<0.0001. Patients treated with TARGIT in 2 hospitals in semirural locations were spared much longer journeys (753 miles, 30 h, 215 kg CO2 per patient). The use of TARGIT intraoperative radiotherapy for eligible patients with breast cancer significantly reduces their journeys for treatment and has environmental benefits. If widely available, 5 million miles (8 000 000 km) of travel, 170 000 woman-hours and 1200 tonnes of CO2 (a forest of 100 hectares) will be saved annually in the UK. ISRCTN34086741; Post-results.


Antigenicity and immunogenicity of transmitted/founder, consensus, and chronic envelope glycoproteins of human immunodeficiency virus type 1.
Human immunodeficiency virus type 1 (HIV-1) vaccine development requires selection of appropriate envelope (Env) immunogens. Twenty HIV-1 Env glycoproteins were examined for their ability to bind human anti-HIV-1 monoclonal antibodies (MAbs) and then used as immunogens in guinea pigs to identify promising immunogens. These included five Envs derived from chronically infected individuals, each representing one of five common clades and eight consensus Envs based on these five clades, as well as the consensus of the entire HIV-1 M group, and seven transmitted/founder (T/F) Envs from clades B and C. Sera from immunized guinea pigs were tested for neutralizing activity using 36 HIV-1 Env-pseudotyped viruses. All Envs bound to CD4 binding site, membrane-proximal, and V1/V2 MAbs with similar apparent affinities, although the T/F Envs bound with higher affinity to the MAb 17b, a CCR5 coreceptor binding site antibody. However, the various Envs differed in their ability to induce neutralizing antibodies. Consensus Envs elicited the most potent responses, but neutralized only a subset of viruses, including mostly easy-to-neutralize tier 1 and some more-difficult-to-neutralize tier 2 viruses. T/F Envs elicited fewer potent neutralizing antibodies but exhibited greater breadth than chronic or consensus Envs. Finally, chronic Envs elicited the lowest level and most limited breadth of neutralizing antibodies overall. Thus, each group of Env immunogens elicited a different antibody response profile. The complementary benefits of consensus and T/F Env immunogens raise the possibility that vaccines utilizing a combination of consensus and T/F Envs may be able to induce neutralizing responses with greater breadth and potency than single Env immunogens.


Structural features of caspase-activating complexes.
Apoptosis, also called programmed cell death, is an orderly cellular suicide program that is critical for the development, immune regulation and homeostasis of a multi-cellular organism. Failure to control this process can lead to serious human diseases, including many types of cancer, neurodegenerative diseases, and autoimmununity. The process of apoptosis is mediated by the sequential activation of caspases, which are cysteine proteases. Initiator caspases, such as caspase-2, -8, -9, and -10, are activated by formation of caspase-activating complexes, which function as a platform to recruit caspases, providing proximity for self-activation. Well-known initiator caspase-activating complexes include (1) DISC (Death Inducing Signaling Complex), which activates caspases-8 and 10; (2) Apoptosome, which activates caspase-9; and (3) PIDDosome, which activates caspase-2. Because of the fundamental biological importance of capases, many structural and biochemical studies to understand the molecular basis of assembly mechanism of caspase-activating complexes have been performed. In this review, we summarize previous studies that have examined the structural and biochemical features of caspase-activating complexes. By analyzing the structural basis for the assembly mechanism of the caspase-activating complex, we hope to provide a comprehensive understanding of caspase activation by these important oligomeric complexes.


Grief symptoms and primary care use: a prospective study of family caregivers.
Family caregivers to patients who are severely ill have high use of primary health care and psychotropic medication. However, it remains sparsely investigated whether healthcare services target the most vulnerable caregivers. This study aimed to examine associations between family caregivers' grief trajectories of persistent high-grief symptom level (high-grief trajectory) versus persistent low-grief symptom level (low-grief trajectory), as well as early contacts with GPs or psychologists and the use of psychotropic medication. A population-based cohort study of family caregivers (n = 1735) in Denmark was undertaken. The Prolonged Grief-13 (PG-13) scale measured family caregivers' grief symptoms at inclusion (during the patient's terminal illness), 6 months after bereavement, and 3 years after bereavement. Multinomial regression was used to analyse register-based information on GP consultations, psychologist sessions, and psychotropic medication prescriptions in the 6 months before inclusion. A total of 1447 (83.4%) family caregivers contacted their GP, and 91.6% of participants in the high-grief trajectory had GP contact. Compared with family caregivers in the low-grief trajectory, family caregivers in the high-grief trajectory had ≥4 face-to-face GP consultations (odds ratio [OR] = 2.6; 95% confidence interval [CI] = 1.3 to 5.0), more GP talk therapy (OR =4.4; 95% CI = 1.9 to 10.0), and more psychotropic medication, but not significantly more psychologist sessions (OR = 1.7; 95% CI = 0.5 to 6.6). Family caregivers in the high-grief trajectory had more contact with their GP, but their persisting grief symptoms suggest that primary care interventions for family caregivers should be optimised. Future research is warranted in such interventions and in the referral patterns to specialised mental health care.


Subcellular probes for neurochemical recording from multiple brain sites.
Dysregulation of neurochemicals, in particular, dopamine, is epitomized in numerous debilitating disorders that impair normal movement and mood aspects of our everyday behavior. Neurochemical transmission is a neuron-specific process, and further exhibits region-specific signaling in the brain. Tools are needed to monitor the heterogeneous spatiotemporal dynamics of dopamine neurotransmission without compromising the physiological processes of the neuronal environment. We developed neurochemical probes that are ten times smaller than any existing dopamine sensor, based on the size of the entire implanted shaft and its sensing tip. The microfabricated probe occupies a spatial footprint (9 μm) coordinate with the average size of individual neuronal cells (∼10 μm). These cellular-scale probes were shown to reduce inflammatory response of the implanted brain tissue environment. The probes are further configured in the form of a microarray to permit electrochemical sampling of dopamine and other neurotransmitters at unprecedented spatial densities and distributions. Dopamine recording was performed concurrently from up to 16 sites in the striatum of rats, revealing a remarkable spatiotemporal contrast in dopamine transmission as well as site-specific pharmacological modulation. Collectively, the reported platform endeavors to enable high density mapping of the chemical messengers fundamentally involved in neuronal communication through the use of minimally invasive probes that help preserve the neuronal viability of the implant environment.


Client Violence Against Youth Care Workers: Findings of an Exploratory Study of Workforce Issues in Residential Treatment.
Residential treatment centers (RTCs) for youth are plagued by high turnover of youth care workers who provide round-the-clock treatment and supervision to youth with severe affective and behavioral problems. This article presents findings from a 15-month ethnographic study of workforce issues in one RTC related to youth care workers' exposure to client violence (CV). Findings are based on 65 semistructured interviews and 490 hours of participant observation with consenting employees. Participants reported CV incidents, including punching, kicking, biting, hair pulling, choking, threats or assaults with a weapon, and other physical and sexualized violence. Workers viewed CV as an inevitable aspect of youth care work that could be reduced-though not eliminated-through proper use of de-escalation and behavior management techniques. Participants reported that exposure to CV sometimes resulted in serious physical injury and/or missed work, as well as substance abuse, anxiety, sleep disturbance, and memory loss. Participants reported that CV was the most difficult part of their jobs and cited it as a reason for leaving or wishing to leave youth care work. We conceptualize youth care workers in RTCs as a vulnerable class whose biopsychosocial well-being must be protected to better serve the vulnerable youth in their care. To that end, we suggest directions for future research on CV in residential treatment and propose measures RTCs can take immediately to better understand and prevent CV in their organizations.


Changing histologic spectrum of adult nephrotic syndrome over five decades in north India: A single center experience.
Glomerular diseases are an important cause of chronic renal failure in developing countries. The spectrum of diseases causing nephrotic syndrome is changing globally in the last few decades. The aim of this prospective study was to look at this spectrum at a tertiary care center in North India and to analyze the changing trends over the last five decades. Patients in the age group 18-60 years with nephrotic syndrome were consecutively included in the study. Renal biopsies were performed in all patients and were subjected to light microscopy, immunofluorescence (IF) and electron microscopy (EM). While the IF was performed in 78% of cases, EM was available in one-fourth of cases. During 2002-2007, 364 patients (60.2% males) were included in the study. The mean age was 31.5 years. Primary glomerular diseases accounted for 89% of cases while lupus nephritis was the most common secondary glomerular disease. Focal segmental glomerulosclerosis (FSGS) accounted for 30.6% of primary glomerular diseases making it the most common cause of nephrotic syndrome. It was followed by membranous glomerulonephritis (MGN) in 24.4%, mesangiocapillary glomerulonephritis in 17.9% and minimal change disease in 14.8%. In the age group >40 years, MGN was the most common lesion (32.5%) followed by FSGS (27.7%). Over the last five decades, there was a nearly five-fold increase in the incidence of FSGS, 3-fold increase in MGN and a 10-fold reduction in diffuse proliferative glomerulonephritis while there was no major change in incidence of other diseases. The biopsy diagnosis of FSGS has increased considerably in last few decades and it is now the most common cause of nephrotic syndrome in adults in North India. MGN is the most common lesion in patients over 40 years of age.


