How to review and assess a systematic review and meta-analysis article: a methodological study (secondary publication).
Systematic reviews and meta-analyses have become central in many research fields, particularly medicine. They offer the highest level of evidence in evidence-based medicine and support the development and revision of clinical practice guidelines, which offer recommendations for clinicians caring for patients with specific diseases and conditions. This review summarizes the concepts of systematic reviews and meta-analyses and provides guidance on reviewing and assessing such papers. A systematic review refers to a review of a research question that uses explicit and systematic methods to identify, select, and critically appraise relevant research. In contrast, a meta-analysis is a quantitative statistical analysis that combines individual results on the same research question to estimate the common or mean effect. Conducting a meta-analysis involves defining a research topic, selecting a study design, searching literature in electronic databases, selecting relevant studies, and conducting the analysis. One can assess the findings of a meta-analysis by interpreting a forest plot and a funnel plot and by examining heterogeneity. When reviewing systematic reviews and meta-analyses, several essential points must be considered, including the originality and significance of the work, the comprehensiveness of the database search, the selection of studies based on inclusion and exclusion criteria, subgroup analyses by various factors, and the interpretation of the results based on the levels of evidence. This review will provide readers with helpful guidance to help them read, understand, and evaluate these articles.


HIV transmission through donor artificial insemination.
To investigate and report cases of human immunodeficiency virus (HIV) transmission through donor artificial insemination (AI) before 1986 at five infertility clinics. Two types of look-back studies were performed: (1) identification of an HIV-infected woman who reported previous AI, followed by identification of the infected donor(s) and contact tracing of women who were inseminated with his semen, and (2) identification of an HIV-infected donor and subsequent examination of women receiving AI procedures using his semen. Five infertility clinics in Los Angeles County, California; San Diego County, California; Arizona; and Vancouver, British Columbia. A total of 230 women were inseminated with semen from any one of the five identified HIV-infected donors; 199 (87%) consented to HIV testing. Seropositivity for HIV among AI recipients. Seven (3.52%) of the 199 women (95% confidence interval, 1.55% to 7.41%) who were artificially inseminated with semen from any of five HIV-infected donors and consented to HIV testing tested HIV-seropositive. Information on HIV risk was available for three of the five donors; all three reported a history of having sex with men. Four HIV-infected women were identified through uncommon circumstances, rather than through routine look-back studies of donors. Infection with HIV through donor AI performed before routine HIV screening of semen donors represents a potentially serious threat to women who underwent AI procedures. Public health policies requiring retrospective identification of HIV-infected semen donors and patients receiving AI before 1986, especially in acquired immunodeficiency syndrome (AIDS)-prevalent areas, should be considered routine. Women diagnosed with AIDS or HIV infection, in whom no identified risk of HIV acquisition is established, should be questioned about previous AI procedures.


Substrate Spatial Complexity Analysis for the Prediction of Ventricular Arrhythmias in Patients With Ischemic Cardiomyopathy.
Transition zones between healthy myocardium and scar form a spatially complex substrate that may give rise to reentrant ventricular arrhythmias (VAs). We sought to assess the utility of a novel machine learning approach for quantifying 3-dimensional spatial complexity of grayscale patterns on late gadolinium enhanced cardiac magnetic resonance images to predict VAs in patients with ischemic cardiomyopathy. One hundred twenty-two consecutive ischemic cardiomyopathy patients with left ventricular ejection fraction ≤35% without prior history of VAs underwent late gadolinium enhanced cardiac magnetic resonance images. From raw grayscale data, we generated graphs encoding the 3-dimensional geometry of the left ventricle. A novel technique, adapted to these graphs, assessed global regularity of signal intensity patterns using Fourier-like analysis and generated a substrate spatial complexity profile for each patient. A machine learning statistical algorithm was employed to discern which substrate spatial complexity profiles correlated with VA events (appropriate implantable cardioverter-defibrillator firings and arrhythmic sudden cardiac death) at 5 years of follow-up. From the statistical machine learning results, a complexity score ranging from 0 to 1 was calculated for each patient and tested using multivariable Cox regression models. At 5 years of follow-up, 40 patients had VA events. The machine learning algorithm classified with 81% overall accuracy and correctly classified 86% of those without VAs. Overall negative predictive value was 91%. Average complexity score was significantly higher in patients with VA events versus those without (0.5±0.5 versus 0.1±0.2; P<0.0001) and was independently associated with VA events in a multivariable model (hazard ratio, 1.5 [1.2-2.0]; P=0.002). Substrate spatial complexity analysis of late gadolinium enhanced cardiac magnetic resonance images may be helpful in refining VA risk in patients with ischemic cardiomyopathy, particularly to identify low-risk patients who may not benefit from prophylactic implantable cardioverter-defibrillator therapy. Visual Overview: A visual overview is available for this article.


Chronic kidney disease alters vascular smooth muscle cell phenotype.
Vascular access dysfunction associated with arteriovenous grafts and fistulas contributes to the morbidity and mortality of chronic kidney disease (CKD) patients receiving hemodialysis. We hypothesized that the uremic conditions associated with CKD promote a pathophysiological vascular smooth muscle cell (VSMC) phenotype that contributes to neointimal hyperplasia. We analyzed the effect of culturing human VSMC with uremic serum. Expression of VSMC contractile marker genes was reduced 50-80% in cells exposed to uremic serum and the decreased expression was accompanied by changes in histone marks. There was an increase in proliferation in cells exposed to uremic conditions, with no change in the levels of apoptosis. Interestingly, we found that uremic serum inhibited PDGF-induced migration of VSMC. Histomorphometric analysis revealed venous neointimal hyperplasia in veins from chronic kidney disease (CKD) patients prior to any surgical manipulation as compared to veins from patients with no kidney disease. We conclude that uremia associated with CKD alters VSMC phenotype in vitro and contributes to neointimal hyperplasia formation in vivo contributing to the pathogenesis of vascular access dysfunction in CKD patients.


The intermanual transfer of anticipatory force control in precision grip lifting is not influenced by the perception of weight.
Passing objects from one hand to the other occurs frequently in our daily life. What kind of information about the weight of the object is transferred between the holding and lifting hand? To examine this, we asked people to hold (and heft) an object in one hand and then pick it up with the other. The objects were presented in the context of a size-weight illusion: that is, two objects of different sizes but the same weight were used. One group of participants held one of the objects in their left hand and then picked it up with their right. Another group of participants simply picked up the objects from a table. Thus, the former group had on-line information about the weight of the object, whereas the latter did not. Both groups showed a strong and equivalent size-weight illusion throughout the experiment. At the same time, the group that lifted the objects from the hefting hand applied equal grip force to the small and large object right from the start; in contrast, the group lifting the objects from the table, initially applied more grip force to the large than to the small object before eventually applying the same force to both. In two additional groups, a delay period was imposed between the lifting of the first and the second hands. The force parameters employed by these last two groups were virtually identical to those used by the group that lifted the object directly from the other hand. These results suggest that the initial calibration of grip force uses veridical information about the weight of the object provided by the other hand. This veridical information about weight is available on-line and is retained in memory for later access. The perceived weight of the object is basically ignored in forming grasping forces.


