In vivo evaluation of a breast-specific magnetic resonance guided focused ultrasound system in a goat udder model.
This work further evaluates the functionality, efficacy, and safety of a new breast-specific magnetic resonance guided high intensity focused ultrasound (MRgFUS) system in an in vivo goat udder model. Eight female goats underwent an MRgFUS ablation procedure using the breast-specific MRgFUS system. Tissue classification was achieved through the 3D magnetic resonance imaging (MRI) acquisition of several contrasts (T1w, T2w, PDw, 3-point Dixon). The MRgFUS treatment was performed with a grid trajectory executed in one or two planes within the glandular tissue of the goat udder. Temperature was monitored using a 3D proton resonance frequency (PRF) MRI technique. Delayed contrast enhanced-MR images were acquired immediately and 14 days post MRgFUS treatment. A localized tissue excision was performed in one animal and histological analysis was performed. Animals were available for adoption at the conclusion of the study. The breast-specific MRgFUS system was able to ablate regions ranging in size from 0.4 to 3.6 cm(3) in the goat udder model. Tissue damage was confirmed through the correlation of thermal dose measurements obtained with realtime 3D MR thermometry to delayed contrast enhanced-MR images immediately after the treatment and 14 days postablation. In general, lesions were longer in the ultrasound propagation direction, which is consistent with the dimensions of the ultrasound focal spot. Thermal dose volumes had better agreement with nonenhancing areas of the DCE-MRI images obtained 14 days after the MRgFUS treatment. The system was able to successfully ablate lesions up to 3.6 cm(3). The thermal dose volume was found to correlate better with the 14-day postablation nonenhancing delayed contrast enhanced-MR image volumes. While the goat udder is not an ideal model for the human breast, this study has proven the feasibility of using this system on a wide variety of udder shapes and sizes, demonstrating the flexibility that would be required in order to treat human subjects.


NINscope, a versatile miniscope for multi-region circuit investigations.
Miniaturized fluorescence microscopes (miniscopes) have been instrumental to monitor neural signals during unrestrained behavior and their open-source versions have made them affordable. Often, the footprint and weight of open-source miniscopes is sacrificed for added functionality. Here, we present NINscope: a light-weight miniscope with a small footprint that integrates a high-sensitivity image sensor, an inertial measurement unit and an LED driver for an external optogenetic probe. We use it to perform the first concurrent cellular resolution recordings from cerebellum and cerebral cortex in unrestrained mice, demonstrate its optogenetic stimulation capabilities to examine cerebello-cerebral or cortico-striatal connectivity, and replicate findings of action encoding in dorsal striatum. In combination with cross-platform acquisition and control software, our miniscope is a versatile addition to the expanding tool chest of open-source miniscopes that will increase access to multi-region circuit investigations during unrestrained behavior.


Is a Pathological Complete Response Following Neoadjuvant Chemoradiation Associated With Prolonged Survival in Patients With Pancreatic Cancer?
To describe the survival outcome of patients with borderline resectable or locally advanced pancreatic ductal adenocarcinoma (BR/LA-PDAC) who have a pathologic complete response (pCR) following neoadjuvant chemoradiation. Patients with BR/LA-PDAC are often treated with neoadjuvant chemoradiation in an attempt to downstage the tumor. Uncommonly, a pCR may result. A retrospective review of a prospectively maintained database was performed at a single institution. pCR was defined as no viable tumor identified in the pancreas or lymph nodes by pathology. A near complete response (nCR) was defined as a primary tumor less than 1 cm, without nodal metastasis. Overall survival (OS) and disease-free survival (DFS) were reported. One hundred eighty-six patients with BR/LA-PDAC underwent neoadjuvant chemoradiation and subsequent pancreatectomy. Nineteen patients (10%) had a pCR, 29 (16%) had an nCR, and the remaining 138 (74%) had a limited response. Median DFS was 26 months in patients with pCR, which was superior to nCR (12 months, P = 0.019) and limited response (12 months, P < 0.001). The median OS of nCR (27 months, P = 0.003) or limited response (26 months, P = 0.001) was less than that of pCR (more than 60 months). In multivariable analyses pCR was an independent prognostic factor for DFS (HR = 0.45; 0.22-0.93, P = 0.030) and OS (HR=0.41; 0.17-0.97, P = 0.044). Neoadjuvant FOLFIRINOX (HR=0.47; 0.26-0.87, P = 0.015) and negative lymph node status (HR=0.57; 0.36-0.90, P = 0.018) were also associated with improved survival. Patients with BR/LA-PDAC who had a pCR after neoadjuvant chemoradiation had a significantly prolonged survival compared with those who had nCR or a limited response.


Cost-effectiveness of implantable defibrillators after myocardial infarction based on 8-year follow-up data (MADIT II).
About 190,000 Germans experience a myocardial infarction each year. Of these, 25% may be eligible for an implantable cardioverter defibrillator (ICD) due to low left ventricular ejection fraction. Given the high costs of implantation, the purpose of this study was to assess the cost-effectiveness of ICDs compared to conventional therapy in patients with an ejection fraction 30% or less after MI in Germany. The economic evaluation was performed from the perspective of the German statutory health insurance. To simulate costs and effectiveness over lifetime, a Markov model was constructed with seven health states. The model was based on 8-year follow-up data for ICD implantation after myocardial infarction (MADIT II), which was published recently. The analysis shows that ICD implantation compared to conventional therapy in patients fulfilling MADIT-II criteria has a cost-effectiveness ratio of €44,736 per quality-adjusted life year gained. If every patient insured by the statutory health insurance and fulfilling the MADIT-II criteria would receive an ICD, the model suggests expenditures between €173 million and €1.7 billion per year. ICD therapy cannot be considered clearly cost-effective when compared to many well-accepted interventions. If policy makers decide to reimburse ICDs in the MADIT-II population, they will need to either raise premiums or abandon coverage for other currently funded medical interventions.


An AHSG gene variant modulates basal metabolic rate and body composition development after a short-time lifestyle intervention.
The AHSG (alpha2 Heremans-Schmid glycoprotein) gene is suggested to be important for the regulation of body fat and insulin sensitivity. Our study aimed to investigate the relationship between the common Thr248Met (rs4917) variant and obesity characteristics after an intervention with overweight females. We analyzed 105 unrelated overweight/obese nondiabetic Czech adult females (49.0 ± 12.1 years, BMI over 28.6 kg/m2, mean BMI before intervention 32.8 ± 4.1 kg/m2) before and after 10 weeks of lifestyle modification. Biochemical and anthropometrical measurements were performed. The life style modification program consisted of a reduction of energy intake to an age-adjusted optimum and an exercise program (four units per week). The mean weight loss was 3.2 ± 3.5 kg (3.7 ± 4.0%). Thr/Thr homozygotes (N=52) increased lean muscle mass (p<0.05), decreased total body fat (kg) (p<0.005) and increased basal metabolic rate (BMR) per 1 kg body weight (p<0.005) in comparison with the Met carriers (N=52), but an association between BMI decrease and AHSG variants was not found. AHSG gene variants modify the effect of physical activity on BMR. Carriers of the Thr248Thr genotype showed a higher benefit from the lifestyle intervention (expressed as changes in body fat, active muscle and basal metabolic rate).


Plasma-assisted pretreatment of wheat straw for ethanol production.
The potential of wheat straw for ethanol production after pretreatment with O(3) generated in a plasma at atmospheric pressure and room temperature followed by fermentation was investigated. We found that cellulose and hemicellulose remained unaltered after ozonisation and a subsequent washing step, while lignin was degraded up to 95% by O(3). The loss of biomass after washing could be explained by the amount of lignin degraded. The washing water of pretreated samples (0-7 h) was analyzed for potential fermentation inhibitors. Approximately 30 lignin degradation products and a number of simple carboxylic acids and phenolic compounds were found, e.g., vanillic acid, acetic acid, and formic acid. Some components had the highest concentration at the beginning of the ozonisation process (0.5, 1 h), e.g., 4-hydroxybenzladehyde, while the concentration of others increased during the entire pretreatment (0-7 h), e.g., oxalic acid and acetovanillon. Interestingly, washing had no effect on the ethanol production with pretreatment times up to 1 h. Washing improved the glucose availability with pretreatment times of more than 2 h. One hour of ozonisation was found to be optimal for the use of washed and unwashed wheat straw for ethanol production (maximum ethanol yield, 52%). O(3) cost estimations were made for the production of ethanol at standard conditions.


Recoverable impacts of ocean acidification on the tubeworm, Hydroides elegans: implication for biofouling in future coastal oceans.
Ocean uptake of anthropogenic CO2 causes ocean acidification (OA), which not only decreases the calcification rate, but also impairs the formation of calcareous shells or tubes in marine invertebrates such as the dominant biofouling tubeworm species, Hydroides elegans. This study examined the ability of tubeworms to resume normal tube calcification when returned to ambient pH 8.1 from a projected near-future OA level of pH 7.8. Tubeworms produced structurally impaired and mechanically weaker calcareous tubes at pH 7.8 compared to at pH 8.1, but were able to recover when the pH was restored to ambient levels. This suggests that tubeworms can physiologically recover from the impacts of OA on tube calcification, composition, density, hardness and stiffness when returned to optimal conditions. These results help understanding of the progression of biofouling communities dominated by tubeworms in future oceans with low pH induced by OA.


Study of candidate genes for dyslexia in Brazilian individuals.
Dyslexia or reading disability (RD) is the most common childhood learning disorder and a significantly heritable trait. Many recent studies have investigated the genetic basis of dyslexia, and several candidate genes have been proposed. Among these, DCDC2 and KIAA0319 have emerged as the strongest candidate genes for dyslexia; however studies have not provided uniformly supportive results. The aim of this study was to assess the contribution of proposed candidate genes to the molecular etiology of dyslexia in a Brazilian sample. Large deletions and duplications in the candidate genes DCDC2, KIAA0319, and ROBO1 were investigated in 51 dyslexic subjects. Furthermore, a family-based association study was performed to investigate whether associations observed in other populations with variants in the DCDC2 and KIAA0319 genes were reproducible in Brazilian dyslexic individuals. Our analysis did not detect any deletions or duplications in the genes studied, and we found no evidence that the allelic variants in the two candidate genes were significantly associated with RD in our sample. Our data do not support a role of the DCDC2/KIAA0319 locus in influencing dyslexia as a categorical trait. Given the genetic complexity of dyslexia, it is plausible that both genes contribute to an increased risk, but the relative influence of these 2 genes on RD varies in different study samples, and/or depends on analytical approaches.