Alcohol based tissue fixation as an alternative for formaldehyde: influence on immunohistochemistry.
Formaldehyde is commonly used in histopathology to fix tissue. Not only are the carcinogenic properties of this solution a hazard to the people in the workplace, it is also a major burden on the environment, and it crosslinks molecular groups that hinder immunohistochemistry. The influence of two new alcohol based non-crosslinking fixatives on immunohistochemical staining properties was tested on various tissues. Fresh tissue samples were cut into three equal pieces, which were then fixed in the alcohol based fixatives Boonfix or RCL2, or in neutral buffered formaldehyde (NBF) as control. After fixation, tissue was routinely processed to paraffin sections. Deparaffinised slides were blocked for endogenous peroxidase and subsequently submitted to the usual NBF based immunohistochemical protocols for 85 different common antibodies either not requiring antigen retrieval (AR), or AR in citrate buffer, EDTA or pepsin. NBF fixed tissues provided significantly better immunostaining results (84% good staining) than RCL2 (66% good) and Boonfix (60%). The lesser performance of RCL2 and Boonfix was especially caused by pepsin AR which caused significant tissue damage. Omission of pepsin AR resulted in better immunostaining for these antibodies for RCL2 fixed tissues which were overall no longer significantly worse than NBF fixed tissue. Tissues fixed in non-crosslinking alcohol based fixatives can successfully be immunohistochemically stained for most antibodies following the usual NBF based protocols. Omission of pepsin pretreatment seems to be important to retain proper morphology of immunostained tissues preserved in alcohol based fixatives. Therefore, when switching to less toxic and non-carcinogenic alcohol-based fixatives like RCL2, no major changes in the daily routine of immunohistochemistry are anticipated.


Chronic heart failure due to severe endocardiosis in a Gambian giant pouched rat (Cricetomys gambianus).
A 1.5-yr-old captive male Gambian giant pouched rat (Cricetomys gambianus) died after suffering from anorexia, weakness, and dyspnea for 3 wk. Thoracic radiographs of thorax and abdomen and computed tomography showed a severe biventricular enlargement of the heart and a moderate hepatomegaly. Necropsy revealed a severe, bilateral hypertrophic cardiomyopathy and dilation of the right ventricle due to multifocal bilateral, valvular endocardiosis of all atrioventricular valves and acute hepatic congestion. Histologically, the atrioventricular valves were multifocally thickened by a marked endocardiosis with stromal accumulation of Periodic acid-Schiff (PAS)-positive, mucinous material. Although common in dogs, endocardiosis has not been described in Nesomyidaes. As in other affected species, the pathogenesis of endocardiosis in this species remains unclear.


Influence of proximal box elevation on the marginal quality and fracture behavior of root-filled molars restored with CAD/CAM ceramic or composite onlays.
This study investigated the influence of proximal box elevation (PBE) with composite resin when applied to deep proximal defects in root-filled molars with mesio-occluso-distal (MOD) cavities, which were subsequently restored with computer-aided designed/computer-aided manufacturing (CAD/CAM) ceramic or composite restorations. Root canal treatment was performed on 48 human mandibular molars. Standardized MOD cavities were prepared with the distal box located 2 mm below the cemento-enamel junction (CEJ). The teeth were randomly assigned to one of four experimental groups (n = 12). In groups G1 and G2, the distal proximal box was elevated up to the level of the CEJ with composite resin (PBE). No elevation was performed in the remaining two groups (G3, G4). CAD/CAM restorations were fabricated with feldspathic ceramic (Vita Mark II, CER) in groups G1 (PBE-CER) and G3 (CER) or with resin nano-ceramic blocks (Lava Ultimate, LAV) in groups G2 (PBE-LAV) and G4 (LAV). Replicas were taken before and after thermomechanical loading (TML; 1.2 Mio cycles; 49 N; 3,000 thermocycles between 50 °C and 5 °C). Following TML, load was applied until failure. Fracture analysis was performed under a stereomicroscope (×16). Marginal quality before and after TML (tooth restoration, composite restoration) was evaluated using scanning electron microscopy (×200). After TML, lower percentages of continuous margins were observed in groups G1-G3 compared with pre-TML assessments; however, the differences were not statistically significant. For group G4-LAV, the marginal quality after TML was significantly better than in any other group. The highest mean fracture value was recorded for group G4. No significant difference was found for this value between the groups with PBE compared with the groups without PBE, regardless of the material used. The specimens restored with ceramic onlays exhibited fractures that were mainly restricted to the restoration while, in teeth restored with composite onlays, the percentage of catastrophic failures (fractures beyond bone level) was increased. PBE had no impact on either the marginal integrity or the fracture behavior of root canal-treated mandibular molars restored with feldspathic ceramic onlays. CAD/CAM-fabricated composite onlays were more favorable than ceramic onlays in terms of both marginal quality and fracture resistance, particularly in specimens without PBE. Composite onlays with or without PBE may be a viable approach for the restoration of root-filled molars with subgingival MOD cavities.


Microbial fuel cells and microbial ecology: applications in ruminant health and production research.
Microbial fuel cell (MFC) systems employ the catalytic activity of microbes to produce electricity from the oxidation of organic, and in some cases inorganic, substrates. MFC systems have been primarily explored for their use in bioremediation and bioenergy applications; however, these systems also offer a unique strategy for the cultivation of synergistic microbial communities. It has been hypothesized that the mechanism(s) of microbial electron transfer that enable electricity production in MFCs may be a cooperative strategy within mixed microbial consortia that is associated with, or is an alternative to, interspecies hydrogen (H(2)) transfer. Microbial fermentation processes and methanogenesis in ruminant animals are highly dependent on the consumption and production of H(2)in the rumen. Given the crucial role that H(2) plays in ruminant digestion, it is desirable to understand the microbial relationships that control H(2) partial pressures within the rumen; MFCs may serve as unique tools for studying this complex ecological system. Further, MFC systems offer a novel approach to studying biofilms that form under different redox conditions and may be applied to achieve a greater understanding of how microbial biofilms impact animal health. Here, we present a brief summary of the efforts made towards understanding rumen microbial ecology, microbial biofilms related to animal health, and how MFCs may be further applied in ruminant research.


Young-onset frontotemporal dementia with FUS pathology.
Frontotemporal dementia (FTD) is an uncommon cause of behavioural change in adults under the age of 50. A 44-year-old man presented with progressive neuropsychiatric disturbance characterised by social withdrawal, apathy, loss of empathy, motor stereotypies and hyperorality. Cognitive testing identified severe impairment, including executive dysfunction. MR scan of the brain showed bilateral symmetrical frontal atrophy. There was no relevant family history, and targeted genetic testing for FTD-associated variants in MAPT, GRN and C9orf72 genes proved negative. He became more withdrawn with disinhibited behaviour; his condition progressively worsened and he died 6 years later. The pathological diagnosis was frontotemporal lobar degeneration with fused-in-sarcoma (FUS) pathology, a rare sporadic cause of FTD, accounting for only 5%-10% of cases, its characteristic features including very young onset, motor stereotypies and hyperorality.


[Activity of daptomycin, ciprofloxacin, clindamycin and cotrimoxazole against coagulase-negative Staphylococcus strains with diminished susceptibility to vancomycin].
Coagulase Negative Staphylococci (CNS) have become one of the most common nosocomial pathogens and it has a high mortality rate due to the increased of seriously ill patients survival, long states immunosuppression and presence of foreign bodies, such as catheters, prostheses, pacemakers, etc. In addition, there is a significant increase in resistance to antimicrobial drugs, especially beta-lactams, and the increase in the MIC for vancomycin leads to a loss of clinical efficacy. This necessitates the search for new therapeutic alternatives, such as daptomycin. The aim of this paper is to study the activity of daptomycin, ciprofloxacin, clindamycin and cotrimoxazole in two groups of clinically significant CNS: a MIC₉₀with vancomycin ≤ 1 mg/L and the other with MIC₉₀ 2 mg/L. We identified and studied MIC₉₀ to ciprofloxacin, clindamycin and cotrimoxazole from 54 strains of clinically significant by the CNS Combo 22 Microscan panels (Dade Behring, Siemens). The MIC₉₀for daptomycin was performed using Etest (AB BioMérieux, Solna, Sweden) on Mueller Hinton plates (BioMérieux, France). In Group I (vancomycin MIC₉₀ ≤ 1 mg/L) were 19 strains whereas in Group II (vancomycin MIC₉₀ =2 mg/L) were 35 strains. Expressed in mg/L, MIC₉₀ ranges for daptomycin were 0.047-0.5 in Group I and 0.064-0.5 in Group II. for ciprofloxacin were 8 sensitive strains and 11 resistant in Group I and 10 sensitive and 25 resistant in Group II. For clindamycin were 7 sensitive strains and 12 resistant in Group I and 16 sensitive and 19 resistant in Group II. Finally, for cotrimoxazole were 10 sensitive strains and 9 resistant in Group I and 19 sensitive and 16 resistant in Group II. The MIC levels to daptomycin were not influenced by the increase in the MIC for vancomycin. There was no statistically significant difference for the sensitivity of ciprofloxacin between the two groups of vancomycin. Regardless of vancomycin, there were a clear relationship between the sensitivity of ciprofloxacin with clindamycin and cotrimoxazole.