The Metabolic Syndrome: Emerging Novel Insights Regarding the Relationship between the Homeostasis Model Assessment of Insulin Resistance and other Key Predictive Markers in Young Adults of Western Algeria.
Several biological markers have been identified as risk factors for cardiovascular disease and are associated with increased risk of metabolic syndrome (MetS). This study provides a factual information on promising biomarkers that are associated with MetS and can aid in early detection and management of MetS in young adults of Western Algeria. We studied a total of one hundred subjects aged between thirty and forty years with MetS, in which anthropometric measurements, insulin resistance, C peptide and HbA1c, lipid profile, circulating adipokines and glucagon-like peptide-1 were measured by suitable methods, in comparison to two groups of control. MetS is closely linked to altered glucose homeostasis, the plasma insulin/glucose ratio; i.e., the insulinogenic index helps to estimate the level of insulin secretion and also for assessing β-cell function. The correlation between homeostasis model assessment insulin resistance index (HOMA-IR) and HbA1c, body mass index or plasma triglycerides yielded positive and significant values. Biomarkers with a known and predictable association with MetS can provide a means to detect those at risk and intervene as needed. This could significantly decrease the burden complications impose on patients and the healthcare system.


Effect of exercise training on plasma levels of C-reactive protein in healthy adults: the HERITAGE Family Study.
To study the effect of exercise training on plasma C-reactive protein, a marker of inflammation. We performed a 20 week standardized exercise training programme in 652 sedentary healthy white and black men and women. C-reactive protein was measured with a high sensitivity assay. The study sample was stratified according to baseline C-reactive protein levels using a recommended classification (low <1.0 mg/L, n=265; moderate 1.0-3.0 mg/L, n=225; high >3.0 mg/L, n=162). The median C-reactive protein reduction was 1.34 mg/L in the high baseline C-reactive protein group. C-reactive protein levels did not change in the low or moderate baseline C-reactive protein groups. The difference among the C-reactive protein groups was significant adjusting for all correlates of baseline C-reactive protein (P<0.001) and additionally for changes in body weight, glucose, insulin, LDL cholesterol, HDL cholesterol, triglycerides, systolic and diastolic blood pressure, and maximal oxygen uptake (P<0.001). The C-reactive protein reduction in the high baseline C-reactive protein group was consistent across all population groups (P<0.001 for difference among baseline C-reactive protein groups). Plasma C-reactive protein levels are reduced in response to exercise training in sedentary healthy adults with high initial C-reactive protein levels. This finding may partly explain the effectiveness of regular physical activity in the prevention and treatment of cardiovascular and metabolic diseases.


Four centuries of change in northeastern United States forests.
The northeastern United States is a predominately-forested region that, like most of the eastern U.S., has undergone a 400-year history of intense logging, land clearance for agriculture, and natural reforestation. This setting affords the opportunity to address a major ecological question: How similar are today's forests to those existing prior to European colonization? Working throughout a nine-state region spanning Maine to Pennsylvania, we assembled a comprehensive database of archival land-survey records describing the forests at the time of European colonization. We compared these records to modern forest inventory data and described: (1) the magnitude and attributes of forest compositional change, (2) the geography of change, and (3) the relationships between change and environmental factors and historical land use. We found that with few exceptions, notably the American chestnut, the same taxa that made up the pre-colonial forest still comprise the forest today, despite ample opportunities for species invasion and loss. Nonetheless, there have been dramatic shifts in the relative abundance of forest taxa. The magnitude of change is spatially clustered at local scales (<125 km) but exhibits little evidence of regional-scale gradients. Compositional change is most strongly associated with the historical extent of agricultural clearing. Throughout the region, there has been a broad ecological shift away from late successional taxa, such as beech and hemlock, in favor of early- and mid-successional taxa, such as red maple and poplar. Additionally, the modern forest composition is more homogeneous and less coupled to local climatic controls.


Should We Scan Hidradenitis Suppurativa Patients? A Systematic Review of Radiologic Findings.
To bring awareness and close gaps between dermatologists and radiologists about the contribution of imaging techniques for diagnosis, treatment, and follow-up of hidradenitis suppurativa (HS). Investigators searched the PubMed database for articles on HS and radiology techniques. Databases were searched up to December 2018. The query retrieved 257 publications, of which 103 were unique; of these, 7 were inaccessible. From the remaining 96, 33 were irrelevant (did not discuss HS lesion features). After applying the inclusion criteria, 63 studies were relevant to this study. A standardized form was constructed to extract data from eligible studies by two independent authors. Imaging techniques are significant and useful tools in HS management. Imaging should be carried out to evaluate disease severity, subclinical features, treatment success, and intraoperative patient assessment. Providers should consider nonconventional radiology techniques, which are underused in clinical management of HS. Further, dermatology and radiology require a shared terminology of disease features to better understand patient status. Publications on HS lesion imaging have increased over the years. Imaging techniques have proven useful for determining HS severity and treatment effectiveness, as well as intraoperative patient assessment. These authors strongly recommend the use of these techniques in routine clinical practice for patients with HS.


Endothelial cells are activated by cytokine treatment to kill an intravascular parasite, Schistosoma mansoni, through the production of nitric oxide.
Like many pathogens that undergo an intravascular stage of development, larvae of the helminth parasite Schistosoma mansoni migrate through the blood vessels, where they are in close contact with endothelial cells. In vitro exposure of murine endothelial cells to various cytokines (interferon gamma, tumor necrosis factor alpha, and interleukin 1 alpha or 1 beta) resulted in their activation to kill schistosomula through an arginine-dependent mechanism involving production of nitric oxide (NO). Cytokine-treated endothelial cells showed increased expression of mRNA for the inducible form of the NO synthase, and both NO production and larval killing were suppressed by treatment with competitive inhibitors. The effector function of cytokine-treated endothelial cells was similar to that of activated inflammatory tissue macrophages, although activation appeared to be differentially regulated in these two cell types. Activated endothelial cells killed older (18-day) forms of the parasite, such as those currently thought to be a primary target of immune elimination in the lungs of mice previously vaccinated with radiation-attenuated cercariae, as well as newly transformed larvae. In C57BL/6 mice, which become resistant to S. mansoni infection as a result of vaccination with irradiated cercariae, endothelial cell morphology characteristic of activation was observed in the lung by 1-2 weeks after challenge infection. Similar endothelial cell changes were absent in P-strain mice, which do not become resistant as a result of vaccination. Together, these observations indicate that endothelial cells, not traditionally considered to be part of the immune system, may play an important role in immunity to S. mansoni and, by means of NO-dependent killing, could serve as effectors of resistance to other intravascular pathogens.