Alterations of serum brain-derived neurotrophic factor levels in early alcohol withdrawal.
Alcohol withdrawal-enhanced neurotoxicity contributes to the addictive process. Brain-derived neurotrophic factor (BDNF) plays an important role in neuronal plasticity and learning. In this study, we explored the changes of serum BDNF levels in alcoholic patients at baseline and after one-week alcohol withdrawal. Twenty-five alcoholic patients were admitted for alcohol detoxification treatment, and 22 healthy control subjects were also enrolled. We collected blood samples of the patient group on the first and seventh day of alcohol withdrawal, and measured serum BDNF level with sandwich enzyme-linked immunosorbent assay. The severity of withdrawal symptoms was evaluated by the Clinical Institute Withdrawal Assessment-Alcohol, Revised every eight hours. Serum BDNF levels did not differ significantly between alcoholic patients and control subjects. But BDNF levels were found to be significantly increased one week after alcohol withdrawal (from 13.9 +/- 3.8 ng/ml to 15.4 +/- 3.8 ng/ml, P = 0.03). A significant positive correlation was found between baseline BDNF level and baseline withdrawal severity (r = 0.45, P = 0.03). The present study suggests that elevated serum BDNF levels were found in early alcohol withdrawal, implying that BDNF may involve in neuroadaptation during the period.


Association Between Lowering LDL-C and Cardiovascular Risk Reduction Among Different Therapeutic Interventions: A Systematic Review and Meta-analysis.
The comparative clinical benefit of nonstatin therapies that reduce low-density lipoprotein cholesterol (LDL-C) remains uncertain. To evaluate the association between lowering LDL-C and relative cardiovascular risk reduction across different statin and nonstatin therapies. The MEDLINE and EMBASE databases were searched (1966-July 2016). The key inclusion criteria were that the study was a randomized clinical trial and the reported clinical outcomes included myocardial infarction (MI). Studies were excluded if the duration was less than 6 months or had fewer than 50 clinical events. Studies of 9 different types of LDL-C reduction approaches were included. Two authors independently extracted and entered data into standardized data sheets and data were analyzed using meta-regression. The relative risk (RR) of major vascular events (a composite of cardiovascular death, acute MI or other acute coronary syndrome, coronary revascularization, or stroke) associated with the absolute reduction in LDL-C level; 5-year rate of major coronary events (coronary death or MI) associated with achieved LDL-C level. A total of 312 175 participants (mean age, 62 years; 24% women; mean baseline LDL-C level of 3.16 mmol/L [122.3 mg/dL]) from 49 trials with 39 645 major vascular events were included. The RR for major vascular events per 1-mmol/L (38.7-mg/dL) reduction in LDL-C level was 0.77 (95% CI, 0.71-0.84; P < .001) for statins and 0.75 (95% CI, 0.66-0.86; P = .002) for established nonstatin interventions that work primarily via upregulation of LDL receptor expression (ie, diet, bile acid sequestrants, ileal bypass, and ezetimibe) (between-group difference, P = .72). For these 5 therapies combined, the RR was 0.77 (95% CI, 0.75-0.79, P < .001) for major vascular events per 1-mmol/L reduction in LDL-C level. For other interventions, the observed RRs vs the expected RRs based on the degree of LDL-C reduction in the trials were 0.94 (95% CI, 0.89-0.99) vs 0.91 (95% CI, 0.90-0.92) for niacin (P = .24); 0.88 (95% CI, 0.83-0.92) vs 0.94 (95% CI, 0.93-0.94) for fibrates (P = .02), which was lower than expected (ie, greater risk reduction); 1.01 (95% CI, 0.94-1.09) vs 0.90 (95% CI, 0.89-0.91) for cholesteryl ester transfer protein inhibitors (P = .002), which was higher than expected (ie, less risk reduction); and 0.49 (95% CI, 0.34-0.71) vs 0.61 (95% CI, 0.58-0.65) for proprotein convertase subtilisin/kexin type 9 inhibitors (P = .25). The achieved absolute LDL-C level was significantly associated with the absolute rate of major coronary events (11 301 events, including coronary death or MI) for primary prevention trials (1.5% lower event rate [95% CI, 0.5%-2.6%] per each 1-mmol/L lower LDL-C level; P = .008) and secondary prevention trials (4.6% lower event rate [95% CI, 2.9%-6.4%] per each 1-mmol/L lower LDL-C level; P < .001). In this meta-regression analysis, the use of statin and nonstatin therapies that act via upregulation of LDL receptor expression to reduce LDL-C were associated with similar RRs of major vascular events per change in LDL-C. Lower achieved LDL-C levels were associated with lower rates of major coronary events.


Explosively Puffed Ginseng Ameliorates Ionizing Radiation-Induced Injury of Colon by Decreasing Oxidative Stress-Related Apoptotic Cell Execution in Mice.
Although radiation therapy (RT) is a feasible treatment approach for early colorectal cancer, RT is considerably toxic to normal tissues due to the increased reactive oxygen species production, which can induce tissue damage. Ginseng, a natural antioxidant agent, exhibits the protective effects against ionizing radiation (IR)-induced damage in in vitro and in vivo models. The explosive puffing of ginseng has been investigated as a process to improve the efficacy of ginseng due to the resulting physicochemical changes in its functional components. In this study, we provided the evidence for promotion in the beneficial role of puffed ginseng extract (PGE) and associated mechanisms of action, in comparison with white ginseng extract (WGE), against IR-induced colorectal injury, using in vivo study on a mouse model. To study the role of PGE in preventing IR-induced damage, we examined colorectal injury and apoptotic changes in mice exposed to 137Cs at 8 Gy. High-performance liquid chromatography analysis showed that PGE had an increased total ginsenoside concentration with new generation of Rg3, Rg5, and Rk1, compared with the concentrations in WGE. Administering PGE, but not WGE, significantly ameliorated IR-induced colorectal cell death through negative regulation of apoptotic signaling pathways. These antiapoptotic effects of PGE were linked to the capacity to suppress the p53-mediated DNA damage response and NF-κB-mediated apoptotic signaling. Moreover, IR-induced oxidative stress in the colorectal epithelium was markedly reduced by PGE administration. Collectively, this study establishes a mechanism of action by which PGE counteracts IR-induced colorectal injury as a novel radioprotective agent.


Choanal Atresia and Craniosynostosis: Development and Disease.
A number of textbooks, review articles, and case reports highlight the potential comorbidity of choanal atresia in craniosynostosis patients. However, the lack of a precise definition of choanal atresia within the current craniosynostosis literature and widely varying methods of detection and diagnosis have produced uncertainty regarding the true coincidence of these conditions. The authors review the anatomy and embryologic basis of the human choanae, provide an overview of choanal atresia, and analyze the available literature that links choanal atresia and craniosynostosis. Review of over 50 case reports that describe patients diagnosed with both conditions reveals inconsistent descriptions of choanal atresia and limited use of definitive diagnostic methodologies. The authors further present preliminary analysis of three-dimensional medical head computed tomographic scans of children diagnosed with craniosynostosis syndromes (e.g., Apert, Pfeiffer, Muenke, and Crouzon) and typically developing children and, although finding no evidence of choanal atresia, report the potentially reduced nasal airway volumes in children diagnosed with Apert and Pfeiffer syndromes. A recent study of the Fgfr2c Crouzon/Pfeiffer syndrome mouse model similarly found a significant reduction in nasal airway volumes in littermates carrying this FGFR2 mutation relative to unaffected littermates, without detection of choanal atresia. The significant correlation between specific craniosynostosis syndromes and reduced nasal airway volume in mouse models for craniosynostosis and human pediatric patients indicates comorbidity of choanal and nasopharyngeal dysmorphologies and craniosynostosis conditions. Genetic, developmental, and epidemiologic sources of these interactions are areas particularly worthy of further research.


Molecular ecology studies of species radiations: current research gaps, opportunities and challenges.
Understanding the drivers and limits of species radiations is a crucial goal of evolutionary genetics and molecular ecology, yet research on this topic has been hampered by the notorious difficulty of connecting micro- and macroevolutionary approaches to studying the drivers of diversification. To chart the current research gaps, opportunities and challenges of molecular ecology approaches to studying radiations, we examine the literature in the journal Molecular Ecology and revisit recent high-profile examples of evolutionary genomic research on radiations. We find that available studies of radiations are highly unevenly distributed among taxa, with many ecologically important and species-rich organismal groups remaining severely understudied, including arthropods, plants and fungi. Most studies employed molecular methods suitable over either short or long evolutionary time scales, such as microsatellites or restriction site-associated DNA sequencing (RAD-seq) in the former case and conventional amplicon sequencing of organellar DNA in the latter. The potential of molecular ecology studies to address and resolve patterns and processes around the species level in radiating groups of taxa is currently limited primarily by sample size and a dearth of information on radiating nuclear genomes as opposed to organellar ones. Based on our literature survey and personal experience, we suggest possible ways forward in the coming years. We touch on the potential and current limitations of whole-genome sequencing (WGS) in studies of radiations. We suggest that WGS and targeted ('capture') resequencing emerge as the methods of choice for scaling up the sampling of populations, species and genomes, including currently understudied organismal groups and the genes or regulatory elements expected to matter most to species radiations.


Huntington CAG repeat size does not modify onset age in familial Parkinson's disease: the GenePD study.
The ATP/ADP ratio reflects mitochondrial function and has been reported to be influenced by the size of the Huntington disease gene (HD) repeat. Impaired mitochondrial function has long been implicated in the pathogenesis of Parkinson's disease (PD), and therefore, we evaluated the relationship of the HD CAG repeat size to PD onset age in a large sample of familial PD cases. PD affected siblings (n = 495), with known onset ages from 248 families, were genotyped for the HD CAG repeat. Genotyping failed in 11 cases leaving 484 for analysis, including 35 LRRK2 carriers. All cases had HD CAG repeats (range, 15-34) below the clinical range for HD, although 5.2% of the sample (n = 25) had repeats in the intermediate range (the intermediate range lower limit = 27; upper limit = 35 repeats), suggesting that the prevalence of intermediate allele carriers in the general population is significant. No relation between the HD CAG repeat size and the age at onset for PD was found in this sample of familial PD.