Calpain activation causes a proteasome-dependent increase in protein degradation and inhibits the Akt signalling pathway in rat diaphragm muscle.
The role of the calpain proteases in skeletal muscle atrophy is poorly understood. One goal of these experiments was to clarify whether calpains act upstream of the ubiquitin-proteasome pathway (UPP). Calpain activation may also inhibit the anabolic signalling of Akt, since a molecular chaperone previously shown to mediate Akt activity, heat shock protein 90 (HSP 90), is a calpain substrate. Thus, an additional objective was to determine whether calpain activation affects the Akt signalling pathway. Ex vivo experiments were conducted using isolated rat diaphragm muscle. Calpain activation increased total protein degradation by 65%. Proteasome inhibition prevented this large rise in proteolysis, demonstrating that the proteasome was necessary for calpain-activated protein degradation. In addition, calpain activation increased proteasome-dependent proteolysis by 144%, further supporting the idea of sequential proteolytic pathways. Calpain reduced Akt and mammalian target of rapamycin (mTOR) phosphorylation by 35 and 50%, respectively, and activated glycogen synthase kinase-3 beta (GSK-3beta) by 40%. Additionally, calpain activation reduced HSP 90beta and mTOR protein content by 33 and 50%, respectively. These data suggest that calpains play a dual role in protein metabolism by concomitantly activating proteasome-dependent proteolysis and inhibiting the Akt pathway of protein synthesis.


Transcatheter Aortic Valve Implantation for Failed Surgical Aortic Bioprostheses Using a Self-Expanding Device (from the Prospective VIVA Post Market Study).
Patients with symptomatic aortic stenosis are often treated with a surgical valve replacement. Surgical bioprosthetic valves degenerate over time and therefore may necessitate a redo surgery. This analysis reports the 2-year clinical outcomes of the Valve-in-Valve study, which evaluated transcatheter aortic valve implantation using the CoreValve and Evolut R devices in patients with degenerated surgical aortic bioprostheses at high risk for surgery. The prospective Valve-in-Valve study enrolled 202 eligible patients with failing surgical aortic bioprostheses due to stenosis, regurgitation, or a combination of both. The Evolut R bioprosthesis was used in 90.5% of valve-in-valve transcatheter aortic valve implantation cases. Two-year all-cause and cardiovascular mortality rates were 16.5% and 11.1%, respectively. Other clinical events included stroke (7.9%), disabling stroke (1.7%), and new pacemaker implantation (10.1%). The 2-year all-cause mortality rate was significantly higher in patients with discharge mean gradients ≥20 mmHg vs. those with lower mean gradients (21.0% vs 7.6%, p = 0.025). Discharge mean gradients ≥20 mm Hg were associated with smaller surgical bioprostheses (OR, 7.2 [95% CI 2.3 to 22.1]. In patients with failing surgical aortic bioprostheses, valve-in-valve treatment using a supra-annular self-expanding bioprosthesis provides significant functional improvements with acceptable rates of complications, especially if a postprocedural mean gradient of <20 mmHg can be achieved.


Evaluation of a novel electronic genetic screening and clinical decision support tool in prenatal clinical settings.
"The Pregnancy and Health Profile" (PHP) is a free prenatal genetic screening and clinical decision support (CDS) software tool for prenatal providers. PHP collects family health history (FHH) during intake and provides point-of-care risk assessment for providers and education for patients. This pilot study evaluated patient and provider responses to PHP and effects of using PHP in practice. PHP was implemented in four clinics. Surveys assessed provider confidence and knowledge and patient and provider satisfaction with PHP. Data on the implementation process were obtained through semi-structured interviews with administrators. Quantitative survey data were analyzed using Chi square test, Fisher's exact test, paired t tests, and multivariate logistic regression. Open-ended survey questions and interviews were analyzed using qualitative thematic analysis. Of the 83% (513/618) of patients that provided feedback, 97% felt PHP was easy to use and 98% easy to understand. Thirty percent (21/71) of participating physicians completed both pre- and post-implementation feedback surveys [13 obstetricians (OBs) and 8 family medicine physicians (FPs)]. Confidence in managing genetic risks significantly improved for OBs on 2/6 measures (p values ≤0.001) but not for FPs. Physician knowledge did not significantly change. Providers reported value in added patient engagement and reported mixed feedback about the CDS report. We identified key steps, resources, and staff support required to implement PHP in a clinical setting. To our knowledge, this study is the first to report on the integration of patient-completed, electronically captured and CDS-enabled FHH software into primary prenatal practice. PHP is acceptable to patients and providers. Key to successful implementation in the future will be customization options and interoperability with electronic health records.


Protection from cerebral ischemia by brain cooling without reduced lactate accumulation in dogs.
Hypothermia protects tissue function in ischemia. This study determined if selective brain cooling inhibits cerebral cortical lactate accumulation and thus accounts for imporved neurologic outcome after complete cerebral ischemia in dogs. The brain was selectively cooled (hippocampal temperature 33 degrees C) by nasal lavage with water at 5 degrees C. Control dogs received nasal lavage with water at 39 degrees C. Mean +/- SEM rectal temperature in both groups was 39 +/- 1 degree C prior to ischemia. Selective brain cooling before and during 10 minutes of cardiac arrest was associated with significantly improved neurologic function and 100% survival, whereas normothermic cardiac arrest produced marked neurologic dysfunction and 100% mortality. Cerebral cortical lactate accumulation was measured in a complementary series of dogs exposed to the same two treatments but with the addition of six cerebral cortical brain biopsies taken before, during, and immediately after cardiac arrest. Brain and rectal temperatures of dogs in the brain biopsy protocol were similar to those of dogs in the recovery protocol. There was no difference detected in cerebral lactate accumulation during ischemia between brain-cooled and control dogs. Thus, reduction in cortical brain lactate during ischemia cannot account for the postischemic functional protection afforded by preischemic selective brain cooling.


Importance of myeloid dendritic cells in persistent airway disease after repeated allergen exposure.
There is conflicting information about the development and resolution of airway inflammation and airway hyperresponsiveness (AHR) after repeated airway exposure to allergen in sensitized mice. Sensitized BALB/c and C57BL/6 mice were exposed to repeated allergen challenge on 3, 7, or 11 occasions. Airway function in response to inhaled methacholine was monitored; bronchoalveolar lavage fluid inflammatory cells were counted; and goblet cell metaplasia, peribronchial fibrosis, and smooth muscle hypertrophy were quantitated on tissue sections. Bone marrow-derived dendritic cells were generated after differentiation of bone marrow cells in the presence of growth factors. Sensitization to ovalbumin (OVA) in alum, followed by three airway exposures to OVA, induced lung eosinophilia, goblet cell metaplasia, mild peribronchial fibrosis, and peribronchial smooth muscle hypertrophy; increased levels of interleukin (IL)-4, IL-5, IL-13, granulocyte-macrophage colony-stimulating factor, transforming growth factor-beta(1), eotaxin-1, RANTES (regulated on activation, normal T-cell expressed and secreted), and OVA-specific IgG1 and IgE; and resulted in AHR. After seven airway challenges, development of AHR was markedly decreased as was the production of IL-4, IL-5, and IL-13. Levels of IL-10 in both strains and the level of IL-12 in BALB/c mice increased. After 11 challenges, airway eosinophilia and peribronchial fibrosis further declined and the cytokine and chemokine profiles continued to change. At this time point, the number of myeloid dendritic cells and expression of CD80 and CD86 in lungs were decreased compared with three challenges. After 11 challenges, intratracheal instillation of bone marrow-derived dendritic cells restored AHR and airway eosinophilia. These data suggest that repeated allergen exposure leads to progressive decreases in AHR and allergic inflammation, through decreases in myeloid dendritic cell numbers.


Association of vitamin D binding protein variants with susceptibility to chronic obstructive pulmonary disease.
Chronic obstructive pulmonary disease (COPD) is characterized by chronic airflow limitation and it is thought that neutrophils play a major role in the disease pathogenesis. Genetic polymorphism of the vitamin-D-binding protein (VDBP) gene is considered one of the candidates for variation in susceptibility to COPD. To evaluate the potential influences of VDBP gene polymorphisms on COPD, a case-control study was conducted in the Han population of north-east China. The VDBP polymorphic site was genotyped in 100 COPD patients and 100 controls. Genotypes were determined by polymerase chain reaction-restriction fragment length polymorphism. A significantly higher proportion of VDBP-1F homozygosity was found in COPD patients, while the frequency of VDBP-2 homozygosity was significantly lower in COPD patients, which seemed to suggest that VDBP-2 homozygocity provided a protective effect. These data suggest that the VDBP gene may be involved in COPD susceptibility in Chinese Han population.


Hsp27 Inhibition with OGX-427 Sensitizes Non-Small Cell Lung Cancer Cells to Erlotinib and Chemotherapy.
Non-small cell lung cancer (NSCLC) is the most frequent cause of death from cancer worldwide. Despite the availability of active chemotherapy regimens and EGFR tyrosine kinase inhibitors, all advanced patients develop recurrent disease after first-line therapy. Although Hsp27 is a stress-induced chaperone that promotes acquired resistance in several cancers, its relationship to treatment resistance in NSCLC has not been defined. Understanding adaptive responses of acquired resistance will help guide new strategies to control NSCLC. Hsp27 levels were evaluated in an HCC827 erlotinib-resistant-derived cell line (HCC-827Resistant), and sensitivity to erlotinib was examined in Hsp27-overexpressing A549 cells. The role of Hsp27 in both erlotinib and cytotoxic treatment resistance was evaluated in HCC-827 and A549 NSCLC cells using the Hsp27 antisense drug OGX-427. The effect of OGX-427 in combination with erlotinib was also assessed in mice bearing A549 xenografts. Hsp27 is induced by erlotinib and protects NSCLC cells from treatment-induced apoptosis, whereas OGX-427 sensitizes NSCLC cells to erlotinib. Interestingly, increased resistance to erlotinib was observed when Hsp27 was increased either in HCC827 erlotinib-resistant or overexpressing A549 cells. Combining OGX-427 with erlotinib significantly enhanced antitumor effects in vitro and delayed A549 xenograft growth in vivo. OGX-427 also significantly enhanced the activity of cytotoxic drugs used for NSCLC. These data indicate that treatment-induced Hsp27 contributes to the development of resistance, and provides preclinical proof-of-principle that inhibition of stress adaptive pathways mediated by Hsp27 enhances the activity of erlotinib and chemotherapeutics.