Stimulation of collagen galactosyltransferase and glucosyltransferase activities by lysophosphatidylcholine.
Lysophosphatidylcholine stimulated the activities of collagen galactosyl- and glucosyl-transferases in chick-embryo extract and its particulate fractions in vitro, whereas essentially no stimulation was noted in the high-speed supernatant, where the enzymes are soluble and membrane-free. The stimulatory effect of lysophosphatidylcholine was masked by 0.1% Triton X-100. In kinetic experiments lysophosphatidylcholine raised the maximum velocities with respect to the substrates and co-substrates, whereas no changes were observed in the apparant Km values. Phospholipase A preincubation of the chick-embryo extract resulted in stimulation of both transferase activities, probably gy generating lysophosphatides from endogenous phospholipids. No stimulation by lysophosphatidylcholine was found when tested with 500-fold-purified glycosyltransferase. The results suggest that collagen glycosyltransferases must be associated with the membrane structures of the cell in order to be stimulated by lysophosphatidylcholine. Lysophosphatidylcholine could have some regulatory significance in vivo, since its concentration in the cell is comparable with that which produced marked stimulation in vitro.


Elemental composition of the Martian crust.
The composition of Mars' crust records the planet's integrated geologic history and provides clues to its differentiation. Spacecraft and meteorite data now provide a global view of the chemistry of the igneous crust that can be used to assess this history. Surface rocks on Mars are dominantly tholeiitic basalts formed by extensive partial melting and are not highly weathered. Siliceous or calc-alkaline rocks produced by melting and/or fractional crystallization of hydrated, recycled mantle sources, and silica-poor rocks produced by limited melting of alkali-rich mantle sources, are uncommon or absent. Spacecraft data suggest that martian meteorites are not representative of older, more voluminous crust and prompt questions about their use in defining diagnostic geochemical characteristics and in constraining mantle compositional models for Mars.


The evolution of active vibrissal sensing in mammals: evidence from vibrissal musculature and function in the marsupial opossum Monodelphis domestica.
Facial vibrissae, or whiskers, are found in nearly all extant mammal species and are likely to have been present in early mammalian ancestors. A sub-set of modern mammals, including many rodents, move their long mystacial whiskers back and forth at high speed whilst exploring in a behaviour known as 'whisking'. It is not known whether the vibrissae of early mammals moved in this way. The grey short-tailed opossum, Monodelphis domestica, is considered a useful species from the perspective of tracing the evolution of modern mammals. Interestingly, these marsupials engage in whisking bouts similar to those seen in rodents. To better assess the likelihood that active vibrissal sensing was present in ancestral mammals, we examined the vibrissal musculature of the opossum using digital miscroscopy to see whether this resembles that of rodents. Although opossums have fewer whiskers than rats, our investigation found that they have a similar vibrissal musculature. In particular, in both rats and opossums, the musculature includes both intrinsic and extrinsic muscles with the intrinsic muscles positioned as slings linking pairs of large vibrissae within rows. We identified some differences in the extrinsic musculature which, interestingly, matched with behavioural data obtained through high-speed video recording, and indicated additional degrees of freedom for positioning the vibrissae in rats. These data show that the whisker movements of opossum and rat exploit similar underlying mechanisms. Paired with earlier results suggesting similar patterns of vibrissal movement, this strongly implies that early therian (marsupial and placental) mammals were whisking animals that actively controlled their vibrissae.


Morphology and monoterpene biosynthetic capabilities of secretory cell clusters isolated from glandular trichomes of peppermint (Mentha piperita L.).
Secretory cells were isolated from the monoterpene-producing glandular trichomes (peltate form) of peppermint as clusters of eight cells each. These isolated structures were shown to be non-specifically permeable to low-molecular-weight, water-soluble cofactors and substrates. Short incubation periods with the polar dye Lucifer yellow iodoacetamide (Mr=660) resulted in a uniform staining of the cytoplasm, with exclusion of the dye from the vacuole. The molecular-weight exclusion limit for this permeability was shown to be less than approx. 1800, based on exclusion of fluorescein-conjugated dextran (Mr ∼ 1800). Intact secretory cell clusters very efficiently incorporated [(3)H]geranyl pyrophosphate into monoterpenes. The addition of exogenous cofactors and redox substrates affected the distribution of monoterpenes synthesized from [(3)H]geranyl pyrophosphate, demonstrating that the cell clusters were permeable to these compounds and that the levels of endogenous cofactors and redox substrates were depleted in the isolated cells. When provided with the appropriate cofactors, such as NADPH, NAD(+), ATP, ADP and coenzyme A, the isolated secretory cell clusters incorporated [(14)C]sucrose into monoterpenes, indicating that these structures are capable of the de-novo biosynthesis of monoterpenes from a primary carbon source, and that they maintain a high degree of metabolic competence in spite of their permeable nature.


An adrenal beta-arrestin 1-mediated signaling pathway underlies angiotensin II-induced aldosterone production in vitro and in vivo.
Aldosterone produces a multitude of effects in vivo, including promotion of postmyocardial infarction adverse cardiac remodeling and heart failure progression. It is produced and secreted by the adrenocortical zona glomerulosa (AZG) cells after angiotensin II (AngII) activation of AngII type 1 receptors (AT(1)Rs). Until now, the general consensus for AngII signaling to aldosterone production has been that it proceeds via activation of G(q/11)-proteins, to which the AT(1)R normally couples. Here, we describe a novel signaling pathway underlying this AT(1)R-dependent aldosterone production mediated by beta-arrestin-1 (betaarr1), a universal heptahelical receptor adapter/scaffolding protein. This pathway results in sustained ERK activation and subsequent up-regulation of steroidogenic acute regulatory protein, a steroid transport protein regulating aldosterone biosynthesis in AZG cells. Also, this betaarr1-mediated pathway appears capable of promoting aldosterone turnover independently of G protein activation, because treatment of AZG cells with SII, an AngII analog that induces betaarr, but not G protein coupling to the AT(1)R, recapitulates the effects of AngII on aldosterone production and secretion. In vivo, increased adrenal betaarr1 activity, by means of adrenal-targeted adenoviral-mediated gene delivery of a betaarr1 transgene, resulted in a marked elevation of circulating aldosterone levels in otherwise normal animals, suggesting that this adrenocortical betaarr1-mediated signaling pathway is operative, and promotes aldosterone production and secretion in vivo, as well. Thus, inhibition of adrenal betaarr1 activity on AT(1)Rs might be of therapeutic value in pathological conditions characterized and aggravated by hyperaldosteronism.


[The alimentary status sisk of the hevophilia with the lesion of jointts].
The diagnostic findings sick of a hemophilia with recurring hemarthrosis are presented. At studying of componential structure of a body by a method of bioimpedansometriya considerable fluctuations of an index of weight of a body, a poor development of a muscular fabric, increase in percentage of a fatty fabric that is connected with low, physical activity and increase in the contribution of fat in power value of a food ration have been found out in patients. Results of research of an actual food by a frequency method with a quantitative estimation at sick of hemophilia and healthy students testify to probable risk of insufficient consumption of vitamins B1, B2 and calcium, magnesium that demands individual correction.