The effects of gender and CYP46 and apo E polymorphism on 24S-hydroxycholesterol levels in Alzheimer's patients treated with statins.
To examine the effect of gender and polymorphisms of CYP46 and apo E on plasma levels of 24S-hydroxycholesterol in Alzheimer's disease (AD) patients and to determine whether these factors contribute to the variability in responses to statin treatment. Fifty-three AD patients had measurement of plasma levels of 24S-hydroxycholesterol, plasma and lipoprotein cholesterol and genotyping of CYP46 and apo E. Thirty-nine of the subjects subsequently participated in a statin trial for 6 weeks, and had a repetition of the baseline measurements. Baseline levels of 24S-hydroxycholesterol were higher in women than in men. There was a positive and significant correlation of plasma oxysterol levels with levels of total plasma cholesterol (women: r = .72, P < .0001; men: r = .47, P = .02) and non-HDL cholesterol (women: r = .68, P < .0001; men: r = 0.51, P = .01) (and LDL cholesterol) but not HDL cholesterol levels. There was no association of CYP46 or apo E polymorphisms with plasma levels of 24S-hydroxycholesterol. AD subjects treated with statins had a similar percent reduction in lathosterol, 24S-hydroxycholesterol, total cholesterol and non-HDL (and LDL) cholesterol regardless of gender and polymorphisms of CYP46. Subjects with the 4/4 polymorphism had less reduction in the ratios of 24S-hydroxycholesterol-LDL cholesterol. Women with AD had higher levels of plasma 24S-hydroxycholesterol levels than men. Women also showed a very strong correlation of plasma levels of 24S-hydroxycholesterol-to-total and non-HDL cholesterol. This may suggest that the oxysterol may be an important marker of AD risk instead of total cholesterol, as suggested by others. Polymorphisms of CYP46 or apo E do not explain levels of oxysterol or non-HDL cholesterol or the responsiveness to statin treatment in this study.


Toward a phylogenetic classification of the leotiomycetes based on rDNA data.
Phylogenetic relationships of one of the largest nonlichen-forming ascomycetous groups, the Leotiomycetes, were inferred from genes encoding three rDNA regions (SSU+LSU+5.8S rDNA). A dataset was prepared with rDNA sequences data from 108 isolates, among which we sampled 85 taxa representing four orders and 16 families in the Leotiomycetes. Equally weighted parsimony and Bayesian analyses were performed. Bootstrap proportion and Bayesian posterior probability under the GTR+gamma+iota model were estimated along the branches. Based on our results the Leotiomycetes is relatively well defined as a class and it includes the Cyttariales, Erysiphales, Helotiales, Rhytismatales and two families of uncertain position, Myxotrichaceae and Pseudeurotiaceae. The placements of the Thelebolales and Ascocorticiaceae are not examined and are accepted as tentative in the Leotiomycetes. Our results agree with previous studies to remove the Geoglossaceae, including Geoglossum, Trichoglossum and Sarcoleotia, from the Leotiomycetes. Positions of the Erysiphales and Rhytismatales in the Leotiomycetes are confirmed. The Helotiales and Myxotrichaceae are paraphyletic. Close relationships are supported strongly among the Hemiphacidiaceae, Rutstroemiaceae and Sclerotiniaceae, among Loramycetaceae, the northern hemisphere Vibrisseaceae, the Dark Septate Endophyte fungus Phialocephala fortinii and Mollisia cinerea, and between species of Bulgaria and Phadidiopycnis. Sequence data of rDNA regions are not adequate to resolve the relationships among major groups of the Leotiomycetes.


Engineering lithoheterotrophy in an obligate chemolithoautotrophic Fe(II) oxidizing bacterium.
Neutrophilic Fe(II) oxidizing bacteria like Mariprofundus ferrooxydans are obligate chemolithoautotrophic bacteria that play an important role in the biogeochemical cycling of iron and other elements in multiple environments. These bacteria generally exhibit a singular metabolic mode of growth which prohibits comparative "omics" studies. Furthermore, these bacteria are considered non-amenable to classical genetic methods due to low cell densities, the inability to form colonies on solid medium, and production of copious amounts of insoluble iron oxyhydroxides as their metabolic byproduct. Consequently, the molecular and biochemical understanding of these bacteria remains speculative despite the availability of substantial genomic information. Here we develop the first genetic system in neutrophilic Fe(II) oxidizing bacterium and use it to engineer lithoheterotrophy in M. ferrooxydans, a metabolism that has been speculated but not experimentally validated. This synthetic biology approach could be extended to gain physiological understanding and domesticate other bacteria that grow using a single metabolic mode.


Cost-effectiveness of traditional and endovenous treatments for varicose veins.
The aim of this study was to evaluate the cost-effectiveness of traditional and endovenous treatments for patients with primary great saphenous varicose veins. A Markov model was constructed to compare costs and quality-adjusted life years (QALYs) for great saphenous vein (GSV) reflux. Eight popular treatment strategies were compared up to 5 years. Estimates for the effectiveness of treatments were obtained from published randomized studies and cost values were obtained from published National Health Service (NHS) healthcare resource group tariffs and device manufacturers. Parameter uncertainty was tested using sensitivity analysis and Monte Carlo simulation. Ultrasound-guided foam sclerotherapy (UGFS) had the lowest initial cost, but a higher requirement for further interventions. Day-case surgery (with concomitant treatment of varicosities), endovenous laser ablation (EVLA) and radiofrequency ablation (RFA) performed in an outpatient or office setting (with staged treatment of varicosities) were likely to be cost-effective treatment strategies. The incremental cost-effectiveness ratio (ICER) for UGFS (versus conservative care), EVLA (versus UGFS) and RFA (versus EVLA) were £1366, £5799 and £17 350 per QALY respectively. The ICER for traditional surgery (performed on a day-case basis) was £19 012 compared with RFA. Other strategies were not cost-effective using the NHS threshold of £20 000 per QALY. Day-case surgery or endovenous ablation using EVLA or RFA performed as an outpatient are likely to be cost-effective treatment strategies for patients with primary unilateral GSV reflux requiring treatment.


The use of the life course paradigm and life course charts to explore referral for family history of breast cancer.
Life course research methodologies are used extensively in historical and social science research. In 1998 the life course paradigm was introduced to provide a way of tracing the interplay of person and setting. The method has had a very limited use in nursing research, but in this study it was utilized as a way of capturing dynamic change by placing the individual within a context of four domains; location in time and place, linked lives, human agency and timing of lives. To describe the paradigm, review its use in healthcare research and provide a specific example of its use in healthcare. This paper discusses a novel method of creating life course charts for a qualitative study exploring the differing experiences of women referred from primary care to specialist services due to a family history of breast cancer. A nurse-led breast cancer family history clinic in the UK. Twenty-two women. Life charts were used in conjunction with a grounded theory approach to analyse data collected from semi-structured interviews. Twenty-two life charts were created and the ability to layer the charts of multiple women to visualise similarities and differences aided the analysis. The life charts were a useful tool in the development of theoretical understandings and the psychosocial process of realisation of risk emerged as central to the initiation of referral. This was often apparent when approaching the age of an affected relative (anticipated onset) or when current circumstances emulate past experience (generational transference). This approach to charting complex psychological, social and contextual factors throughout the life course was methodologically beneficial and could have a wider utility in nursing and healthcare research. As a research tool it enhanced a holistic approach to patient care issues and was helpful as an aid to understanding health behaviours linked to familial risk.


Presymptomatic neuromuscular disorders disclosed following statin treatment.
It is well recognized that statins affect muscular tissue adversely and that their use is associated with clinically important myositis, rhabdomyolysis, mild elevation of serum creatine kinase (CK) levels, myalgias, muscle weakness, muscle cramps, and persistent myalgias or serum CK level elevations after statin treatment is discontinued. The association between statins and the disclosure of presymptomatic metabolic myopathy is another underrated phenomenon related to statin therapy that was recently recognized in rare cases. The purpose of this report is to provide additional support for this association and to report other neuromuscular disorders that have also been seen following statin intake. The present case series illustrates that statins may act as unmasking agents in asymptomatic patients with a latent neuromuscular disorder. Thus, it may be postulated that statin intake may be a sufficient insult to precipitate neuromuscular symptoms and substantially increase muscle enzymes in presymptomatic patients with an abnormal neuromuscular substrate. In conclusion, muscular symptoms or increased serum CK levels persisting after statin treatment discontinuation should alert the clinician to pursue further diagnostic evaluations for the detection of potential underlying neuromuscular diseases.


Concordance Between Romantic Orientations and Sexual Attitudes: Comparing Allosexual and Asexual Adults.
Sexual and romantic orientations are often considered one and the same, and attitudes about engaging in sexual behavior are assumed to be predominantly positive. The current study explored the concordance between sexual and romantic orientations among allosexual and asexual adults as well as the frequency with which they identify as having a sex-positive, sex-neutral, or sex-averse attitude. As expected, allosexual adults were largely sex-positive (82%) and almost all (89%) had a romantic orientation that matched their sexual orientation. In contrast, we found that only 37% of asexual adults had concordant sexual and romantic orientations and that most asexual adults self-identify as either sex-neutral (41%) or sex-averse (54%). Further, we used a semantic differential task to assess sexual intimacy attitudes and how they varied for adults based on sexual attitude. Asexual adults, regardless of sexual attitude, had less positive attitudes overall than allosexual adults. Interestingly, aromantic asexual adults did not have more negative attitudes about sexual intimacy than romantic asexual participants. Although asexual adults held less positive attitudes about sex than allosexual adults, there was considerable heterogeneity within our asexual sample. The current study provides further insight into the concordance between romantic and sexual orientation, and the associations among sexual and intimacy attitudes for both allosexual and asexual adults. These findings will have implications for future research on how asexual adults navigate romantic relationships.