Diethylstilbestrol inhibits the expression of the steroidogenic acute regulatory protein in mouse fetal testis.
This study investigated the early deleterious effects of an in-utero exposure to diethylstilbestrol (DES) on mouse testicular development. To that purpose, pregnant mice were injected daily with up to 100 microg/kg DES from 10.5 to 17.5 days postcoitum (dpc). At 18.5 dpc, testes were removed from fetuses for RNA (RT-PCR) and protein (Western blot, immunohistochemistry) analysis. Twenty-two genes were selected among which transcription factors, markers of differentiation of the different testicular cell lineages, steroidogenic enzymes and hormone receptors. The Steroidogenic Acute Regulatory (StAR) protein produced by the fetal Leydig cells was dramatically reduced in the DES-exposed testes. The P450c17 was the other gene modified following DES exposure. The alteration of these two genes is consistent with the decrease observed in the intratesticular testosterone levels, in the DES-exposed testes. Collectively, we demonstrated that DES did not alter testicular cell lineage specification but that it strongly inhibited the major function of the fetal Leydig cells.


Shunting with gravitational valves--can adjustments end the era of revisions for overdrainage-related events?: clinical article.
Overdrainage of CSF remains an unsolved problem in shunt therapy. The aim of the present study was to evaluate treatment options on overdrainage-related events enabled by the new generation of adjustable gravity-assisted valves. The authors retrospectively studied the clinical course of 250 consecutive adult patients with various etiologies of hydrocephalus after shunt insertion for different signs and symptoms of overdrainage. Primary and secondary overdrainage were differentiated. The authors correlated the incidence of overdrainage with etiology of hydrocephalus, opening valve pressure, and patient parameters such as weight and size. Depending on the severity of overdrainage, they elevated the opening pressure, and follow-up was performed until overdrainage was resolved. The authors found 39 cases (15.6%) involving overdrainage-related problems--23 primary and 16 secondary overdrainage. The median follow-up period in these 39 patients was 2.1 years. There was no correlation between the incidence of overdrainage and any of the following factors: sex, age, size, or weight of the patients. There was also no statistical significance among the different etiologies of hydrocephalus, with the exception of congenital hydrocephalus. All of the "complications" could be resolved by readjusting the opening pressure of the valve in one or multiple steps, avoiding further operations. Modern adjustable and gravity-assisted valves enable surgeons to set the opening pressure relatively low to avoid underdrainage without significantly raising the incidence of overdrainage and to treat overdrainage-related clinical and radiological complications without surgical intervention.


Case series: toxicity from 25B-NBOMe--a cluster of N-bomb cases.
Background A new class of hallucinogens called NBOMes has emerged. This class includes analogues 25I-NBOMe, 25C-NBOMe and 25B-NBOMe. Case reports and judicial seizures indicate that 25I-NBOMe and 25C-NBOMe are more prevalently abused. There have been a few confirmed reports of 25B-NBOMe use or toxicity. Report Observational case series. This report describes a series of 10 patients who suffered adverse effects from 25B-NBOMe. Hallucinations and violent agitation predominate along with serotonergic/stimulant signs such as mydriasis, tachycardia, hypertension and hyperthermia. The majority (7/10) required sedation with benzodiazepines. Analytical method 25B-NBOMe concentrations in plasma and urine were quantified in all patients using a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. Peak plasma levels were measured between 0.7-10.1 ng/ml. Discussion The NBOMes are desired by users because of their hallucinogenic and stimulant effects. They are often sold as LSD or synthetic LSD. Reported cases of 25B- NBOMe toxicity are reviewed and compared to our series. Seizures and one pharmacological death have been described but neither were observed in our series. Based on our experience with cases of mild to moderate toxicity, we suggest that management should be supportive and focused on preventing further (self) harm. High doses of benzodiazepines may be required to control agitation. Patients who develop significant hyperthermia need to be actively managed. Conclusions Effects from 25B-NBOMe in our series were similar to previous individual case reports. The clinical features were also similar to effects from other analogues in the class (25I-NBOMe, 25C-NBOMe). Violent agitation frequently present along with signs of serotonergic stimulation. Hyperthermia, rhabdomyolysis and kidney injury were also observed.


Exercise prescription for chronic back or neck pain: who prescribes it? who gets it? What is prescribed?
To describe exercise prescription in routine clinical practice for individuals with chronic back or neck pain because, although current practice guidelines promote exercise for chronic back and neck pain, little is known about exercise prescription in routine care. We conducted a computer-assisted telephone survey of a representative sample of individuals (n = 684) with chronic back or neck pain who saw a physician, chiropractor, and/or physical therapist (PT) in the past 12 months. Individuals were asked about whether they were prescribed exercise, the amount of supervision received, and the type, duration, and frequency of the prescribed exercise. Descriptive and multivariable regression analyses were conducted. Of the 684 subjects, 48% were prescribed exercise. Of those prescribed exercise, 46% received the prescription from a PT, 29% from a physician, 21% from a chiropractor, and 4% from other. In multivariable analyses, seeing a PT or a chiropractor were the strongest predictors of exercise prescription. The likelihood of exercise prescription was increased in women, those with higher education, and those receiving worker's compensation. PTs were more likely to provide supervision and prescribe strengthening exercises compared with physicians and chiropractors, and were more likely to prescribe stretching exercises compared with physicians. Our findings suggest that exercise is being underutilized as a treatment for chronic back and neck pain and, to some extent, that the amount of supervision and types of exercises prescribed do not follow current practice guidelines. Exercise prescription provided by PTs appears to be most in line with current guidelines.


Uniform inhibition of dopamine neurons in the ventral tegmental area by aversive stimuli.
Dopamine neurons play a key role in reward-related behaviors. Reward coding theories predict that dopamine neurons will be inhibited by or will not respond to aversive stimuli. Paradoxically, between 3 and 49% of presumed dopamine neurons are excited by aversive stimuli. We found that, in the ventral tegmental area of anesthetized rats, the population of presumed dopamine neurons that are excited by aversive stimuli is actually not dopaminergic. The identified dopamine neurons were inhibited by the aversive stimulus. These findings suggest that dopamine neurons are specifically excited by reward and that a population of nondopamine neurons is excited by aversive stimuli.


Systems and complexity thinking in the general practice literature: an integrative, historical narrative review.
Over the past 7 decades, theories in the systems and complexity sciences have had a major influence on academic thinking and research. We assessed the impact of complexity science on general practice/family medicine. We performed a historical integrative review using the following systematic search strategy: medical subject heading [humans] combined in turn with the terms complex adaptive systems, nonlinear dynamics, systems biology, and systems theory, limited to general practice/family medicine and published before December 2010. A total of 16,242 articles were retrieved, of which 49 were published in general practice/family medicine journals. Hand searches and snowballing retrieved another 35. After a full-text review, we included 56 articles dealing specifically with systems sciences and general/family practice. General practice/family medicine engaged with the emerging systems and complexity theories in 4 stages. Before 1995, articles tended to explore common phenomenologic general practice/family medicine experiences. Between 1995 and 2000, articles described the complex adaptive nature of this discipline. Those published between 2000 and 2005 focused on describing the system dynamics of medical practice. After 2005, articles increasingly applied the breadth of complex science theories to health care, health care reform, and the future of medicine. This historical review describes the development of general practice/family medicine in relation to complex adaptive systems theories, and shows how systems sciences more accurately reflect the discipline's philosophy and identity. Analysis suggests that general practice/family medicine first embraced systems theories through conscious reorganization of its boundaries and scope, before applying empirical tools. Future research should concentrate on applying nonlinear dynamics and empirical modeling to patient care, and to organizing and developing local practices, engaging in community development, and influencing health care reform.


Rufinamide from clinical trials to clinical practice in the United States and Europe.
Rufinamide is a triazole derivative structurally unrelated to other antiepileptic drugs that is indicated for the adjunctive treatment of seizures associated with Lennox-Gastaut syndrome (LGS) in patients aged ≥4 years. Originally granted orphan drug status, marketing authorisation was obtained on the basis of a randomised, double-blind, placebo-controlled trial conducted in 138 LGS patients. An open-label extension study subsequently demonstrated that rufinamide's efficacy and tolerability were maintained over the longer term (median duration of treatment, 432 days). Recently published reports from Europe and the United States have described the use of adjunctive rufinamide to treat LGS in clinical practice. These data complement the clinical trial results, by providing information on the efficacy and tolerability of rufinamide when used on an individualised basis in real-world practice, under less tightly restricted conditions in terms of patient population and dosing strategies. A comparison of the data reveals that a "lower and slower" dosing strategy tends to be adopted in clinical practice, in comparison with the clinical trial, which does not appear to compromise efficacy, but may provide improvements in tolerability. Individual case reports provide additional valuable information on how rufinamide is being used to treat different seizure types associated with LGS. Since clinical experience with rufinamide is currently at an early stage, there are still unanswered questions relating to its use, and it is likely that its place in the adjunctive treatment of LGS will evolve as further data emerge.