SARS-CoV-2 innate effector associations and viral load in early nasopharyngeal infection.
COVID-19 causes severe disease with poor outcomes. We tested the hypothesis that early SARS-CoV-2 viral infection disrupts innate immune responses. These changes may be important for understanding subsequent clinical outcomes. We obtained residual nasopharyngeal swab samples from individuals who requested COVID-19 testing for symptoms at drive-through COVID-19 clinical testing sites operated by the University of Utah. We applied multiplex immunoassays, real-time polymerase chain reaction assays and quantitative proteomics to 20 virus-positive and 20 virus-negative samples. ACE-2 transcripts increased with infection (OR =17.4, 95% CI [CI] =4.78-63.8) and increasing viral N1 protein transcript load (OR =1.16, CI =1.10-1.23). Transcripts for two interferons (IFN) were elevated, IFN-λ1 (OR =71, CI =7.07-713) and IFN-λ2 (OR =40.2, CI =3.86-419), and closely associated with viral N1 transcripts (OR =1.35, CI =1.23-1.49 and OR =1.33 CI =1.20-1.47, respectively). Only transcripts for IP-10 were increased among systemic inflammatory cytokines that we examined (OR =131, CI =1.01-2620). We found widespread discrepancies between transcription and translation. IFN proteins were unchanged or decreased in infected samples (IFN-γ OR =0.90 CI =0.33-0.79, IFN-λ2,3 OR =0.60 CI =0.48-0.74) suggesting viral-induced shut-off of host antiviral protein responses. However, proteins for IP-10 (OR =3.74 CI =2.07-6.77) and several interferon-stimulated genes (ISG) increased with viral load (BST-1 OR =25.1, CI =3.33-188; IFIT1 OR =19.5, CI =4.25-89.2; IFIT3 OR =245, CI =15-4020; MX-1 OR =3.33, CI =1.44-7.70). Older age was associated with substantial modifications of some effects. Ambulatory symptomatic patients had an innate immune response with SARS-CoV-2 infection characterized by elevated IFN, proinflammatory cytokine and ISG transcripts, but there is evidence of a viral-induced host shut-off of antiviral responses. Our findings may characterize the disrupted immune landscape common in patients with early disease.


An empowerment-based diabetes self-management education program for Hispanic/Latinos: a quasi-experimental pilot study.
The purpose of this pilot study was to evaluate the effects of a culturally sensitive, empowerment-based diabetes self-management education program for Spanish-speaking Hispanic/Latinos. A prospective quasi-experimental repeated measures design tested the effectiveness of the ¡Si, Yo Puedo Controlar Mi Diabetes! diabetes self-management education program. In sum, 144 persons residing in 2 Texas counties at the Texas-Mexico border (Starr and Hidalgo) served as participants. Two groups were formed, an intervention and a control (wait list). Clinical (A1C), cognitive, attitudinal, behavioral, and cultural assessments were collected at baseline and 3 months. Demographic characteristics for the intervention and control groups were similar. Both groups were predominately female, low income, older than 40 years, and minimally acculturated. Baseline and posttest findings showed that the intervention group had a significant reduction in A1C values; median difference was 0.3 (n = 45), especially for those with higher baseline values. Participants in the intervention group also improved in their self-efficacy and self-care scores. Findings from the study suggest that additional dissemination of a diabetes self-management education program for Spanish-speaking Hispanic/Latinos is warranted to improve clinical outcomes and associated diabetes self-efficacy and self-care behaviors.


ERADICATION THERAPY OF HELICOBACTER PYLORI: PRESENT AND FUTURE.
Recently the rate of successful H. pylod eradication while using existing treatment regimens continues to decline, primarily due to the appearance of antibiotic-resistant strains of the microorganism. Recent studies confirm the fact that the standard triple therapy becomes ineffective method of H. pylori eradication, due to the increase of drug-resistant strains of.H. pylon. H. pylori resistance level to antibacterial agents is not the same in different countries, as well as in certain regions within the same country. Thus, studing the regional features of H. pylori resistance to certain antibiotics with subsequent development of eradication regimens that are effective in particular region becomes extremely actual. Still bismuth containing quadruple therapy remains an effective method of H. pylori eradication, allowing to achieve good results. In recent years, several alternative schemes of H. pylori eradication were proposed, such as sequential, concomitant, hybrid therapy including three antimicrobial agents. Currently; these regimens allow to achieve quite high H. pyloneradication level.


LINC00612/miR-31-5p/Notch1 Axis Regulates Apoptosis, Inflammation, and Oxidative Stress in Human Pulmonary Microvascular Endothelial Cells Induced by Cigarette Smoke Extract.
Long non-coding RNAs (lncRNAs) have been reported as key regulators in chronic obstructive pulmonary disease (COPD). However, the precise role of LINC00612 remains unclear. The real-time quantitative polymerase chain reaction (RT-qPCR) was used to quantify the expression levels of LINC00612, miR-31-5p, and Notch homolog 1 (Notch1) in lung tissues and cells. Under a cigarette smoke extract (CSE) stimulation condition, the apoptosis was analyzed by flow cytometry assay. Caspase-3 activity was examined with a caspase-3 activity assay kit; besides, inflammation and oxidative stress were assessed by measuring interleukin-6, tumor necrosis factor-α, glutathione/oxidized glutathione, reactive oxygen species, malondialdehyde, and superoxide dismutase activity. The interaction relationship between miR-31-5p and LINC00612 or Notch1 was predicted by bioinformatics databases, while dual-luciferase reporter, RNA immunoprecipitation, and RNA pull-down assays were performed to confirm prediction. Eventually, the related protein expression was estimated with western blot assay. LINC00612 was downregulated in COPD tissues when compared with controls. Consistently, CSE inhibited LINC00612 expression in HPMECs with a dose/time-dependent method. Gain-of-function experiments indicated that the upregulation of LINC00612 could repress cell apoptosis, inflammation, and oxidative stress in HPMECs induced by CSE. In addition, miR-31-5p was negatively regulated by LINC00612 in HPMECs treated with CSE. The overexpression of miR-31-5p could abolish LINC00612-induced effects on HPMECs exposed to CSE. Importantly, LINC00612 could weaken CSE-induced cell apoptosis, inflammation, and oxidative stress in HPMECs by regulating the miR-31-5p/Notch1 signaling pathway. Current findings suggest that CSE-mediated cell apoptosis, inflammation, and oxidative stress in HPMECs were abolished by upregulation of LINC00612. Furthermore, the LINC00612/miR-31-5p/Notch1 axis may represent a novel regulator of apoptosis, inflammation, and oxidative stress of HPMECs, which may be a potential therapeutic target for COPD in the future.