The sounds of silence: cessation of singing and song pausing are ultrasound-induced acoustic startle behaviors in the katydid Neoconocephalus ensiger (Orthoptera; Tettigoniidae).
Previous studies of acoustic startle in insects have dealt with behavioral and/or neural mechanisms employed in evading aerially hawking, echolocating bats; however, insects also face terrestrial predators. Here we describe an acoustic startle response of the nocturnal katydid, Neoconocephalus ensiger. Stridulating males disturbed in the field perform obvious antipredatory behaviors--cessation of singing, freezing, jumping, and evasive flight. Under controlled laboratory conditions we found that cessation of singing and song pausing are ultrasound-specific behaviors: when stimulated with pulsed ultrasound (20-100 kHz), but not audio-sound (< 20 kHz), males cease mate calling or insert pauses in their song. A second factor influencing acoustic startle is the phase of stimulation: an acoustic startle response occurs only when the pulse of ultrasound arrives during the window of silence between stridulatory syllables. The average startle threshold and response latency was 70 +/- 5 dB SPL and 34.2 +/- 6.0 ms, respectively. N. ensiger is particularly useful for examining acoustic startle responses of nonflying insects because (1) its calling song is broadband and contains ultrasound, thus the possibility exists of confusion over the biological meaning of ultrasound, and (2) this species shows the classic bat-avoidance response while flying, so a direct comparison between two types of acoustic startle is possible within the same species.


Accumulation of a tetrahydroisoquinoline in phenylketonuria.
3',4'-Deoxynorlaudanosolinecarboxylic acid (DNLCA), a tetrahydroisoquinoline derived from dopamine and phenylpyruvic acid, has been detected by computerized mass fragmentography in urine of phenylketonuric children and in urine and brain of rats with experimentally induced hyperphenylalaninemia. Levels of DNLCA in brain of treated animals were more than tenfold higher than controls, and the excess tetrahydroisoquinoline appeared to accumulate in the cerebellum and cortex. DNLCA is a noncompetitive inhibitor of dopamine beta-hydroxylase (inhibition constant, Ki, = 0.42 mM) and is taken up by the brain.


Absolute lymphocyte count predicts overall survival in follicular lymphomas.
The peripheral blood absolute lymphocyte count (ALC) recovery after autologous stem cell transplantation has been shown to be an independent prognostic factor for survival for different haematologic malignancies. The role of ALC at diagnosis for follicular (grades 1 and 2) lymphomas (FL) on survival is not well described. The primary objective of this study was to assess the role of ALC on overall survival (OS) in FL patients. Of 1104 FL patients, 228 patients were originally diagnosed, followed, and had all treatment at the Mayo Clinic from 1984 and 1999, were evaluated. The median follow-up was 89 months (range: 8.35-248). ALC as a continuous variable was identified as a predictor for OS [Hazard ratio (HR) = 0.74, P < 0.04]. ALC >/= 1.0 x 10(9)/l (n = 164) predicted a longer OS versus ALC < 1.0 x 10(9)/l (n = 64; 175 vs. 73 months respectively, P < 0.0001). When compared with the Follicular Lymphoma International Prognostic Index (FLIPI), ALC was an independent prognostic factor for OS by multivariate analysis (HR = 0.677, P < 0.0001). These data suggest a critical role of FL patients' immune status at diagnosis on survival.


Contrast-induced nephropathy in patients undergoing intravenous contrast-enhanced computed tomography in Korea: a multi-institutional study in 101487 patients.
To evaluate the prevalence of known risk factors for contrast-induced nephropathy (CIN) and their association with the actual occurrence of CIN in patients undergoing intravenous contrast-enhanced computed tomography (CECT) in Korea. Patients who underwent CECT in 2008 were identified in the electronic medical records of 16 tertiary hospitals of Korea. Data on demographics, comorbidities, prescriptions and laboratory test results of patients were collected following a standard data extraction protocol. The baseline renal function was assessed using the estimated glomerular filtration rate (eGFR). We identified the prevalence of risk factors along the eGFR strata and evaluated their influence on the incidence of CIN, defined as a 0.5 mg/dL or 25% increase in serum creatinine after CECT. Of 432425 CECT examinations in 272136 patients, 140838 examinations in 101487 patients met the eligibility criteria for analysis. The mean age of the participants was 57.9 ± 15.5 years; 25.1% of the patients were older than 70 years. The prevalence of diabetes mellitus was 11.9%, of hypertension 13.7%, of gout 0.55% and of heart failure was 1.7%. Preventive measures were used in 40238 CECT examinations (28.6%). The prevalence of risk factors and use of preventive measures increased as the renal function became worse. A CIN was occurred after 3103 (2.2%) CECT examinations, revealing a significant association with decreased eGFR, diabetes mellitus, and congestive heart failure after adjustment. Risk factors for CIN are prevalent among the patients undergoing CECT. Preventive measures were seemingly underutilized and a system is needed to improve preventive care.


Surface structure determines dynamic wetting.
Liquid wetting of a surface is omnipresent in nature and the advance of micro-fabrication and assembly techniques in recent years offers increasing ability to control this phenomenon. Here, we identify how surface roughness influences the initial dynamic spreading of a partially wetting droplet by studying the spreading on a solid substrate patterned with microstructures just a few micrometers in size. We reveal that the roughness influence can be quantified in terms of a line friction coefficient for the energy dissipation rate at the contact line, and that this can be described in a simple formula in terms of the geometrical parameters of the roughness and the line-friction coefficient of the planar surface. We further identify a criterion to predict if the spreading will be controlled by this surface roughness or by liquid inertia. Our results point to the possibility of selectively controlling the wetting behavior by engineering the surface structure.


Endocannabinoid signaling in microglial cells.
The endocannabinoid signaling system (eCBSS) is composed of cannabinoid (CB) receptors, their endogenous ligands (the endocannabinoids, eCB) and the enzymes that produce and inactivate these ligands. Neurons use this signaling system to communicate with each other and Delta9-tetrahydrocannabinol (THC), the main psychotropic ingredient of Cannabis sativa, induces profound behavioral effects by impinging on this communication. Evidence now shows that microglia, the macrophages of the brain, also express a functional eCBSS and that activation of CB receptors expressed by activated microglia controls their immune-related functions. This review summarizes this evidence, discusses how microglia might use the eCBSS to communicate with each other and neighboring cells, and argues that compounds selectively targeting the eCBSS expressed by microglia constitute valuable therapeutics to manage acute and chronic neuroinflammation, without inducing the psychotropic effects and underlying addictive properties commonly associated with THC.


Estimation of copy number aberrations: Comparison of exome sequencing data with SNP microarrays identifies homozygous deletions of 19q13.2 and CIC in neuroblastoma.
In the pediatric cancer neuroblastoma, analysis of recurrent chromosomal aberrations such as loss of chromosome 1p, 11q, gain of 17q and MYCN amplification are used for patient stratification and subsequent therapy decision making. Different analysis techniques have been used for detection of segmental abnormalities, including fluorescence in situ hybridization (FISH), comparative genomic hybridization (CGH)-microarrays and multiplex ligation-dependent probe amplification (MLPA). However, as next-generation sequencing becomes available for clinical use, this technique could also be used for assessment of copy number alterations simultaneously with mutational analysis. In this study we compare genomic profiles generated through exome sequencing data with profiles generated from high resolution Affymetrix single nucleotide polymorphism (SNP) microarrays on 30 neuroblastoma tumors of different stages. Normalized coverage reads for tumors were calculated using Control-FREEC software and visualized through a web based Shiny application, prior to comparison with corresponding SNP-microarray data. The two methods show high-level agreement for breakpoints and copy number of larger segmental aberrations and numerical aneuploidies. However, several smaller gene containing deletions that could not readily be detected through the SNP-microarray analyses were identified through exome profiling, most likely due to difference between spatial distribution of microarray probes and targeted regions of the exome capture. These smaller aberrations included focal ATRX deletion in two tumors and three cases of novel deletions in chromosomal region 19q13.2 causing homozygous loss of multiple genes including the CIC (Capicua) gene. In conclusion, genomic profiles generated from normalized coverage of exome sequencing show concordance with SNP microarray generated genomic profiles. Exome sequencing is therefore a useful diagnostic tool for copy number variant (CNV) detection in neuroblastoma tumors, especially considering the combination with mutational screening. This enables detection of theranostic targets such as ALK and ATRX together with detection of significant segmental aneuploidies, such as 2p-gain, 17q-gain, 11q-deletion as well as MYCN amplification.


Gold-carbonyl group interactions in the electrochemistry of anthraquinone thiols self-assembled on Au(111)-surfaces.
New anthraquinone derivatives with either a single or two thiol groups (AQ1 and AQ2) were synthesized and immobilized in self-assembled monolayers (SAMs) on Au(111) electrodes via Au-S bonds. The resultant AQ1- and AQ2-SAMs were studied by cyclic voltammetry (CV) and electrochemical impedance spectroscopy (EIS), which enabled mapping of the gold-carbonyl group interactions and other dynamics in the Au-S bound molecular framework. Understanding of these interactions is important for research on thiol-coated gold nanoclusters, since (I) anthraquinone derivatives are a major compound family for providing desired redox functionality in multifarious assays or devices, and (II) the gold-carbonyl interactions can strongly affect anthraquinone electrochemistry. Based on equivalent circuit analysis, it was found that there is a significant rise in polarization resistance (related to SAM structural reorganization) at potentials that can be attributed to the quinone/semi-quinone interconversion. The equivalent circuit model was validated by calculation of pseudocapacitance for quinone-to-hydroquinone interconversion, in good agreement with the values derived from CV. The EIS and CV patterns obtained provide consistent evidence for two different ECEC (i.e. proton-controlled ET steps, PCET) pathways in AQ1- and AQ2-SAMs. Notably, it was found that the formal reorganization (free) energies obtained for the elementary PCET steps are unexpectedly small for both SAMs studied. This anomaly suggests high layer rigidity and recumbent molecular orientation on gold surfaces, especially for the AQ2-SAMs. The results strongly indicate that gold-carbonyl group interactions can be controlled by favorable structural organization of anthraquinone-based molecules on gold surfaces.


Expression and function of the homoeotic genes Antennapedia and Sex combs reduced in the embryonic midgut of Drosophila.
Drosophila homoeotic genes control the formation of external morphological features of the embryo and adult, and in addition affect differentiation of the nervous system. Here we describe the morphogenetic events in the midgut that are controlled by the homoeotic genes Sex combs reduced (Scr) and Antennapedia (Antp). The midgut is composed of two cell layers, an inner endoderm and an outer visceral mesoderm that surround the yolk. Scr and Antp are expressed in the visceral mesoderm but not in the endoderm. The two genes are required for different aspects of the midgut morphogenesis. In Scr null mutant embryos the gastric caeca fail to form. Scr is expressed in the visceral mesoderm cells posterior to the primordia of the gastric caeca and appears to be indirectly required for the formation of the caeca. Antp is expressed in visceral mesoderm cells that overlie a part of the midgut where a constriction will form, and Antp null mutant embryos fail to form this constriction. An ultrastructural analysis of the midgut reveals that the visceral mesoderm imposes the constriction on the endoderm and the yolk. The mesodermal tissue contracts within the constriction and thereby penetrates the layer of the midgut endoderm. Microtubules participate in the morphological changes of the visceral mesoderm cells. The analysis of the expression of Scr in Antp mutant embryos revealed a case of tissue-specific regulation of Scr expression by Antp. In the epidermis, Antp has been shown to negatively regulate Scr, but it positively regulates Scr in the visceral mesoderm.