4 Gbps impulse radio (IR) ultra-wideband (UWB) transmission over 100 meters multi mode fiber with 4 meters wireless transmission.
We present experimental demonstrations of in-building impulse radio (IR) ultra-wideband (UWB) link consisting of 100 m multi mode fiber (MMF) and 4 m wireless transmission at a record 4 Gbps, and a record 8 m wireless transmission at 2.5 Gbps. A directly modulated vertical cavity surface emitting laser (VCSEL) was used for the generation of the optical signal. 8 m at 2.5 Gbps corresponds to a bit rate--distance product of 20; the highest yet reported for wireless IR-UWB transmission.


Inhibition of TRAIL-induced apoptosis and forced internalization of TRAIL receptor 1 by adenovirus proteins.
Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) induces apoptosis through two receptors, TRAIL-R1 (also known as death receptor 4) and TRAIL-R2 (also known as death receptor 5), that are members of the TNF receptor superfamily of death domain-containing receptors. We show that human adenovirus type 5 encodes three proteins, named RID (previously named E3-10.4K/14.5K), E3-14.7K, and E1B-19K, that independently inhibit TRAIL-induced apoptosis of infected human cells. This conclusion was derived from studies using wild-type adenovirus, adenovirus replication-competent mutants that lack one or more of the RID, E3-14.7K, and E1B-19K genes, and adenovirus E1-minus replication-defective vectors that express all E3 genes, RID plus E3-14.7K only, RID only, or E3-14.7K only. RID inhibits TRAIL-induced apoptosis when cells are sensitized to TRAIL either by adenovirus infection or treatment with cycloheximide. RID induces the internalization of TRAIL-R1 from the cell surface, as shown by flow cytometry and indirect immunofluorescence for TRAIL-R1. TRAIL-R1 was internalized in distinct vesicles which are very likely to be endosomes and lysosomes. TRAIL-R1 is degraded, as indicated by the disappearance of the TRAIL-R1 immunofluorescence signal. Degradation was inhibited by bafilomycin A1, a drug that prevents acidification of vesicles and the sorting of receptors from late endosomes to lysosomes, implying that degradation occurs in lysosomes. RID was also shown previously to internalize and degrade another death domain receptor, Fas, and to prevent apoptosis through Fas and the TNF receptor. RID was shown previously to force the internalization and degradation of the epidermal growth factor receptor. E1B-19K was shown previously to block apoptosis through Fas, and both E1B-19K and E3-14.7K were found to prevent apoptosis through the TNF receptor. These findings suggest that the receptors for TRAIL, Fas ligand, and TNF play a role in limiting virus infections. The ability of adenovirus to inhibit killing through these receptors may prolong acute and persistent infections.


Selected infectious agents and risk of schizophrenia among U.S. military personnel.
A number of studies have reported associations between Toxoplasma gondii (T. gondii) infection and the risk of schizophrenia. Most existing studies have used small populations and postdiagnosis specimens. As part of a larger research program, the authors conducted a hypothesis-generating case control study of T. gondii antibodies among individuals discharged from the U.S. military with a diagnosis of schizophrenia and serum specimens available from both before and after diagnosis. The patients (N=180) were military members who had been hospitalized and discharged from military service with a diagnosis of schizophrenia. Healthy comparison subjects (3:1 matched on several factors) were members of the military who were not discharged. The U.S. military routinely collects and stores serum specimens of military service members. The authors used microplate-enzyme immunoassay to measure immunoglobulin G (IgG) antibody levels to T. gondii, six herpes viruses, and influenza A and B viruses and immunoglobulin M (IgM) antibody levels to T. gondii in pre- and postdiagnosis serum specimens. A significant positive association between the T. gondii IgG antibody and schizophrenia was found; the overall hazard ratio was 1.24. The association between IgG and schizophrenia varied by the time between the serum specimen collection and onset of illness. The authors found significant associations between increased levels of scaled T. gondii IgG antibodies and schizophrenia for antibodies measured both prior to and after diagnosis.


Empirical study of physicochemical and spectral properties of CuII-containing chelate-based ionic liquids.
The physicochemical properties including melting point, density, viscosity, conductivity, and surface tension as well as spectral properties such as infrared and EPR spectra of the chelate-based ILs [Cnmim][Cu(F6-acac)3] (n = 6, 8, 10, 12, 14) were studied as functions of temperature and chain length. The thermodynamic properties such as the standard molar entropy and crystal energy were estimated by Glasser's theory, the molar enthalpy of vaporization was calculated by Kabo's method, and the ionicity was estimated by the Walden rule. Compared with the common ILs, the chelate-based ILs have larger molecular volume, larger density, smaller crystal energy, poorer ionicity and larger enthalpy of vaporization. The infrared spectra data of the ILs showed a red shift of the C-H bond stretching vibration of the alkyl chain in the cation and the EPR spectra showed that the crystal field of Cu2+ was kept when the chain length was elongated, which indicated the existence of microphase separation in the ILs. This work is helpful in understanding the structure-property relations of chelate-based ILs for further application.


Free-space optical communications link budget estimation.
This paper describes a new methodology of estimating free-space optical communications link budgets to be expected in conditions of severe turbulence. The approach is derived from observing that the ability of an adaptive optics (AO) system to compensate turbulence along a path is limited by the transmitter and receiver Rayleigh range, proportional to the diameter of the optics squared and inverse of the wavelength of light utilized. The method uses the Fried parameter computed over the range outside of the transmitter and receiver Rayleigh ranges, to calculate the Strehl ratios that yield a reasonable prediction of the light impinging on the receiving telescope aperture and the power coupling into the fiber. Comparisons will be given between theory and field measurements. These comparisons show that AO is most effective within the Rayleigh ranges, or when an atmospheric gradient is present, and lesser so when the total range is much greater than the sum of the Rayleigh ranges.


Prescribing pattern of angiotensin receptor blocker: A study of errors and drug-drug interactions.
Prescriptions comprising multi-drug therapy mostly illustrate the prescribing error. The phenomenon of error is bonded with human inaccuracy. The erroneous practice is observed in under developed countries like Pakistan, Bangladesh and also in developed ones. Consequently drug-drug interaction is one of the most common error associated with potentially serious adverse response even death. Accordingly the present study was conducted to assess the prevalence of prescribing errors and drug-drug interactions in out-patients receiving angiotensin receptor blockers. The study was done with population size one hundred fifty prescriptions obtained from different out-patient settings in Karachi. The prescriptions were screened for prescribing errors and risk factors for drug-drug interactions. Drug-drug interactions were recognized by Micromedex.2.0.Drug-Reax®database. The most common type of error was omission error. These errors were patient's age, weight and diagnosis found in 51.3%, 97.3% and 74% of prescriptions, respectively. The prevalence of drug-drug interaction was 38%. A total of 746 drugs were prescribed with an average of 5 drugs per prescription and 450 medication errors were detected. Majority of the interaction were moderate (19.33%), others were minor (14%) and major (6%) in severity. Patients who prescribed many drugs (more than 5 drugs in a while) had a higher risk of developing drug-drug interactions (OR=4.76; 95% CI=2.30-9.64; p=0.0001*).The study data reports the occurrence of prescribing errors in Karachi and also necessitate the need of clinical pharmacist's services in health care system. The step will help to minimize the risk factors by having the drug prescriptions reviewed by the pharmacists.


Patients' satisfaction and quality of life in coronary artery disease.
To assess satisfaction of survivors of coronary artery diseases (CAD) with healthcare services and to determine whether specific components of standard health-related quality of life (HRQL) assessment tools might identify areas of satisfaction and dissatisfaction. A specific tool developed to provide a comprehensive assessment of healthcare needs was administered concomitantly with generic and specific HRQL instruments, on 242 patients with CAD, admitted to an acute coronary unit during a single year. 92.5% of patients confirmed their trust in and satisfaction with the care given by their General Practitioner; even so, one third experienced difficulty getting an appointment and a quarter wanted more time for each consultation or prompt referral to a specialist when needed. Around a third expressed dissatisfaction with advice from the practice nurse or hospital consultant. Overall 54% were highly satisfied with services, 33% moderately satisfied and 13% dissatisfied. Cronbach's alpha was 0.87; the corrected total-item correlation ranged between 0.55-0.75, with trivial 'floor' score and low 'ceiling' effect. Several domains in all three HRQL tools correlated with items relating to satisfaction. The Seattle Angina Questionnaire Treatment Score correlated significantly with all satisfaction items and with the global satisfaction score. Cardiac patients' demanded better services and advice from, and more time with, health professionals and easier surgery access. The satisfaction tool showed acceptable psychometric properties. In this patient group, disease-specific HRQL tools seem more appropriate than generic tools for surveys of patient satisfaction.