Trigger factor from the psychrophilic bacterium Psychrobacter frigidicola is a monomeric chaperone.
In eubacteria, trigger factor (TF) is the first chaperone to interact with newly synthesized polypeptides and assist their folding as they emerge from the ribosome. We report the first characterization of a TF from a psychrophilic organism. TF from Psychrobacter frigidicola (TF(Pf)) was cloned, produced in Escherichia coli, and purified. Strikingly, cross-linking and fluorescence anisotropy analyses revealed it to exist in solution as a monomer, unlike the well-characterized, dimeric E. coli TF (TF(Ec)). Moreover, TF(Pf) did not exhibit the downturn in reactivation of unfolded GAPDH (glyceraldehyde-3-phosphate dehydrogenase) that is observed with its E. coli counterpart, even at high TF/GAPDH molar ratios and revealed dramatically reduced retardation of membrane translocation by a model recombinant protein compared to the E. coli chaperone. TF(Pf) was also significantly more effective than TF(Ec) at increasing the yield of soluble and functional recombinant protein in a cell-free protein synthesis system, indicating that it is not dependent on downstream systems for its chaperoning activity. We propose that TF(Pf) differs from TF(Ec) in its quaternary structure and chaperone activity, and we discuss the potential significance of these differences in its native environment.


A comparative study on polyp classification using convolutional neural networks.
Colorectal cancer is the third most common cancer diagnosed in both men and women in the United States. Most colorectal cancers start as a growth on the inner lining of the colon or rectum, called 'polyp'. Not all polyps are cancerous, but some can develop into cancer. Early detection and recognition of the type of polyps is critical to prevent cancer and change outcomes. However, visual classification of polyps is challenging due to varying illumination conditions of endoscopy, variant texture, appearance, and overlapping morphology between polyps. More importantly, evaluation of polyp patterns by gastroenterologists is subjective leading to a poor agreement among observers. Deep convolutional neural networks have proven very successful in object classification across various object categories. In this work, we compare the performance of the state-of-the-art general object classification models for polyp classification. We trained a total of six CNN models end-to-end using a dataset of 157 video sequences composed of two types of polyps: hyperplastic and adenomatous. Our results demonstrate that the state-of-the-art CNN models can successfully classify polyps with an accuracy comparable or better than reported among gastroenterologists. The results of this study can guide future research in polyp classification.


Genetic diversity in Iranian indigenous sheep vis-à-vis selected exogenous sheep breeds and wild mouflon.
The heterogeneity of climate and different agro-ecological conditions in Iran have resulted in development of 27 indigenous sheep breeds. Wild Asiatic mouflon (Ovis orientalis) is believed to be the ancestor of Iranian sheep. Evaluation of genetic diversity and population structure within and among domestic breeds has important implications for animal breeding programs and genetic resources management. Based on 50K SNP genotype data, we studied the genetic diversity of five indigenous Iranian sheep breeds: Afshari (n = 37), Moghani (n = 34), Qezel (n = 35), Zel (n = 46) and Lori-Bakhtiari (n = 46), and Asiatic mouflon (n = 8) sampled from Iran. Furthermore, genetic diversity and the breed admixture of Iranian sheep were assessed on a larger geographic scale using a reference panel comprising: three indigenous Afghan breeds - Arabi (n = 15), Balouchi (n = 15) and Gadik (n = 15); three indigenous breeds from Turkey and Cyprus - Cyprus Fat Tail (n = 30), Karakas (n = 18) and Norduz (n = 20); and three commercial European breeds - Suffolk (n = 19), Comisana (n = 24) and Engadine Red Sheep (n = 24). The results revealed that the investigated breeds are divided into five genetically distinct clusters according to their geographic origin. Afshari was closest to the local mouflon population and showed signs of mouflon admixture. Qezel was identified as a hybrid sheep breed. Much evidence supported the Afghan breeds being identical. Inbreeding values, which were estimated based on ROHs, were highest for Suffolk (FROH = 0.0544) and lowest for Balouchi (FROH = 0.0078). In conclusion, analysis of selected breeds from neighboring countries along with Asiatic mouflon gave a deeper insight into the evolutionary history and origin of Iranian sheep with important implications for future breed management.


The role of oxidative and conjugative pathways in the activation of 1,2-dibromo-3-chloropropane to DNA-damaging products in rat testicular cells.
The ability of 1,2-dibromo-3-chloropropane (DBCP), several methylated analogs of DBCP and perdeuterated DBCP (DBCP-D5) to cause DNA damage in isolated testicular cells from rats was measured by the alkaline elution technique. Of the methylated analogs studied, only the C3-methyl analog was capable of causing significant DNA damage at concentrations of 0-50 microM. In both time- (0-60 min) and concentration- (0-10 microM) dependent experiments, the testicular cell DNA damage caused by the perdeuterated analog of DBCP closely mimicked the damage resulting from DBCP itself. The lack of an isotope effect between DBCP-D5 and DBCP strongly suggests that metabolism via a cytochrome P-450-dependent pathway is not involved in the DNA-damaging effects of DBCP in rat testicular cells. In contrast, preincubation for 1 hr with diethylmaleate (DEM) inhibited DBCP-induced (10 microM) DNA damage in a concentration-dependent manner (0-500 microM DEM). The decrease in testicular DNA damage was proportional to the decrease in cellular nonprotein sulfhydryl levels. Similarly, it was shown that 1,2-dibromoethane (EDB), a structurally related halogenated alkane, produced DNA damage in isolated testicular cells in both a time- (0-60 min) and concentration- (0-600 microM) dependent fashion. The DNA damage produced by EDB (600 microM) was also inhibited by pretreatment of testicular cells with DEM (1 mM). The testicular genotoxicity induced by EDB is thought to involve its initial conjugation to glutathione and the subsequent formation of a reactive episulfonium ion. The data presented indicate that similar events may be occurring in DBCP-induced DNA damage in rat testicular cells.


Continuous and intermittent levodopa differentially affect basal ganglia function.
The effects of continuous and intermittent levodopa treatment on behavioral and biochemical indexes of basal ganglia function were compared in rats with unilateral 6-hydroxydopamine lesions of the nigrostriatal dopamine pathway. Animals treated for 30 days with intermittent levodopa exhibited behavioral sensitization manifested by an enhanced rotational response to apomorphine; the rotational response of rats treated with an equivalent dose of levodopa by continuous infusion did not differ from that of saline-treated controls. Dopamine receptor up-regulation in the denervated striatum relative to the intact striatum was statistically significant for D1 but not D2 receptors: This asymmetry in dopamine receptor levels was diminished following intermittent levodopa treatment. Glutamic acid decarboxylase activity, modestly elevated in all groups in the denervated striatum relative to the intact striatum, increased substantially over control values bilaterally as a result of intermittent, but not continuous, levodopa treatment. These findings suggest a relation between the schedule of chronic levodopa administration and the development of behavioral sensitization, possibly as a consequence of alterations in neuronal systems located downstream from striatal dopamine receptors. The behavioral sensitization induced by chronic, intermittent dopaminomimetic treatment may serve as a model for motor fluctuations in Parkinson's disease.