Redox-ligand sustains controlled generation of CF3 radicals by well-defined copper complex.
A well-defined copper complex bearing iminosemiquinone ligands performs single electron reduction of an electrophilic CF3+ source into CF˙3 radicals. This redox behavior is enabled by the ligand which shuttles through two different redox states (iminosemiquinone and iminobenzoquinone) while the copper center is preserved as a Cu(ii). This system was used in the trifluoromethylation of silyl enol ethers, heteroaromatics and in the hydrotrifluoromethylation of alkynes. This is the first example of cooperative redox catalysis for the controlled generation of CF˙3 radicals.


Prevention of atherosclerosis in apolipoprotein E-deficient mice by bone marrow transplantation.
Apolipoprotein E (apoE) deficiency causes severe hyperlipidemia and atherosclerosis in humans and in gene-targeted mice. Although the majority of apoE in plasma is of hepatic origin, apoE is synthesized by a variety of cell types, including macrophages. Because macrophages derive from hematopoietic cells, bone marrow transplantation was used to examine the potential of apoE synthesized by bone marrow-derived cells to correct the hyperlipidemia and atherosclerosis caused by apoE deficiency. After transplantation of bone marrow from mice with the normal apoE gene into apoE-deficient mice, apoE was detected in serum and promoted clearance of lipoproteins and normalization of serum cholesterol levels. ApoE-deficient mice given transplants of normal bone marrow showed virtually complete protection from diet-induced atherosclerosis.


Creation and Validation of Classification Criteria for Discoid Lupus Erythematosus.
Classification criteria are the standardized definitions that are used to enroll uniform cohorts for research studies. They emphasize high specificity and are distinct from diagnostic criteria. No universally recognized classification criteria currently exist for discoid lupus erythematosus (DLE), which has led to problematic heterogeneity in observational and interventional clinical studies across the field. To create and validate classification criteria for DLE using 12 previously defined candidate criteria items. For this diagnostic study, candidate criteria items were prospectively applied by dermatologists and dermatopathologists at clinical visits of patients with DLE or a condition that could be confused for DLE, termed a DLE mimicker, at academic dermatology practices across the United States, Poland, Japan, and South Korea. Data were collected from December 1, 2017, to February 1, 2019, and analyzed from March 1 to September 19, 2019. Clinical features among these 2 groups were calculated and compared with χ2 or Fisher exact tests. Candidate models were identified using best subsets logistic regression analysis. Improvement tests, fit statistics, and discrimination were considered to choose a final model. Nine sites contributed 215 patients, 15 of whom had missing or incomplete data. The final model for DLE classification criteria includes only clinical variables: atrophic scarring (3 points), location in the conchal bowl (2 points), preference for the head and neck (2 points), dyspigmentation (1 point), follicular hyperkeratosis and/or plugging (1 point), and erythematous to violaceous in color (1 point), with an area under the receiving operating characteristic curve of 0.91 (95% CI, 0.87-0.95). A score of at least 5 points yields a sensitivity of 84.1% and a specificity of 75.9% in the classification of DLE, with increasing scores yielding higher specificity. These findings provide the initial validation of classification criteria for DLE for use in observational and clinical trials.


Knowledge, Beliefs and Practices Regarding Antiretroviral Medications for HIV Prevention: Results from a Survey of Healthcare Providers in New England.
Antiretroviral treatment for HIV-infection before immunologic decline (early ART) and pre-exposure chemoprophylaxis (PrEP) can prevent HIV transmission, but routine adoption of these practices by clinicians has been limited. Between September and December 2013, healthcare practitioners affiliated with a regional AIDS Education and Training Center in New England were invited to complete online surveys assessing knowledge, beliefs and practices regarding early ART and PrEP. Multivariable models were utilized to determine characteristics associated with prescribing intentions and practices. Surveys were completed by 184 practitioners. Respondent median age was 44 years, 58% were female, and 82% were white. Among ART-prescribing clinicians (61% of the entire sample), 64% were aware that HIV treatment guidelines from the Department of Health and Human Services recommended early ART, and 69% indicated they would prescribe ART to all HIV-infected patients irrespective of immunologic status. However, 77% of ART-prescribing clinicians would defer ART for patients not ready to initiate treatment. Three-fourths of all respondents were aware of guidance from the U.S. Centers for Disease Control and Prevention recommending PrEP provision, 19% had prescribed PrEP, and 58% of clinicians who had not prescribed PrEP anticipated future prescribing. Practitioners expressed theoretical concerns and perceived practical barriers to prescribing early ART and PrEP. Clinicians with higher percentages of HIV-infected patients (aOR 1.16 per 10% increase in proportion of patients with HIV-infection, 95% CI 1.01-1.34) and infectious diseases specialists (versus primary care physicians; aOR 3.32, 95% CI 0.98-11.2) were more likely to report intentions to prescribe early ART. Higher percentage of HIV-infected patients was also associated with having prescribed PrEP (aOR 1.19, 95% CI 1.06-1.34), whereas female gender (aOR 0.26, 95% CI 0.10-0.71) was associated with having not prescribed PrEP. These findings suggest many clinicians have shifted towards routinely recommending early ART, but not PrEP, so interventions to facilitate PrEP provision are needed.


A novel approach to suicide prevention - Educating when it matters.
Looking at the burden of suicide, there is a dire need for medical schools to incorporate suicide prevention training. Effective communication helps in early detection and management of suicidal behavior. Medical students can act as a GATEKEEPER if they receive adequate training. This was an educational intervention study done at tertiary care teaching hospital to assess the knowledge and attitude of medical students toward depression and suicide and to impart and assess communication skills for suicide prevention in one of the four batches of students in 4th semester. Pretest was conducted to assess knowledge and attitude toward depression and suicide, followed by training using interactive lectures, demonstration of interview, and hands-on training with patients and role-plays. The posttest and objective structured clinical examination (OSCE) were administered for skill assessment. Feedback was taken regarding this intervention. The mean marks of the pre- and post-test were 8.96 (8.3-9.6) and 14.58 (13.8-15.3), respectively, out of 25. The difference was statistically significant (t = 13.24, P ≤ 0.0001) which suggests improvement in knowledge. We found mixed responses in attitude statements showing limited change. Mean obtained marks on OSCE examination out of 66 was 42.7. Among various components of OSCE, students scored high on rapport building. The most useful components of trainings were role-play, OSCE, and interaction with patients as per their feedback. The intervention was found effective in increasing knowledge, changing attitude, and enhancing communication skills of medical students toward suicide prevention. Training of communication skills for suicide prevention in depressed person should be given to every medical student as suggested by feedback.


Etanercept in children with polyarticular juvenile rheumatoid arthritis. Pediatric Rheumatology Collaborative Study Group.
We evaluated the safety and efficacy of etanercept, a soluble tumor necrosis factor receptor (p75):Fc fusion protein, in children with polyarticular juvenile rheumatoid arthritis who did not tolerate or had an inadequate response to methotrexate. Patients 4 to 17 years old received 0.4 mg of etanercept per kilogram of body weight subcutaneously twice weekly for up to three months in the initial, open-label part of a multicenter trial. Those who responded to treatment then entered a double-blind study and were randomly assigned to receive either placebo or etanercept for four months or until a flare of the disease occurred. A response was defined as an improvement of 30 percent or more in at least three of six indicators of disease activity, with no more than one indicator worsening by more than 30 percent. At the end of the open-label study, 51 of the 69 patients (74 percent) had had responses to etanercept treatment. In the double-blind study, 21 of the 26 patients who received placebo (81 percent) withdrew because of disease flare, as compared with 7 of the 25 patients who received etanercept (28 percent) (P=0.003). The median time to disease flare with placebo was 28 days, as compared with more than 116 days with etanercept (P<0.001). In the double-blind study, there were no significant differences between the two treatment groups in the frequency of adverse events. Treatment with etanercept leads to significant improvement in patients with active polyarticular juvenile rheumatoid arthritis. Etanercept is well tolerated by pediatric patients.


Neuroimaging and the functional neuroanatomy of psychotherapy.
Studies measuring the effects of psychotherapy on brain function are under-represented relative to analogous studies of medications, possibly reflecting historical biases. However, psychological constructs relevant to several modalities of psychotherapy have demonstrable neurobiological correlates, as indicated by functional neuroimaging studies in healthy subjects. This review examines initial attempts to measure directly the effects of psychotherapy on brain function in patients with depression or anxiety disorders. Fourteen published, peer-reviewed functional neuroimaging investigations of psychotherapy were identified through a MEDLINE search and critically reviewed. Studies were compared for consistency of findings both within specific diagnostic categories, and between specific modalities of psychotherapy. Results were also compared to predicted neural models of psychotherapeutic interventions. Behavioral therapy for anxiety disorders was consistently associated with attenuation of brain-imaging abnormalities in regions linked to the pathophysiology of anxiety, and with activation in regions related to positive reappraisal of anxiogenic stimuli. In studies of major depressive disorder, cognitive behavioral therapy and interpersonal therapy were associated with markedly similar changes in cortical-subcortical circuitry, but in unexpected directions. For any given psychiatric disorder, there was only partial overlap between the brain-imaging changes associated with pharmacotherapy and those associated with psychotherapy. Despite methodological limitations, initial neuroimaging studies have revealed convergent and mechanistically sensible effects of psychotherapy on brain function across a range of psychiatric disorders. Further research in this area may take advantage of emerging neuroimaging techniques to explore a broader range of psychotherapies, with the ultimate goal of improving clinical decision-making and treatment.