Effect of maternal separation and chronic stress on hippocampal-dependent memory in young adult rats: evidence for the match-mismatch hypothesis.
Adverse experiences early in life may sensitize the hippocampus to subsequent stressors throughout the individual's life. We analyzed in male rats, whether, the interaction between early maternal separation and chronic stress affects: (1) the volume of the dorsal hippocampus, (2) CA1, CA2/3 and dentate gyrus (DG) and (3) hippocampal-dependent memory in adulthood. Male Wistar rats were subjected to daily maternal separation for 4.5 h between postnatal days 1-21. From postnatal day 50, animals were exposed to a chronic unpredictable stress paradigm during 24 days. The volumes of the dorsal hippocampus, their areas or strata did not reveal significant differences between treatments. Non-maternally separated and stressed animals showed poor hippocampal performance in a contextual fear conditioning test, with a significant reduction in freezing behavior during post-conditioning compared with control and maternally separated and stressed animals. Also, memory retrieval 24 h after conditioning was significantly weaker in this group than in control animals. Memory performance in maternally separated and stressed rats was similar to control animals. Our results show an interaction between early environment experiences and chronic variable stress in young adulthood as evidence that early stressful experiences do not necessarily lead to a negative outcome but can help in maintaining brain plasticity and increase fitness when animals reach adulthood.


N‑Myc downstream‑regulated gene 2 suppresses the proliferation of T24 human bladder cancer cells via induction of oncosis.
Previous studies have reported the antitumor activity of N‑Myc downstream‑regulated gene 2 (NDRG2), a novel p53‑inducible gene, in several types of cancer. The present study aimed to investigate the effects of NDRG2 expression on the proliferation of a human bladder cancer cell line. NDRG2 and control green fluorescent protein (GFP) recombinant adenovirus plasmids were constructed and transfected into a bladder cancer cell line with mutant p53 (T24 cells). NDRG2 expression was analyzed using western blot analysis and immunofluorescence assay (IFA); in addition, the subcellular localization of NDRG2 was detected using a confocal microscope. The proliferation rate of cells was measured using colony formation and MTT assays. Furthermore, the cell cycle of transfected T24 cells was detected by flow cytometry. The results indicated that T24 cells expressed low levels of NDRG2 prior to infection with GFP‑NDRG2 recombinant adenovirus; by contrast, following infection, NDRG2 was primarily overexpressed in mitochondria. The proliferation rate of T24 cells was significantly reduced by NDRG2 expression (P<0.01). In addition, 82.1% of NDRG2‑expressing cells were in S‑phase, compared to 74.4% in the control virus‑infected cells (P<0.05). Furthermore, upregulation of NDRG2 induced an increase in oncosis, rather than apoptosis, in T24 cell. In conclusion, the results of the present study indicated that NDRG2 expression in mitochondria may arrest bladder cancer cells in S‑phase as well as decrease cell proliferation through inducing oncosis. It was therefore proposed that NDRG2 was not only a biomarker, but also a tumor suppressor for bladder cancer.


Predictors of outcomes after rotator cuff repair-A meta-analysis.
Systematic review. Clinical outcomes associated with rotator cuff repair (RCR) are generally favorable, but no study has attempted to establish a set of predictors that affect outcomes. This study aims to statistically analyze articles and establish a set of predictors that affect outcomes after RCR. An electronic literature search of multiple databases was conducted to identify studies that addressed prognosis after RCR. Quality ratings were conducted with a prognostic study evaluation tool. Summary data for predictors and outcomes were extracted, entered in comprehensive meta-analysis software, transformed where necessary, and pooled to allow for estimation of odds ratio for each predictor. From 18 studies, 3 were high quality, 7 were moderate and 8 were low-quality studies. Fatty infiltration had a significant negative effect (OR = 9.3), whereas larger tear size, lower preoperative muscle strength (OR = 4.0), multiple tendon involvement (OR = 6.0), diabetes, and worker's compensation status (OR = 8.7) had a moderate negative effect on outcomes after RCR. Older age had a modest negative effect on cuff integrity at follow-up (OR = 2.8), but no significant effect on function. In addition, a history of trauma, smoking, and duration of symptoms before surgery had no significant effect on outcomes. Injury to the cuff (body structure), physical impairment, personal factors and social factors affects outcomes; although the importance of predictors varies between anatomic and functional outcomes. A multifactorial biopsychosocial prognosis should be considered in management. Level 2.


IgM Augments Complement Bactericidal Activity with Serum from a Patient with a Novel CD79a Mutation.
Antibody replacement therapy for patients with antibody deficiencies contains only IgG. As a result, concurrent IgM and IgA deficiency present in a large proportion of antibody deficient patients persists. Especially patients with IgM deficiency remain at risk for recurrent infections of the gastrointestinal and respiratory tract. The lack of IgM in the current IgG replacement therapy is likely to contribute to the persistence of these mucosal infections because this antibody class is especially important for complement activation on the mucosal surface. We evaluated whether supplementation with IgM increased serum bactericidal capacity in vitro. Serum was collected from a patient with agammaglobulinemia and supplemented with purified serum IgM to normal levels. Antibody and complement deposition on the bacterial surface was determined by multi-color flow cytometry. Bacterial survival in serum was determined by colony-forming unit counts. We present a patient previously diagnosed with agammaglobulinemia due to CD79A (Igα) deficiency revealing a novel pathogenic insertion variant in the CD79a gene (NM_001783.3:c.353_354insT). Despite IgG replacement therapy and antibiotic prophylaxis, this patient developed a Campylobacter jejuni spondylodiscitis of lumbar vertebrae L4-L5. We found that serum IgM significantly contributes to complement activation on the bacterial surface of C. jejuni. Furthermore, supplementation of serum IgM augmented serum bactericidal activity significantly. In conclusion, supplementation of intravenous IgG replacement therapy with IgM may potentially offer greater protection against bacterial infections, also in the context of increasing antibiotic resistance.


Hybrid atomic structure of the Schmid cluster Au55(PPh3)12Cl6 resolved by aberration-corrected STEM.
We have investigated the atomic structure of the Au55(PPh3)12Cl6 Schmid cluster by using aberration-corrected scanning transmission electron microscopy (STEM) combined with multislice simulation of STEM images. Atom counting was employed, with size-selected clusters as mass standards, to "fractionate" the correct cluster size in the image analysis. Systematic structure analysis shows that a hybrid structure, predicted by density functional theory, best matches nearly half the clusters observed. Most other clusters are amorphous. We believe our conclusions are consistent with all the previous, apparently contradictory structural studies of the Schmid cluster.


N-Doped porous carbon nanosheets decorated with graphitized carbon layer encapsulated Co9S8 nanoparticles: an efficient bifunctional electrocatalyst for the OER and ORR.
Electrocatalysts with highly effective activity for the oxygen reduction reaction (ORR) and oxygen evolution reaction (OER) are considered to be the key factor of renewable energy technologies. Herein, we designed and synthesized bi-functional electrocatalyst Co9S8/C nanosheets (NSs) by reducing the Co3O4/C NS precursor with sodium sulfide. From the structural characterization, Co9S8 is anchored on the graphitized carbon NSs homogeneously. According to the electrochemical measurements, the Co9S8/C NSs show excellent electrocatalytic activity towards both the ORR (Eonset = 0.892 V vs. RHE and E1/2 is 0.778 V vs. RHE) and OER (Eonset = 1.50 V vs. RHE and the overpotential is 0.434 V vs. RHE at 10 mA cm-2) in 0.1 M KOH solution. In the ORR, Co9S8/C catalyzes through a 4-electron process like the commercial Pt-based catalyst. In addition, the Co9S8/C NSs show great long-term stability. The Co9S8/C NSs show excellent catalytic performance due to the rich active sites and two-dimensional sheet structure. The developed strategy offers an effective method for preparing bi-functional electrocatalysts for both the OER and ORR.


IL-36R signalling activates intestinal epithelial cells and fibroblasts and promotes mucosal healing in vivo.
Interleukin (IL)-36R signalling plays a proinflammatory role in different organs including the skin, but the expression of IL-36R ligands and their molecular function in intestinal inflammation are largely unknown. We studied the characteristics of IL-36R ligand expression in IBDs and experimental colitis. The functional role of IL-36R signalling in the intestine was addressed in experimental colitis and wound healing models in vivo by using mice with defective IL-36R signalling (IL-36R-/-) or Myd88, neutralising anti-IL-36R antibodies, recombinant IL-36R ligands and RNA-seq genome expression analysis. Expression of IL-36α and IL-36γ was significantly elevated in active human IBD and experimental colitis. While IL-36γ was predominantly detected in nuclei of the intestinal epithelium, IL-36α was mainly found in the cytoplasm of CD14+ inflammatory macrophages. Functional studies showed that defective IL-36R signalling causes high susceptibility to acute dextran sodium sulfate colitis and impairs wound healing. Mechanistically, IL-36R ligands released upon mucosal damage activated IL-36R+ colonic fibroblasts via Myd88 thereby inducing expression of chemokines, granulocyte-macrophage colony-stimulating factor (GM-CSF) and IL-6. Moreover, they induced proliferation of intestinal epithelial cells (IECs) and expression of the antimicrobial protein lipocalin 2. Finally, treatment of experimental intestinal wounds with IL-36R ligands significantly accelerated mucosal healing in vivo. IL-36R signalling is activated upon intestinal damage, stimulates IECs and fibroblasts and drives mucosal healing. Modulation of the IL-36R pathway emerges as a potential therapeutic strategy for induction of mucosal healing in IBD.