OTX2 exhibits cell-context-dependent effects on cellular and molecular properties of human embryonic neural precursors and medulloblastoma cells.
Medulloblastoma (MB) is the most common malignant primary pediatric brain tumor and is currently divided into four subtypes based on different genomic alterations, gene expression profiles and response to treatment: WNT, Sonic Hedgehog (SHH), Group 3 and Group 4. This extensive heterogeneity has made it difficult to assess the functional relevance of genes to malignant progression. For example, expression of the transcription factor Orthodenticle homeobox2 (OTX2) is frequently dysregulated in multiple MB variants; however, its role may be subtype specific. We recently demonstrated that neural precursors derived from transformed human embryonic stem cells (trans-hENs), but not their normal counterparts (hENs), resemble Groups 3 and 4 MB in vitro and in vivo. Here, we tested the utility of this model system as a means of dissecting the role of OTX2 in MB using gain- and loss-of-function studies in hENs and trans-hENs, respectively. Parallel experiments with MB cells revealed that OTX2 exerts inhibitory effects on hEN and SHH MB cells by regulating growth, self-renewal and migration in vitro and tumor growth in vivo. This was accompanied by decreased expression of pluripotent genes, such as SOX2, and was supported by overexpression of SOX2 in OTX2+ SHH MB and hENs that resulted in significant rescue of self-renewal and cell migration. By contrast, OTX2 is oncogenic and promotes self-renewal of trans-hENs and Groups 3 and 4 MB independent of pluripotent gene expression. Our results demonstrate a novel role for OTX2 in self-renewal and migration of hENs and MB cells and reveal a cell-context-dependent link between OTX2 and pluripotent genes. Our study underscores the value of human embryonic stem cell derivatives as alternatives to cell lines and heterogeneous patient samples for investigating the contribution of key developmental regulators to MB progression.


Role of Ca2+ for protein turnover in isolated rat hepatocytes.
Experiments with bivalent-cation chelators (EGTA and EDTA), a Ca2+ ionophore (A23187) and a Ca2+-channel blocker (verapamil) indicate that Ca2+ is required for the lysosomal degradation of endogenous protein in hepatocytes. A distinction is made between lysosomal and non-lysosomal degradation by using the lysosomotropic agent methylamine. As Ca2+ does not appear to be required for the lysosomal degradation of endocytosed asialo-fetuin, the Ca2+-dependence for the degradation of endogenous protein is probably connected with the formation of autophagic vacuoles or the fusion of autophagic vacuoles with lysosomes. EGTA and EDTA had a slight inhibitory effect on the non-lysosomal degradation. This effect could be due to the activity of non-lysosomal Ca2+-dependent thiol proteinases. Together with previous experiments with thiol-proteinase inhibitors, the present experiments indicate that these proteinases have a very limited impact on the bulk protein degradation in the isolated hepatocytes.


Molecular Delineation of Partial Trisomy 14q and Partial Trisomy 12p in a Patient with Dysmorphic Features, Heart Defect and Developmental Delay.
This study describes a molecular analysis of partial trisomy 14q and partial trisomy 12p in a 5-year-old male child presenting with dysmorphic features, congenital heart disease and global developmental delay. Chromosomal analysis of the patient with GTG bands revealed a 47,XY,+der(14)t(12;14)(p13;q22)mat karyotype; the mother's karyotype was 46,XX,t(12;14)(p13;q22). Further, oligonucleotide array- CGH studies revealed an amplification of 32.3 Mb in the 14q11.1q22.1 region, substantiating partial trisomy 14q and additionally displaying an amplification of ∼1 Mb in the 12p13.3pter region for partial trisomy 12p. This is the first study to demonstrate a novel association of partial trisomies of 14q and 12p due to a 3:1 segregation of a maternal balanced translocation involving chromosomes 12 and 14. Gene ontology studies indicated 5 potential candidate genes in the amplified regions for the observed congenital anomalies.


[Perianal Kaposi's sarcoma. A case report and a review of the literature].
Kaposi's sarcoma is the most common cancer in men who have sex with men with AIDS. The estimated prevalence in the United States is 25% in patients with positive serology for the human immunodeficiency virus (HIV). The commitment of the gastrointestinal tract is seen in 40% of patients with Kaposi's sarcoma related to AIDS but lesions can occur anywhere in the body and evolve rapidly. We present a 33-year-old patient who kept sex with men, with epidemiological history of hepatitis B and syphilis, who consulted the service of Coloproctology for perianal ulcer. He was studied according to the protocols of sexually transmitted diseases, was diagnosed HIV and an excision biopsy of the lesion was performed. The diagnosis of perianal Kaposi's sarcoma was reached. Kaposi's sarcoma-HIV was staged, no other lesions were found and the patient started antiretrovirals with poor response to therapy. He evolved with rapid progression of the disease and died with the presumptive diagnosis of Fournier's syndrome at three months after the excision biopsy. We conclude that perianal ulcers are a relatively common pathology in the office of Coloproctology and differential diagnosis are different according to the positivity for HIV or not and the patient's sexual practices. We consider that is important to publish and spread these cases.


Wnt signaling promotes proliferation and stemness regulation of spermatogonial stem/progenitor cells.
Spermatogonial stem cells (SSCs) self-renew throughout life to produce progenitor cells that are able to differentiate into spermatozoa. However, the mechanisms underlying the cell fate determination between self-renewal and differentiation have not yet been delineated. Culture conditions and growth factors essential for self-renewal and proliferation of mouse SSCs have been investigated, but no information is available related to growth factors that affect fate determination of human spermatogonia. Wnts form a large family of secreted glycoproteins, the members of which are involved in cell proliferation, differentiation, organogenesis, and cell migration. Here, we show that Wnts and their receptors Fzs are expressed in mouse spermatogonia and in the C18-4 SSC line. We demonstrate that WNT3A induces cell proliferation, morphological changes, and cell migration in C18-4 cells. Furthermore, we show that beta-catenin is activated during testis development in 21-day-old mice. In addition, our study demonstrates that WNT3A sustained adult human embryonic stem (ES)-like cells derived from human germ cells in an undifferentiated stage, expressing essential human ES cell transcription factors. These results demonstrate for the first time that Wnt/beta-catenin pathways, especially WNT3A, may play an important role in the regulation of mouse and human spermatogonia.