Mic13 Is Essential for Formation of Crista Junctions in Mammalian Cells.
Mitochondrial cristae are connected to the inner boundary membrane via crista junctions which are implicated in the regulation of oxidative phosphorylation, apoptosis, and import of lipids and proteins. The MICOS complex determines formation of crista junctions. We performed complexome profiling and identified Mic13, also termed Qil1, as a subunit of the MICOS complex. We show that MIC13 is an inner membrane protein physically interacting with MIC60, a central subunit of the MICOS complex. Using the CRISPR/Cas method we generated the first cell line deleted for MIC13. These knockout cells show a complete loss of crista junctions demonstrating that MIC13 is strictly required for the formation of crista junctions. MIC13 is required for the assembly of MIC10, MIC26, and MIC27 into the MICOS complex. However, it is not needed for the formation of the MIC60/MIC19/MIC25 subcomplex suggesting that the latter is not sufficient for crista junction formation. MIC13 is also dispensable for assembly of respiratory chain complexes and for maintaining mitochondrial network morphology. Still, lack of MIC13 resulted in a moderate reduction of mitochondrial respiration. In summary, we show that MIC13 has a fundamental role in crista junction formation and that assembly of respiratory chain supercomplexes is independent of mitochondrial cristae shape.


Quality of Colonoscopy Performed in Rural Practice: Experience From the Clinical Outcomes Research Initiative and the Oregon Rural Practice-Based Research Network.
Colon cancer screening is effective. To complete screening in 80% of individuals over age 50 years by 2018 will require adequate colonoscopy capacity throughout the country, including rural areas, where colonoscopy providers may have less specialized training. Our aim was to study the quality of colonoscopy in rural settings. The Clinical Outcomes Research Initiative (CORI) and the Oregon Rural Practice-based Research Network (ORPRN) collaborated to recruit Oregon rural practices to submit colonoscopy reports to CORI's National Endoscopic Database (NED). Ten ORPRN sites were compared to non-ORPRN rural (n = 11) and nonrural (n = 43) sites between January 2009 and October 2011. Established colonoscopy quality measures were calculated for all sites. No ORPRN physicians were gastroenterologists compared with 82% of nonrural physicians. ORPRN practices reached the cecum in 87.4% of exams compared with 89.3% of rural sites (P = .0002) and 90.9% of nonrural sites (P < .0001). Resected polyps were less likely to be retrieved (84.7% vs 91.6%; P < .0001) and sent to pathology (77.1% vs 91.3%; P < .0001) at ORPRN practices compared to nonrural sites. The overall polyp detection (39.0% vs 40.3%) was similar (P = .217) between ORPRN and nonrural practices. Of exams with polyps, the rate for largest polyp on exam 6-9 mm was 20.8% at ORPRN sites, compared to 26.8% at nonrural sites (P < .0001), and for polyps >9mm 16.6% vs 18.7% (P = .106). ORPRN sites performed well on most colonoscopy quality measures, suggesting that high-quality colonoscopy can be performed in rural settings.


Spontaneous assembly of subnanometre-ordered domains in the ligand shell of monolayer-protected nanoparticles.
The properties of materials can be created and improved either by confining their dimensions in the nanoscale or by controlling their nanostructure. We have combined these two concepts, and here we describe a new class of nanostructured nanosized materials that show ordered phase-separated domains at an unprecedented molecular length scale. Scanning tunnelling and transmission electron microscope images of monolayer-protected metal nanoparticles, with ligand shells composed of a mixture of molecules, show that the ligands phase-separate into ordered domains as small as 5 A. Importantly, the domain shape and dimensions can be controlled by varying the ligand composition or the metallic core size. We demonstrate that the formation of ordered domains depends on the curvature of the underlying substrate, and that novel properties result from this nanostructuring. For example, because the size of the domains is much smaller than the typical dimensions of a protein, these materials are extremely effective in avoiding non-specific adsorption of a variety of proteins.


Squeezing and expanding light without reflections via transformation optics.
We study the reflection properties of squeezing devices based on transformation optics. An analytical expression for the angle-dependent reflection coefficient of a generic three-dimensional squeezer is derived. In contrast with previous studies, we find that there exist several conditions that guarantee no reflections so it is possible to build transformation-optics-based reflectionless squeezers. Moreover, it is shown that the design of antireflective coatings for the non-reflectionless case can be reduced to matching the impedance between two dielectrics. We illustrate the potential of these devices by proposing two applications in which a reflectionless squeezer is the key element: an ultra-short perfect coupler for high-index nanophotonic waveguides and a completely flat reflectionless hyperlens. We also apply our theory to the coupling of two metallic waveguides with different cross-section. Finally, we show how the studied devices can be implemented with non-magnetic isotropic materials by using a quasi-conformal mapping technique.


Empathic neural responses are modulated by the perceived fairness of others.
The neural processes underlying empathy are a subject of intense interest within the social neurosciences. However, very little is known about how brain empathic responses are modulated by the affective link between individuals. We show here that empathic responses are modulated by learned preferences, a result consistent with economic models of social preferences. We engaged male and female volunteers in an economic game, in which two confederates played fairly or unfairly, and then measured brain activity with functional magnetic resonance imaging while these same volunteers observed the confederates receiving pain. Both sexes exhibited empathy-related activation in pain-related brain areas (fronto-insular and anterior cingulate cortices) towards fair players. However, these empathy-related responses were significantly reduced in males when observing an unfair person receiving pain. This effect was accompanied by increased activation in reward-related areas, correlated with an expressed desire for revenge. We conclude that in men (at least) empathic responses are shaped by valuation of other people's social behaviour, such that they empathize with fair opponents while favouring the physical punishment of unfair opponents, a finding that echoes recent evidence for altruistic punishment.


Dynamic conservation of forest genetic resources in 33 European countries.
Dynamic conservation of forest genetic resources (FGR) means maintaining the genetic diversity of trees within an evolutionary process and allowing generation turnover in the forest. We assessed the network of forests areas managed for the dynamic conservation of FGR (conservation units) across Europe (33 countries). On the basis of information available in the European Information System on FGR (EUFGIS Portal), species distribution maps, and environmental stratification of the continent, we developed ecogeographic indicators, a marginality index, and demographic indicators to assess and monitor forest conservation efforts. The pan-European network has 1967 conservation units, 2737 populations of target trees, and 86 species of target trees. We detected a poor coincidence between FGR conservation and other biodiversity conservation objectives within this network. We identified 2 complementary strategies: a species-oriented strategy in which national conservation networks are specifically designed for key target species and a site-oriented strategy in which multiple-target units include so-called secondary species conserved within a few sites. The network is highly unbalanced in terms of species representation, and 7 key target species are conserved in 60% of the conservation units. We performed specific gap analyses for 11 tree species, including assessment of ecogeographic, demographic, and genetic criteria. For each species, we identified gaps, particularly in the marginal parts of their distribution range, and found multiple redundant conservation units in other areas. The Mediterranean forests and to a lesser extent the boreal forests are underrepresented. Monitoring the conservation efficiency of each unit remains challenging; however, <2% of the conserved populations seem to be at risk of extinction. On the basis of our results, we recommend combining species-oriented and site-oriented strategies.


Selective Chlorophyll Removal Method to "Degreen" Botanical Extracts.
Chlorophylls are present in all extracts from the aerial parts of green plant materials. Chlorophylls may act as in vitro bioassay nuisance compounds, possibly preventing the reproducibility and accurate measurement of readouts due to their UV/vis absorbance, fluorescence properties, and tendency to precipitate in aqueous media. Despite the diversity of methods used traditionally to remove chlorophylls, details about their mode of operation, specificity, and reproducibility are scarce. Herein, we report a selective and efficient 45 min liquid-liquid/countercurrent chlorophyll cleanup method using Centrifugal Partition Chromatography (CPC) with a solvent system composed of hexanes-EtOAc-MeOH-water (5:5:5:5, v/v) in elution-extrusion mode. The broader utility of the method was assessed with four different extracts prepared from three well-characterized plant materials: Epimedium sagittatum (leaves), Senna alexandrina (leaves), and Trifolium pratense (aerial parts). The reproducibility of the method, the selectivity of the chlorophyll removal, as well as the preservation of the phytochemical integrity of the resulting chlorophyll-free ("degreened") extracts were evaluated using HPTLC, UHPLC-UV, 1H NMR spectroscopy, and LC-MS as orthogonal phytochemical methods. The cleanup process adequately preserves the metabolomic diversity as well as the integrity of the original extracts. This method was found to be sufficiently rapid for the "degreening" of botanical extracts in higher-throughput sample preparation for further biological screening.


Functional difference between Ad4BP and ELP, and their distributions in steroidogenic tissues.
Ad4BP, a zinc finger DNA-binding protein, was identified as a transcription factor regulating steroidogenic P-450 genes in a cAMP-dependent manner. Immunochemical and immunohistochemical studies with steroidogenic tissues, adrenal, ovary, and testis, were performed using the antiserum to Ad4BP. Ad4BP was expressed to the same extent in the three zones of the adrenal cortex. Immunohistochemical examination of ovarian follicle and corpus luteum showed the expression of Ad4BP. The granulosa and thecal cells, the two distinct types of the steroidogenic cells in the follicle, gave Ad4BP signals, which were stronger than in the latter cells than in the former. Immunoblot analyses of mature and regressed corpora lutea indicated a parallel expression of Ad4BP and side-chain cleavage P-450, and both proteins significantly decreased in the regressed tissues. Leydig cells surrounding seminiferous tubules gave clear immunostaining signals for Ad4BP. ELP, a mammalian counterpart of Drosophila FTZ-F1 detected in EC cells, and are isoforms transcribed from the same gene. The Ad4BP and ELP forms recognize same nucleotide sequences. Reverse transcriptase-polymerase chain reaction with specific primers for ELP revealed that steroidogenic tissues contained ELP as well as Ad4BP. The effects of the two proteins on the transcription of the CYP11B gene were compared using the expression vectors of Ad4BP and ELP. ELP did not activate transcription and showed a weak inhibitor effect on the Ad4BP-dependent transactivation of the CYP11B gene promoter when transfected simultaneously. A gel shift analysis using in vitro synthesized Ad4BP and ELP revealed that the binding activity of ELP is significantly weaker than that of Ad4BP.


"You don't go tell White people nothing": African American women's perspectives on the influence of violence and race on depression and depression care.
We sought to understand how African American women's beliefs regarding depression and depression care are influenced by racism, violence, and social context. We conducted a focus group study using a community-based participatory research approach. Participants were low-income African American women with major depressive disorder and histories of violence victimization. Thirty women participated in 4 focus groups. Although women described a vicious cycle of violence, depression, and substance abuse that affected their health, discussions about health care revolved around their perception of racism, with a deep mistrust of the health care system as a "White" system. The image of the "strong Black woman" was seen as a barrier to both recognizing depression and seeking care. Women wanted a community-based depression program staffed by African Americans that addressed violence and drug use. Although violence and drug use were central to our participants' understanding of depression, racism was the predominant issue influencing their views on depression care. Providers should develop a greater appreciation of the effects of racism on depression care. Depression care programs should address issues of violence, substance use, and racism.