A completely biological tissue-engineered human blood vessel.
Mechanically challenged tissue-engineered organs, such as blood vessels, traditionally relied on synthetic or modified biological materials for structural support. In this report, we present a novel approach to tissue-engineered blood vessel (TEBV) production that is based exclusively on the use of cultured human cells, i.e., without any synthetic or exogenous biomaterials. Human vascular smooth muscle cells (SMC) cultured with ascorbic acid produced a cohesive cellular sheet. This sheet was placed around a tubular support to produce the media of the vessel. A similar sheet of human fibroblasts was wrapped around the media to provide the adventitia. After maturation, the tubular support was removed and endothelial cells were seeded in the lumen. This TEBV featured a well-defined, three-layered organization and numerous extracellular matrix proteins, including elastin. In this environment, SMC reexpressed desmin, a differentiation marker known to be lost under standard culture conditions. The endothelium expressed von Willebrand factor, incorporated acetylated LDL, produced PGI2, and strongly inhibited platelet adhesion in vitro. The complete vessel had a burst strength over 2000 mmHg. This is the first completely biological TEBV to display a burst strength comparable to that of human vessels. Short-term grafting experiment in a canine model demonstrated good handling and suturability characteristics. Taken together, these results suggest that this novel technique can produce completely biological vessels fulfilling the fundamental requirements for grafting: high burst strength, positive surgical handling, and a functional endothelium.


Predisposing factors for acute kidney injury in Hispanic patients treated with diuretics for decompensated heart failure.
In patients with congestive heart failure (CHF), use of loop diuretic therapy may result in acute kidney insufficiency (AKI). We assessed the factors that contributed to the development of AKI in patients with CHF treated with loop diuretics in a sample of patients who attended the Cardiovascular Center of Puerto Rico and the Caribbean (CCPRC). Medical records of 236 patients admitted between: January 1, 2008 to December 31, 2008 with the diagnosis of CHF were reviewed. Diagnosis of CHF based on symptoms and signs was confirmed by echocardiography. Twenty six (26) patients with significant valvular disease and four (4) patients who did not receive diuretics during hospitalization were excluded. Hospital course was observed until diuretic therapy was discontinued or patient was discharged. AKI was defined as a 25% increase in serum creatinine level after the start of diuretic therapy. The study sample was categorized in two groups: patients who developed AKI and those who did not. Variables associated with AKI (p<0.05) in the bivariate logistic regression models were included in the multivariate logistic regression models. In the multivariate logistic regression model, only a greater dose of diuretic therapy (>80 mg/dl) and history of diabetes mellitus were significantly (p<0.05) associated with AKI. Analysis of data shows that increased doses of diuretic therapy and history of diabetes mellitus were significantly associated with AKI in patients with CHF. This study highlights the importance of monitoring the doses of diuretic therapy during hospitalization, in this group of patients.


Microhomology directs diverse DNA break repair pathways and chromosomal translocations.
Chromosomal structural change triggers carcinogenesis and the formation of other genetic diseases. The breakpoint junctions of these rearrangements often contain small overlapping sequences called "microhomology," yet the genetic pathway(s) responsible have yet to be defined. We report a simple genetic system to detect microhomology-mediated repair (MHMR) events after a DNA double-strand break (DSB) in budding yeast cells. MHMR using >15 bp operates as a single-strand annealing variant, requiring the non-essential DNA polymerase subunit Pol32. MHMR is inhibited by sequence mismatches, but independent of extensive DNA synthesis like break-induced replication. However, MHMR using less than 14 bp is genetically distinct from that using longer microhomology and far less efficient for the repair of distant DSBs. MHMR catalyzes chromosomal translocation almost as efficiently as intra-chromosomal repair. The results suggest that the intrinsic annealing propensity between microhomology sequences efficiently leads to chromosomal rearrangements.


Multinuclear magnetic resonance analysis of two humic acid fractions from lowland rice soils.
To determine the effects of intensive cropping of tropical lowland rice (Oryza sativa L.) and the associated long-term soil submergence on chemical properties of soil organic matter, we used solid-state 13C and 15N and solution 31P nuclear magnetic resonance (NMR) spectroscopy to analyze the labile mobile humic acid (MHA) and the more recalcitrant calcium humate (CaHA) fractions extracted from a series of soils supporting several long-term field experiments in the Philippines. The soils varied mainly in degree of submergence and cropping intensity, ranging from a rainfed rice field without soil submergence to irrigated double- and triple-cropped fields in which soil remains submerged almost all year long. As reported previously, all analyses associated increasing intensity of rice cropping with larger proportions of less humified material in the MHA and CaHA, such as diester phosphorus (P), amide nitrogen (N), and phenolic carbon (C). We established significant correlations between proportions of various spectral areas as well as between some spectral areas and other humic acid (HA) properties such as visible light absorption and free radical concentration (positive indices of humification) and hydrogen (H) concentration (negative index of humification). For example, spectral proportions of heterocyclic N were positively, and proportions of amide N and phenolic C negatively, correlated with visible light absorption and free radical concentration, and each of these spectral proportions had an opposite sign when correlated with H concentration. The correlations of N-alkyl C proportions were the strongest with these properties and with other functional group proportions.


Evaluation of optical properties of highly scattering media by moments of distributions of times of flight of photons.
A novel method for the determination of the optical properties of tissue from time-domain measurements is presented. The data analysis is based on the evaluation of the first moment and the second centralized moment, i.e., the mean time of flight and the variance of the measured distribution of times of flight (DTOF) of photons injected by short (picosecond) laser pulses. Analytical expressions are derived for calculation of absorption and of reduced scattering coefficients from these moments by application of diffusion theory for infinite and semi-infinite homogeneous media. The proposed method was tested on experimental data obtained with phantoms, and results for absorption and reduced scattering coefficients obtained by the proposed method are compared with those obtained by fitting of the same data with analytical solutions of the diffusion equation. Furthermore, the accuracy of the moment analysis was investigated for a range of integration limits of the DTOF. The moment analysis may serve as a comparatively fast method for evaluating optical properties with sufficient accuracy and can be used, e.g., for on-line monitoring of optical properties of biological tissue.


Genetic and environmental control of temporal and size-dependent sex allocation in a wind-pollinated plant.
Sex allocation in hermaphrodites can be affected by spatial and temporal variation in resources, especially in plants where size-dependent gender modification is commonplace. The evolution of sex allocation will depend on the relative importance of genetic and environmental factors governing patterns of investment in female and male function. In wind-pollinated plants, theoretical models predict a positive relation between size and male investment because of the fitness advantages associated with more effective pollen dispersal. Theory also predicts that the timing and allocation to each sex function should depend on available resources. We grew maternal half-sibling families of annual, wind-pollinated, Ambrosia artemisiifolia in sun and shade treatments to investigate these predictions. There was significant genetic variation for female and male flower production in both sun and shade treatments. Size-dependent sex allocation occurred in the direction predicted by theory, with male flower production increasing more rapidly in larger plants. The timing of sex function also varied, with significant genetic variation for dichogamy within environments and plasticity of this trait between environments. Protandry was expressed more commonly in the sun and protogyny in the shade. The occurrence of dynamic sex allocation with changing size and experimental treatment indicates the potential for adaptive responses under different ecological conditions.


Redox regulation and antioxidative defence in Arabidopsis leaves viewed from a systems biology perspective.
Redox regulation is a central control element in cell metabolism. It is employed to adjust photosynthesis and the antioxidant defence system of leaves to the prevailing environment. During recent years progress has been made in describing the redox-dependent alterations in metabolism, the thiol/disulfide proteome, the redox-dependent and cross-talking signalling pathways and the target genes of redox regulation. Some transcription factors have been identified as proteins that perform thiol/disulfide transitions linked to the redox-regulation of specific plant promoters. In addition first mathematical models have been designed to simulate antioxidant defence and predict its response. Taken together, a profound experimental data set has been generated which allows to approach a systems biology type of understanding of antioxidant defence in photosynthesising cells in the near future. Since oxidative stress is likely to limit plant growth under stress, such a systematic understanding of antioxidant defence will help to define novel targets for breeding stress-tolerant plants.


Predicting renal graft failure by sCD30 levels and de novo HLA antibodies at 1year post-transplantation.
HLA antibodies and sCD30 levels were detected in the serum sampled from 620 renal graft recipients at 1 year post-transplantation, which were followed up for 5 years. Six-year graft and patient survivals were 81.6% and 91.0%. HLA antibodies were detected in 45 recipients (7.3%), of whom there were 14 cases with class I antibodies, 26 cases with class II, and 5 cases with both class I and II. Much more graft loss was record in recipients with HLA antibodies than those without antibodies (60% vs. 15.1%, p<0.001). Significantly higher sCD30 levels were recorded in recipients suffering graft loss than the others (73.9±48.8 U/mL vs. 37.3±14.6 U/mL, p<0.001). Compared with those with high sCD30 levels, recipients with low sCD30 levels (<50 U/mL) had much better 6-year graft survival (92.4% vs. 46.6%, p<0.001). Further statistical analysis showed that detrimental effect of de novo HLA antibodies and high sCD30 on graft survival was not only independent but also additive. Therefore, post-transplantation monitoring of HLA antibodies and sCD30 levels is necessary and recipients with elevated sCD30 level and/or de novo HLA antibody should be paid more attention in order to achieve better graft survival.