Sinomenine Hydrochloride Inhibits Human Glioblastoma Cell Growth through Reactive Oxygen Species Generation and Autophagy-Lysosome Pathway Activation: An In Vitro and In Vivo Study.
Glioblastoma is the most common malignant primary brain tumor, and it is one of the causes of cancer fatality in both adult and pediatric populations. Patients with glioblastoma require chemotherapy after surgical resection and radiotherapy. Therefore, chemotherapy constitutes a viable approach for the eradication of glioblastoma cells. In this study, the anti-tumor activity of sinomenine hydrochloride (SH) was evaluated in U87 and SF767 cells in vitro and in vivo. The results showed that SH potently inhibited U87 and SF767 cell viability and did not cause caspase-dependent cell death, as demonstrated by the absence of significant early apoptosis and caspase-3 cleavage. Instead, SH activated an autophagy-mediated cell death pathway, as indicated by the accumulated microtubule-associated protein light chain 3B (LC3B)-II, triggered autophagic flux and enhanced cell viability after pretreatment with autophagy inhibitors. SH-mediated autophagy in the two cell lines was implicated in reactive oxygen species (ROS) generation, protein kinase B (Akt)-mammalian target of rapamycin (mTOR) pathway suppression and c-Jun NH2-terminal kinase (JNK) pathway activation. The ROS antioxidant N-acetylcysteine (NAC), the Akt-specific activator insulin-like growth factor-1 (IGF-1) and the JNK-specific inhibitor SP600125 attenuated SH-induced autophagy. Moreover, ROS activated autophagy via the Akt-mTOR and JNK pathways. Additionally, SH treatment may promote lysosome biogenesis through activating transcription factor EB (TFEB). The in vivo study found that SH effectively suppressed glioblastoma growth without exhibiting significant toxicity. In conclusion, our findings reveal a novel mechanism of action of SH in cancer cells via the induction of autophagy through ROS generation and autophagy-lysosome pathway activation; these findings also supply a new potential therapeutic agent for the treatment of human glioblastoma.


A crossover study of short burst oxygen therapy (SBOT) for the relief of exercise-induced breathlessness in severe COPD.
Previous small studies suggested SBOT may be ineffective in relieving breathlessness after exercise in COPD. 34 COPD patients with FEV1 <40% predicted and resting oxygen saturation ≥93% undertook an exercise step test 4 times. After exercise, patients were given 4 l/min of oxygen from a simple face mask, 4 l/min air from a face mask (single blind), air from a fan or no intervention. Average oxygen saturation fell from 95.0% to 91.3% after exercise. The mean time to subjective recovery was 3.3 minutes with no difference between treatments. The mean Borg breathlessness score was 1.5/10 at rest, rising to 5.1/10 at the end of exercise (No breathlessness = 0, worst possible breathlessness = 10). Oxygen therapy had no discernable effect on Borg scores even for 14 patients who desaturated below 90%. 15 patients had no preferred treatment, 7 preferred oxygen, 6 preferred the fan, 3 preferred air via a mask and 3 preferred room air. This study provides no support for the idea that COPD patients who are not hypoxaemic at rest derive noticeable benefit from oxygen therapy after exercise. Use of air from a mask or from a fan had no apparent physiological or placebo effect.


Extreme and variable torpor among high-elevation Andean hummingbird species.
Torpor is thought to be particularly important for small endotherms occupying cold environments and with limited fat reserves to fuel metabolism, yet among birds deep torpor is both rare and variable in extent. We investigated torpor in hummingbirds at approximately 3800 m.a.s.l. in the tropical Andes by monitoring body temperature (Tb) in 26 individuals of six species held captive overnight and experiencing natural air temperature (Ta) patterns. All species used pronounced torpor, with one Metallura phoebe reaching a minimum Tb of 3.26°C, the lowest yet reported for any bird or non-hibernating mammal. The extent and duration of torpor varied among species, with overnight body mass (Mb) loss negatively correlated with both minimum Tb and bout duration. We found a significant phylogenetic signal for minimum Tb and overnight Mb loss, consistent with evolutionarily conserved thermoregulatory traits. Our findings suggest deep torpor is routine for high Andean hummingbirds, but evolved species differences affect its depth.


Prognostic Factors for Mortality, Activity of Daily Living, and Quality of Life in Taiwanese Older Patients within 1 Year Following Hip Fracture Surgery.
Hip fractures among older adults are a major public health concern worldwide. This study investigated the potential clinical factors that predict postoperative 1-year activities of daily living (ADL), quality of life (QoL), and mortality in Taiwanese older adults following hip fracture. This is a prospective cohort study enrolling older adults (≥60 years) who had undergone hip fracture surgery in a single medical center. The comprehensive clinical history of each patient was examined. QoL, ADL, and mortality events were recorded consecutively at 3, 6, and 12 months after operation. The multiple logistic regression model and the generalized estimating equation (GEE) were adopted to identify contributing factors for mortality and postoperative ADL and QoL prognosis, respectively. Among 377 participants with hip fracture, 48 died within 1 year of the index operation. ADL and QoL considerably decreased at 3 months following hip surgery. Old age, high Charlson Comorbidity Index, and American Society of Anesthesiologists grading were crucial predictors for mortality at the 1-year follow-up. The generalized estimating equation analysis indicated that the length of postoperative follow-up time, serum albumin level, patient cognitive status, and handgrip strength were considerably associated with QoL and ADL recovery prognosis in the Taiwanese older adults following hip fracture. Hip fractures have long-lasting effects on the older adults. Our data imply several prognosis predicting parameters that may assist clinicians in accounting for an individual's personalized risks in order to improve functional outcomes and reduce mortality.


Exolysin (ExlA) from Pseudomonas aeruginosa Punctures Holes into Target Membranes Using a Molten Globule Domain.
Bacteria employ several mechanisms, and most notably secretion systems, to translocate effectors from the cytoplasm to the extracellular environment or the cell surface. Pseudomonas aeruginosa widely employs secretion machineries such as the Type III Secretion System to support virulence and cytotoxicity. However, recently identified P. aeruginosa strains that do not express the Type III Secretion System have been shown to express ExlA, an exolysin translocated through a two-partner secretion system, and are the causative agents of severe lung hemorrhage. Sequence predictions of ExlA indicate filamentous hemagglutinin (FHA-2) domains as the prevalent features, followed by a C-terminal domain with no known homologs. In this work, we have addressed the mechanism employed by ExlA to target membrane bilayers by using NMR, small-angle X-ray scattering, atomic force microscopy, and cellular infection techniques. We show that the C-terminal domain of ExlA displays a "molten globule-like" fold that punctures small holes into membranes composed of negatively charged lipids, while other domains could play a lesser role in target recognition. In addition, epithelial cells infected with P. aeruginosa strains expressing different ExlA variants allow localization of the toxin to lipid rafts. ExlA homologs have been identified in numerous bacterial strains, indicating that lipid bilayer destruction is an effective strategy employed by bacteria to establish interactions with multiple hosts.


Focal Lymphocytic Thyroiditis Nodules Share the Features of Papillary Thyroid Cancer on Ultrasound.
It is often difficult to discriminate focal lymphocytic thyroiditis (FLT) or adenomatous hyperplasia (AH) from thyroid cancer if they both have suspicious ultrasound (US) findings. We aimed to make a predictive model of FLT from papillary thyroid cancer (PTC) in suspicious nodules with benign cytologic results. We evaluated 214 patients who had undergone fine-needle aspiration biopsy (FNAB) and had shown thyroid nodules with suspicious US features. PTC was confirmed by surgical pathology. FLT and AH were confirmed through more than two separate FNABs. Clinical and biochemical findings, as well as US features, were evaluated. Of 214 patients, 100 patients were diagnosed with PTC, 55 patients with FLT, and 59 patients with AH. The proportion of elevated thyrotropin (TSH) levels (p=0.014) and thyroglobulin antibody (Tg-Ab) or thyroid peroxidase antibody (TPO-Ab) positivity (p<0.001) in the FLT group was significantly higher than that in the PTC group. Regarding US features, absence of calcification (p=0.006) and "diffuse thyroid disease" (DTD) pattern on US (p<0.001) were frequently seen in the FLT group. On multivariate analysis, Tg-Ab positivity, presence of a DTD pattern on US, and absence of calcification in nodules were associated with FLT with the best specificity of 99% and positive predictive value of 96%. In contrast, a taller than wide shape of nodules was the only variable significant for differentiating AH from PTC. Suspicious thyroid nodules with cytologic benign results could be followed up with US rather than repeat FNAB, if patients exhibit Tg-Ab positivity, no calcifications in nodules, and a DTD pattern on US.