Typhoid Control in an Era of Antimicrobial Resistance: Challenges and Opportunities.
Historically, typhoid control has been achieved with water and sanitation interventions. Today, in an era of rising antimicrobial resistance (AMR), two World Health Organization-prequalified vaccines are available to accelerate control in the shorter term. Meanwhile, water and sanitation interventions could be implemented in the longer term to sustainably prevent typhoid in low- and middle-income countries. This article first approaches typhoid control from a historical perspective, subsequently presents how vaccination could complement water and sanitation activities, and finally discusses the challenges and opportunities for impactful control of typhoid infection. It also addresses data blind spots and knowledge gaps to focus on for typhoid control and to ultimately progress towards elimination. This article presents a synthesis of discussions held in December 2021 during a roundtable session at the "12th International Conference on Typhoid and Other Invasive Salmonelloses".


CD4-mimetic sulfopeptide conjugates display sub-nanomolar anti-HIV-1 activity and protect macaques against a SHIV162P3 vaginal challenge.
The CD4 and the cryptic coreceptor binding sites of the HIV-1 envelope glycoprotein are key to viral attachment and entry. We developed new molecules comprising a CD4 mimetic peptide linked to anionic compounds (mCD4.1-HS12 and mCD4.1-PS1), that block the CD4-gp120 interaction and simultaneously induce the exposure of the cryptic coreceptor binding site, rendering it accessible to HS12- or PS1- mediated inhibition. Using a cynomolgus macaque model of vaginal challenge with SHIV162P3, we report that mCD4.1-PS1, formulated into a hydroxyethyl-cellulose gel provides 83% protection (5/6 animals). We next engineered the mCD4 moiety of the compound, giving rise to mCD4.2 and mCD4.3 that, when conjugated to PS1, inhibited cell-free and cell-associated HIV-1 with particularly low IC50, in the nM to pM range, including some viral strains that were resistant to the parent molecule mCD4.1. These chemically defined molecules, which target major sites of vulnerability of gp120, are stable for at least 48 hours in conditions replicating the vaginal milieu (37 °C, pH 4.5). They efficiently mimic several large gp120 ligands, including CD4, coreceptor or neutralizing antibodies, to which their efficacy compares very favorably, despite a molecular mass reduced to 5500 Da. Together, these results support the development of such molecules as potential microbicides.


Localizing protein in 3D neural stem cell culture: a hybrid visualization methodology.
The importance of 3-dimensional (3D) topography in influencing neural stem and progenitor cell (NPC) phenotype is widely acknowledged yet challenging to study. When dissociated from embryonic or post-natal brain, single NPCs will proliferate in suspension to form neurospheres. Daughter cells within these cultures spontaneously adopt distinct developmental lineages (neurons, oligodendrocytes, and astrocytes) over the course of expansion despite being exposed to the same extracellular milieu. This progression recapitulates many of the stages observed over the course of neurogenesis and gliogenesis in post-natal brain and is often used to study basic NPC biology within a controlled environment. Assessing the full impact of 3D topography and cellular positioning within these cultures on NPC fate is, however, difficult. To localize target proteins and identify NPC lineages by immunocytochemistry, free-floating neurospheres must be plated on a substrate or serially sectioned. This processing is required to ensure equivalent cell permeabilization and antibody access throughout the sphere. As a result, 2D epifluorescent images of cryosections or confocal reconstructions of 3D Z-stacks can only provide spatial information about cell position within discrete physical or digital 3D slices and do not visualize cellular position in the intact sphere. Here, to reiterate the topography of the neurosphere culture and permit spatial analysis of protein expression throughout the entire culture, we present a protocol for isolation, expansion, and serial sectioning of post-natal hippocampal neurospheres suitable for epifluorescent or confocal immunodetection of target proteins. Connexin29 (Cx29) is analyzed as an example. Next, using a hybrid of graphic editing and 3D modelling softwares rigorously applied to maintain biological detail, we describe how to re-assemble the 3D structural positioning of these images and digitally map labelled cells within the complete neurosphere. This methodology enables visualization and analysis of the cellular position of target proteins and cells throughout the entire 3D culture topography and will facilitate a more detailed analysis of the spatial relationships between cells over the course of neurogenesis and gliogenesis in vitro.


Significant effect of homologous recombination DNA repair gene polymorphisms on pancreatic cancer survival.
Genetic variation in DNA repair may affect the clinical response to cytotoxic therapies. We investigated the effect of six single nucleotide polymorphisms of the RecQ1, RAD54L, XRCC2, and XRCC3 genes on overall survival of 378 patients with pancreatic adenocarcinoma who were treated at University of Texas M.D. Anderson Cancer Center during February 1999 to October 2004 and were followed up to October 2005. Genotypes were determined using the MassCode method. Survival was determined from pathologic diagnosis to death. Patients who were alive at the last follow-up evaluation were censored at that time. Kaplan-Meier plot, log-rank test, and Cox regression were used to compare overall survival by genotypes. A significant effect on survival of all patients was observed for RecQ1 and RAD54L genes. The median survival time was 19.2, 14.7, and 13.2 months for the RecQ1 159 AA, AC, and CC genotypes, and 16.4, 13.3, and 10.3 months for RAD54L 157 CC, CT, and TT genotypes, respectively. A significantly reduced survival was associated with the variant alleles of XRCC2 R188H and XRCC3 A17893G in subgroup analysis. When the four genes were analyzed in combination, an increasing number of adverse alleles were associated with a significantly decreased survival. Subgroup analyses have shown that the genotype effect on survival was present among patients without metastatic disease or among patients who receive radiotherapy. These observations suggest that polymorphisms of genes involved in the repair of DNA double-strand breaks significantly affect the clinical outcome of patients with pancreatic cancer.


Age-specific incidence rates for dementia and Alzheimer disease in NIA-LOAD/NCRAD and EFIGA families: National Institute on Aging Genetics Initiative for Late-Onset Alzheimer Disease/National Cell Repository for Alzheimer Disease (NIA-LOAD/NCRAD) and Estudio Familiar de Influencia Genetica en Alzheimer (EFIGA).
Late-onset Alzheimer disease (LOAD), defined as onset of symptoms after age 65 years, is the most common form of dementia. Few reports investigate incidence rates in large family-based studies in which the participants were selected for family history of LOAD. To determine the incidence rates of dementia and LOAD in unaffected members in the National Institute on Aging Genetics Initiative for Late-Onset Alzheimer Disease/National Cell Repository for Alzheimer Disease (NIA-LOAD/NCRAD) and Estudio Familiar de Influencia Genetica en Alzheimer (EFIGA) family studies. Families with 2 or more affected siblings who had a clinical or pathological diagnosis of LOAD were recruited as a part of the NIA-LOAD/NCRAD Family Study. A cohort of Caribbean Hispanics with familial LOAD was recruited in a different study at the Taub Institute for Research on Alzheimer's Disease and the Aging Brain in New York and from clinics in the Dominican Republic as part of the EFIGA study. Age-specific incidence rates of LOAD were estimated in the unaffected family members in the NIA-LOAD/NCRAD and EFIGA data sets. We restricted analyses to families with follow-up and complete phenotype information, including 396 NIA-LOAD/NCRAD and 242 EFIGA families. Among the 943 at-risk family members in the NIA-LOAD/NCRAD families, 126 (13.4%) developed dementia, of whom 109 (86.5%) met criteria for LOAD. Among 683 at-risk family members in the EFIGA families, 174 (25.5%) developed dementia during the study period, of whom 145 (83.3%) had LOAD. The annual incidence rates of dementia and LOAD in the NIA-LOAD/NCRAD families per person-year were 0.03 and 0.03, respectively, in participants aged 65 to 74 years; 0.07 and 0.06, respectively, in those aged 75 to 84 years; and 0.08 and 0.07, respectively, in those 85 years or older. Incidence rates in the EFIGA families were slightly higher, at 0.03 and 0.02, 0.06 and 0.05, 0.10 and 0.08, and 0.10 and 0.07, respectively, in the same age groups. Contrasting these results with the population-based estimates, the incidence was increased by 3-fold for NIA-LOAD/NCRAD families (standardized incidence ratio, 3.44) and 2-fold among the EFIGA compared with the NIA-LOAD/NCRAD families (1.71). The incidence rates for familial dementia and LOAD in the NIA-LOAD/NCRAD and EFIGA families are significantly higher than population-based estimates. The incidence rates in all groups increase with age. The higher incidence of LOAD can be explained by segregation of Alzheimer disease-related genes in these families or shared environmental risks.


Description of the registry of patients with ankylosing spondylitis in Turkey: TRASD-IP.
A web-based application patient follow-up program was developed to create a registry of patients with ankylosing spondylitis (AS) by the Turkiye Romatizma Arastirma Savas Dernegi (TRASD) AS Study Group. This study describes the methodological background and patient characteristics. The patient follow-up program is a web-based questionnaire, which contains sections on socio-demographic data, anamnesis, personal and family history, systemic and musculoskeletal examination, laboratory and imaging data and treatment. Between October 1, 2007 and February 28, 2009, 1,381 patients from 41 centers were included in the registry (1,038 males [75.2%]; mean age 39.5 ± 10.7 years). Mean disease duration was 12.1 ± 8.5 years, and mean time from initial symptom to diagnosis was 5 ± 6.8 years (median 2 years). HLA-B27 positivity was detected in 73.7% of 262 patients tested. Manifestations of extraarticular involvement were anterior uveitis (13.2%), psoriasis and other skin and mucous membrane lesions (6%) and inflammatory bowel disease (3.8%). The prevalence of peripheral arthritis was 11.2%. In 51.7% of patients, the Bath AS Disease Activity Index was ≥4. But since our patients consisted of the ones with more severe disease who referred to the tertiary centers and needed a regular follow-up, they may not represent the general AS population. Disease-modifying anti-rheumatic drugs were being used by 41.9% of patients, with 16.4% using anti-TNF agents. TRASD-IP (Izlem Programi: Follow-up program) is the first AS registry in Turkey. Such databases are very useful and provide a basis for data collection from large numbers of subjects. TRASD-IP gives information on the clinical and demographic profiles of patients, and the efficacy and safety of anti-TNF drugs, examines the impact on quality of life, and provides real-life data that may be used in cost-effectiveness analyses.