A MAVS/TICAM-1-independent interferon-inducing pathway contributes to regulation of hepatitis B virus replication in the mouse hydrodynamic injection model.
Toll-like receptors (TLRs) and cytoplasmic RNA sensors have been reported to be involved in the regulation of hepatitis B virus (HBV) replication, but remain controversial due to the lack of a natural infectious model. Our current study sets out to characterize aspects of the role of the innate immune system in eliminating HBV using hydrodynamic-based injection of HBV replicative plasmid and knockout mice deficient in specific pathways of the innate system. The evidence indicated that viral replication was not affected by MAVS or TICAM-1 knockout, but absence of interferon regulatory factor 3 (IRF-3) and IRF-7 transcription factors, as well as the interferon (IFN) receptor, had an adverse effect on the inhibition of HBV replication, demonstrating the dispensability of MAVS and TICAM-1 pathways in the early innate response against HBV. Myd88(-/-) mice did not have a significant increase in the initial viremia, but substantial viral antigen persisted in the mice sera, a response similar to Rag2(-/-) mice, suggesting that the MyD88-dependent pathway participated in evoking an adaptive immune response against the clearance of intrahepatic HBV. Taken together, we show that the RNA-sensing pathways do not participate in the regulation of HBV replication in a mouse model; meanwhile MyD88 is implicated in the HBV clearance.


Soft tissue stability and volumetric changes after 5 years in pontic sites with or without soft tissue grafting: a retrospective cohort study.
To evaluate volumetric changes (VC) of pontic sites with or without soft tissue grafting over 5 years. Twelve patients participating in a prospective clinical trial evaluating fixed dental prostheses (FDPs) were selected on the basis of having received a subepithelial connective tissue graft for soft volume augmentation in pontic sites (augmentation group [AG]). An additional 12 patients, belonging to the same study, that had not received soft tissue grafting were used as controls (control group [CG]). Casts made from dental impressions taken at prosthesis delivery (baseline [BL]) and at 5 years (5-FU) were digitized, and linear and volumetric measurements performed to assess the soft tissue pontic height (PH), abutment height (AH), (VC) and changes in tissue thickness (TT) on the buccal side of the pontics. There were no significant differences at BL between the two groups for linear measurements (P > 0.05). The changes in soft tissue pontic height (PHC) amounted to a loss in the height of 0.34 mm (SD = 0.5) and 0.35 mm (0.2) for AG and CG, respectively. The mean VC amounted to a loss of 5.31 mm(3) (±1.1) (AG) and 4.32 mm(3) (±1.7) (CG). None of the changes between BL and 5-FU in volumetric and linear measurements, including TT and mean mesial and distal abutment height changes (mAHC and dAHC), reached statistically significant differences between AG and CG (P > 0.05). However the changes in linear measurements from BL to 5-FU were significant in all parameters for both groups (P < 0.01). At an observational period of 5 years, pontic sites with or without grafting under FDPs demonstrated similar dimensional stability. Pontic sites with or without grafting are volumetrically stable over 5 years.


The evolution of dinosaurs.
The ascendancy of dinosaurs on land near the close of the Triassic now appears to have been as accidental and opportunistic as their demise and replacement by therian mammals at the end of the Cretaceous. The dinosaurian radiation, launched by 1-meter-long bipeds, was slower in tempo and more restricted in adaptive scope than that of therian mammals. A notable exception was the evolution of birds from small-bodied predatory dinosaurs, which involved a dramatic decrease in body size. Recurring phylogenetic trends among dinosaurs include, to the contrary, increase in body size. There is no evidence for co-evolution between predators and prey or between herbivores and flowering plants. As the major land masses drifted apart, dinosaurian biogeography was molded more by regional extinction and intercontinental dispersal than by the breakup sequence of Pangaea.


Anaesthesia-related maternal mortality in low-income and middle-income countries: a systematic review and meta-analysis.
The risk factors contributing to maternal mortality from anaesthesia in low-income and middle-income countries and the burden of the problem have not been comprehensively studied up to now. We aimed to obtain precise estimates of anaesthesia-attributed deaths in pregnant women exposed to anaesthesia and to identify the factors linked to adverse outcomes in pregnant women exposed to anaesthesia in low-income and middle-income countries. In this systematic review and meta-analysis, we searched major electronic databases from inception until Oct 1, 2015, for studies reporting risks of maternal death from anaesthesia in low-income and middle-income countries. Studies were included if they assessed maternal and perinatal outcomes in pregnant women exposed to anaesthesia for an obstetric procedure in countries categorised as low-income or middle-income by the World Bank. We excluded studies in high-income countries, those involving non-pregnant women, case reports, and studies published before 1990 to ensure that the estimates reflect the current burden of the condition. Two independent reviewers undertook quality assessment and data extraction. We computed odds ratios for risk factors and anaesthesia-related complications, and pooled them using a random effects model. This study is registered with PROSPERO, number CRD42015015805. 44 studies (632,556 pregnancies) reported risks of death from anaesthesia in women who had an obstetric surgical procedure; 95 (32,149,636 pregnancies and 36,144 deaths) provided rates of anaesthesia-attributed deaths as a proportion of maternal deaths. The risk of death from anaesthesia in women undergoing obstetric procedures was 1·2 per 1000 women undergoing obstetric procedures (95% CI 0·8-1·7, I(2)=83%). Anaesthesia accounted for 2·8% (2·4-3·4, I(2)=75%) of all maternal deaths, 3·5% (2·9-4·3, I(2)=79%) of direct maternal deaths (ie, those that resulted from obstetric complications), and 13·8% (9·0-20·7, I(2)=84%) of deaths after caesarean section. Exposure to general anaesthesia increased the odds of maternal (odds ratio [OR] 3·3, 95% CI 1·2-9·0, I(2)=58%), and perinatal deaths (2·3, 1·2-4·1, I(2)=73%) compared with neuraxial anaesthesia. The rate of any maternal death was 9·8 per 1000 anaesthetics (5·2-15·7, I(2)=92%) when managed by non-physician anaesthetists compared with 5·2 per 1000 (0·9-12·6, I(2)=95%) when managed by physician anaesthetists. The current international priority on strengthening health systems should address the risk factors such as general anaesthesia and rural setting for improving anaesthetic care in pregnant women. Ammalife Charity and ELLY Appeal, Bart's Charity.


Association studies for quantitative traits in structured populations.
Association between disease and genetic polymorphisms often contributes critical information in our search for the genetic components of common diseases. Devlin and Roeder [1999: Biometrics 55:997-1004] introduced genomic control, a statistical method that overcomes a drawback to the use of population-based samples for tests of association, namely spurious associations induced by population structure. In essence, genomic control (GC) uses markers throughout the genome to adjust for any inflation in test statistics due to substructure. To date, genomic control (GC) has been developed for binary traits and bi- or multiallelic markers. Tests of association using GC have been limited to single genes. In this report, we generalize GC to quantitative traits (QT) and multilocus models. Using statistical analysis and simulations, we show that GC controls spurious associations in reasonable settings of population substructure for QT models, including gene-gene interaction. Through simulations, we explore GC power for both random and selected samples, assuming the QT locus tested is causal and its specific heritability is 2.5-5%. We find that GC, combined with either random or selected samples, has good power in this setting, and that more complex models induce smaller GC corrections. The latter suggests greater power can be achieved by specifying more complex genetic models, but this observation only follows when such models are largely correct and specified a priori.


Effect of induced myopia on scleral myofibroblasts and in vivo ocular biomechanical compliance in the guinea pig.
To examine the effect of induced myopia on scleral myofibroblast populations and in vivo ocular biomechanical compliance. One-week-old guinea pigs were monocularly deprived (MD) of form vision for 2 weeks. Ocular biomechanical compliance was measured in both eyes of anesthetized animals by increasing the intraocular pressure (IOP) to 50 mm Hg for 1 hour, while A-scan ultrasound measures were made every 10 minutes to investigate the change in axial length. The total cell population and myofibroblast subpopulation of the posterior 100° of the sclera was determined with immunohistochemical techniques. The vitreous chamber depth (VCD) of MD and contralateral control eyes showed significant elastic expansion on increasing the IOP, compared with that of the nonmanipulated normal eyes. The creep response of the VCD in response to increased IOP was initially greater in the normal eyes until eye length was similar to the MD and control eyes. An unexpectedly high proportion of the scleral cell population were myofibroblasts (63.7% ± 1.7%, average ± SEM; n = 30). MD significantly decreased the total number of cells in the region between the optic nerve and 10° nasal (equivalent to myopic crescent location in humans) compared with the number in control or normal eyes, but no significant effect on myofibroblasts or the total number of cells was found elsewhere. A high proportion of scleral cells have contractile potential. This proportion is unaffected by MD. However, there is a significant difference in the in vivo elastic response of the sclera between MD and normal eyes, suggesting that factors other than number of cells have an effect on axial length.


Expanding into new markets--VCP/p97 in endocytosis and autophagy.
The AAA-ATPase p97 (also called VCP for Valosin-containing protein) is essential for a number of cellular processes as diverse as ER-associated degradation, DNA damage response, and cell cycle control. Mechanistically, p97 cooperates with its cofactor Ufd1-Npl4 in these processes to segregate polyubiquitinated misfolded or regulatory client proteins from intracellular structures for subsequent degradation by the proteasome. Recent work now connects p97, independently of Ufd1-Npl4, to endosomal trafficking and autophagy. Interestingly, these pathways also deliver proteins for degradation, albeit by the lysosome. While monoubiquitination and alternative p97-cofactors, including UBXD1, have been associated with these activities, the underlying molecular mechanism(s) are still unclear or controversial. In this review, we aim to summarize the available data and discuss mechanistic models.