An optogenetic toolbox designed for primates.
Optogenetics is a technique for controlling subpopulations of neurons in the intact brain using light. This technique has the potential to enhance basic systems neuroscience research and to inform the mechanisms and treatment of brain injury and disease. Before launching large-scale primate studies, the method needs to be further characterized and adapted for use in the primate brain. We assessed the safety and efficiency of two viral vector systems (lentivirus and adeno-associated virus), two human promoters (human synapsin (hSyn) and human thymocyte-1 (hThy-1)) and three excitatory and inhibitory mammalian codon-optimized opsins (channelrhodopsin-2, enhanced Natronomonas pharaonis halorhodopsin and the step-function opsin), which we characterized electrophysiologically, histologically and behaviorally in rhesus monkeys (Macaca mulatta). We also introduced a new device for measuring in vivo fluorescence over time, allowing minimally invasive assessment of construct expression in the intact brain. We present a set of optogenetic tools designed for optogenetic experiments in the non-human primate brain.


Investigating How Bowel Cancer Survivors Discuss Exercise and Physical Activity Within Web-Based Discussion Forums: Qualitative Analysis.
Online cancer support group discussions enable patients to share their illness experience with others. The sharing of technical and emotional support information and the ability to ask for advice are some of the primary discussions shared online. People with bowel cancer can also use these forums to support each other by sharing information based on personal experiences. This type of support provides newly diagnosed patients with advice about several topics, including exercise from those who have been there. Information gathered from online discussion boards may complement the advice received by health professionals. This study aimed to explore the nature of information related to exercise and physical activity exchanged online for cancer survivors. A public open access bowel cancer discussion board was searched for threads containing information related to physical activity or exercise. Keywords such as exercise, physical activity, moving, walking, lifting, weights training, and resistance were used to search for threads (online conversations) related to exercise or physical activity. Only threads initiated by bowel cancer patients or survivors were included. From more than 6000 posts, the inclusion criteria yielded 75 threads for analysis. Inductive thematic analysis was conducted across all included threads. Analysis yielded 3 main themes: level of exercise competence, beneficial dimensions of exercise, and faith in the knowledge. Level of exercise competence illustrated the varying definitions of exercise that members of the forum discussed in the forum. Beneficial dimensions of exercise revealed that forum members shared both the spiritual benefits associated with exercise as well as the physical benefits or goodness that they feel exercise or physical activity provides them. Faith in the knowledge of exercise demonstrated that forum members were aware of the general benefits of exercise but felt disappointed that it did not keep the cancer at bay. However, members also had faith that exercise would keep them healthy after diagnosis and treatment. The analysis revealed that people with bowel cancer discuss exercise and physical activity online and that they view exercise as having a mostly positive influence on their cancer journey. However, personal definitions of exercise became a source of conflict within the group. People with bowel cancer seeking information about exercise may benefit from participating in online support groups as it appears that there are many similar others willing to share their personal experiences with exercise. In addition, health care professionals responsible for caring for people with bowel cancer may use these findings to discuss exercise with their patients while being mindful of how they may view exercise.


2021 Korean Society of Gastrointestinal Endoscopy Clinical Practice Guidelines for Endoscopic Sedation.
Sedation can resolve anxiety and fear in patients undergoing endoscopy. The use of sedatives has increased in Korea. Appropriate sedation is a state in which the patient feels subjectively comfortable while maintaining the airway reflex for stable spontaneous breathing. The patient should maintain a state of consciousness to the extent that he or she can cooperate with the needs of the medical staff. Despite its benefits, endoscopic sedation has been associated with cardiopulmonary complications. Cardiopulmonary complications are usually temporary. Most patients recover without sequelae. However, they may progress to serious complications, such as cardiovascular collapse. Therefore, it is essential to screen high-risk patients before sedation and reduce complications by meticulous monitoring. Additionally, physicians should be familiar with the management of emergencies. The first Korean clinical practice guideline for endoscopic sedation was developed based on previous worldwide guidelines for endoscopic sedation using an adaptation process. The guideline consists of nine recommendations based on a critical review of currently available data and expert consensus when the guideline was drafted. These guidelines should provide clinicians, nurses, medical school students, and policy makers with information on how to perform endoscopic sedation with minimal risk.


Variation in antibiotic-induced microbial recolonization impacts on the host metabolic phenotypes of rats.
The interaction between the gut microbiota and their mammalian host is known to have far-reaching consequences with respect to metabolism and health. We investigated the effects of eight days of oral antibiotic exposure (penicillin and streptomycin sulfate) on gut microbial composition and host metabolic phenotype in male Han-Wistar rats (n = 6) compared to matched controls. Early recolonization was assessed in a third group exposed to antibiotics for four days followed by four days recovery (n = 6). Fluorescence in situ hybridization analysis of the intestinal contents collected at eight days showed a significant reduction in all bacterial groups measured (control, 10(10.7) cells/g feces; antibiotic-treated, 10(8.4)). Bacterial suppression reduced the excretion of mammalian-microbial urinary cometabolites including hippurate, phenylpropionic acid, phenylacetylglycine and indoxyl-sulfate whereas taurine, glycine, citrate, 2-oxoglutarate, and fumarate excretion was elevated. While total bacterial counts remained notably lower in the recolonized animals (10(9.1) cells/g faeces) compared to the controls, two cage-dependent subgroups emerged with Lactobacillus/Enterococcus probe counts dominant in one subgroup. This dichotomous profile manifested in the metabolic phenotypes with subgroup differences in tricarboxylic acid cycle metabolites and indoxyl-sulfate excretion. Fecal short chain fatty acids were diminished in all treated animals. Antibiotic treatment induced a profound effect on the microbiome structure, which was reflected in the metabotype. Moreover, the recolonization process was sensitive to the microenvironment, which may impact on understanding downstream consequences of antibiotic consumption in human populations.


MDA-7/IL-24 as a cancer therapeutic: from bench to bedside.
The novel cytokine melanoma differentiation associated gene-7 (mda-7) was identified by subtractive hybridization in the mid-1990s as a protein whose expression increased during the induction of terminal differentiation, and that was either not expressed or was present at low levels in tumor cells compared with non-transformed cells. On the basis of conserved structure, chromosomal location and cytokine-like properties, MDA-7, has now been classified as a member of the expanding interleukin (IL)-10 gene family and designated as MDA-7/IL-24. Multiple studies have shown that the expression of MDA-7/IL-24 in a wide variety of tumor cell types, but not in the corresponding equivalent non-transformed cells, causes their growth arrest and ultimately cell death. In addition, MDA-7/IL-24 has been noted to be a radiosensitizing cytokine, which is partly because of the generation of reactive oxygen species and ceramide that cause endoplasmic reticulum stress. Phase I clinical trial data has shown that a recombinant adenovirus expressing MDA-7/IL-24 [Ad.mda-7 (INGN-241)] was safe and had measurable tumoricidal effects in over 40% of patients, which strongly argues that MDA-7/IL-24 may have significant therapeutic value. This review describes what is known about the impact of MDA-7/IL-24 on tumor cell biology and its potential therapeutic applications.


Occupational allergies in the seafood industry--a comparative study of Australian and South African workplaces.
Although seafood allergy due to ingestion is commonly observed in clinical practice, the incidence of seafood allergies in general and more specifically in the occupational setting in Australia is largely unknown. The work practices, occupational health services and allergic health problems in 140 seafood processing workplaces in Australia were examined and compared to previous studies in South Africa. A cross-sectional employer-based survey design was used to conduct the study in both countries. In the South African study a response rate of 60% (n = 41) was obtained, compared to a response rate of 18% (n = 140) in Australia. The most common seafood processed by workplaces in South Africa was finfish (76%) and rock lobster (34%). Similarly in Australia, finfish (34%) was the most frequently handled seafood. However, processing of prawns (24%) and oysters (21%) was more common in Australia. Common work processes in South Africa involved freezing (71%), cutting/filleting (63%) and degutting (58%) procedures. Similar processes were followed in Australian industries with the exception of shucking of oysters, particularly common in the aquaculture industries. About half of the workplaces in both countries provided an occupational health service and medical surveillance of workers. However, none of the workplaces in South Africa and only 9% of the workplaces in Australia had industrial hygiene programs for seafood aerosols in place. In both countries positive trends were observed between the size of the workforce and the provision of occupational health services (p<0.005). Similarly, skin rash accounted for highest of all reported health problems (78-81%) followed by asthmatic symptoms (7-10%) and other non-specific allergic symptoms (9-15%) in both countries. Most workplaces reported the annual prevalence of work-related symptoms to be less than 5%. In Australia 7% of respondents in workplaces reported workers having left their workplace due to work-related allergic problems. Despite a low response rate of contacted companies in Australia, there were great similarities between the two countries suggesting that there is a significantly elevated prevalence of work related allergic symptoms in both countries. Unexpectedly, mollusc processing was more common in Australia although the occupational health related effects among exposed workers has previously not been investigated in detail and merits further study. It is recommended that further epidemiological studies focus on seafood exposure in Australia and identify specific risk factors for sensitisation.


β-sitosterol interacts with pneumolysin to prevent Streptococcus pneumoniae infection.
Pneumolysin is one of the major virulence factors elaborated by Streptococcus pneumoniae; this toxin is a member of the cholesterol-dependent cytolysins. Engagement of cholesterol induces the formation of a multi-subunit complex by pneumolysin that lyses host cells by forming pores on the membrane. Because pneumolysin released by bacteria which have been killed by conventional antibiotics is still active, agents capable of directly attacking the toxin are considered advantageous against antimicrobials in the treatment of S. pneumoniae infections. Here we found that the phytosterol, β-sitosterol, effectively protects against cell lysis caused by pneumolysin. This compound interacts with the toxin at Thr459 and Leu460, two sites important for being recognized by its natural ligand, cholesterol. Similar to cholesterol, β-sitosterol induces pneumolysin oligomerization. This compound also protects cells from damage by other cholesterol-dependent toxins. Finally, this compound protects mice against S. pneumoniae infection. Thus, β-sitosterol is a candidate for the development of anti-virulence agents against pathogens that rely on cholesterol-dependent toxins for successful infections.