Preparation of resin-bound N-(alpha-methoxyalkyl)amides: an advantageous use of solid-phase chemistry for the handling of unstable precursors of the versatile N-acyliminium ions.
The development of a new and efficient synthesis of resin-bound N-(alpha-methoxyalkyl)amides is described. The condensation of aldehydes on a supported amide in the presence of trimethyl orthoformate afforded, in acidic media, the resin-bound N-acyliminium ion precursors. Repeating the reaction a second time led to a great improvement in yields, demonstrating one advantage of the solid-phase chemistry for the handling of sensitive intermediates difficult to isolate.


[Analgesic effect of oral tramadol on transrectal ultrasound-guided needle biopsy of the prostate in a randomized double-blind study].
A total of 121 Japanese patients scheduled for prostate biopsy were randomly and double-blindly assigned to be given a single oral dose of 100 mg Tramadol mixed with 20 ml of sugar syrup or placebo, 30 minutes before the procedure. Pain severity was measured by verbal rating scale (VRS) and visual analog scales (VAS). We also analyzed cardio-respiratory parameters and complications. Of 121 patients, 117 replied validly to VRS and VAS ; and 91 of 117 patients replied to the cohort questionnaire for analysis of the late disorder, patient's impression, prolonged pain and past history of hemorrhoid treatment. Tramadol showed no significant effect on pain severity indicated by VRS and VAS, and no change in cardiorespiratory parameters. Furthermore, 70 patients without a history of hemorrhoid treatment, showed no significant analgesic benefits of Tramadol during the biopsy. In total, 3 patients had side effects of vomiting (CTCAE : grade 1)6), which subsided spontaneously. The oral administration of a single dose of 100 mg Tramadol 30 minutes before a transrectal needle biopsy of the prostate was safe, but was not effective to calm down the pain severity.


Synaptic plasticity in Drosophila memory and hyperexcitable mutants: role of cAMP cascade.
Activity-dependent synaptic plasticity has been implicated in the refinement and modification of neural circuits during development and learning. Previous studies show that activity-induced facilitation and potentiation are disrupted at larval neuromuscular junctions in the memory mutants dunce (dnc) and rutabaga (rut) of Drosophila. The diminished learning-memory capacity and synaptic transmission plasticity have been associated with altered cAMP levels since dnc affects the cAMP-specific phosphodiesterase and rut affects adenylate cyclase. In this study, the morphology of larval motor axon terminals was examined by anti-HRP immunohistochemistry. It was found that the numbers of terminal varicosities and branches were increased in dnc mutants, which have elevated cAMP concentrations. Such increase was suppressed in dnc rut double mutants by rut mutations, which reduce cAMP synthesis. More profuse projections of larval motor axons have also been reported in double-mutant combinations of ether à go-go (eag) and Shaker (Sh) alleles, which display greatly enhanced nerve activity as a result of reduction in different K+ currents. Therefore, we examined combinations of dnc and rut with eag and Sh mutations to explore the possible relation between activity- and cAMP-induced morphological changes. We found that the expanded projections in dnc were further enhanced in double mutants of dnc with either eag or Sh, an effect that could again be suppressed by rut. The results provide evidence for altered plasticity of synaptic morphology in memory mutants dnc and rut and suggest a role of cAMP cascade in mediating activity-dependent synaptic plasticity.


Lactobacillus brevis 23017 Relieves Mercury Toxicity in the Colon by Modulation of Oxidative Stress and Inflammation Through the Interplay of MAPK and NF-κB Signaling Cascades.
Aims: Lactobacillus strains have protective effects against heavy metals while relieving oxidative stress and modulating the immune response. Mechanisms that ameliorate heavy metal toxicity and the relationship between probiotics and gut barrier protection in the process of heavy metal pathogenesis was poorly understood. Methods and Results: In this study, Lactobacillus brevis 23017 (LAB, L. brevis 23017), a selected probiotics strain with strong mercury binding capacities, was applied to evaluate the efficiency against mercury toxicity in a mouse model. Histopathological results along with HE stains show that L. brevis 23017 protects the integrity of the small intestinal villus, which slows weight loss in response to Hg exposure. The qRT-PCR results demonstrate that L. brevis 23017 maintains a normal mucosal barrier via modulation of tight junction proteins. Importantly, the present study demonstrates that L. brevis 23017 effectively ameliorates injury of the small intestine by reducing intestinal inflammation and alleviating oxidative stress in animal models. Moreover, L. brevis 23017 blocks oxidative stress and inflammation through MAPK and NF-κB pathways, as shown by western blot. Conclusions: Together, these results reveal that L. brevis 23017 may have applications in the prevention and treatment of oral Hg exposure with fermented functional foods by protecting gut health in daily life.


Muscle activation in suspension training: a systematic review.
Suspension training is an adjunct to traditional strength and conditioning. The effect of added instability on muscle activation during traditional exercises is unclear and depends on the exercise and type of instability. The purpose of this review was to compare the activations of different muscles in suspension training exercises and their traditional counterparts. A search of the current literature was performed without language restrictions using the electronic databases PubMed (1969-12 January 2017), SPORTDiscus (1969-12 January 2017) and Scopus (1969-12 January 2017). The inclusion criteria were: (1) descriptive studies; (2) physically active participants; and (3) studies that analysed muscle activation using normalised electromyographic signals during different suspension training exercises. Eighteen studies met the inclusion criteria. For the push-up, inverted row, prone bridge and hamstring curl in suspension, the activation of upper-body and core muscles ranged between moderate (21-40% maximum voluntary isometric contraction (MVIC)) and very high (>60% MVIC). Muscle activation in these same muscle groups was greater with suspension exercises relative to comparable traditional exercises, except for the inverted row. Muscle activation in the upper extremity and core muscles varied greatly amongst studies.


Natural history of nonstenotic, asymptomatic ulcerative lesions of the carotid artery.
To define the natural history of the asymptomatic, nonstenotic, ulcerative lesion involving the carotid artery bifurcation, the arteriograms and clinical course of 67 patients with 72 asymptomatic ulcerative lesions of the carotid artery were reviewed. The angiographic appearance of ulceration was classified into three groups: minimal (group A), large (group B), and compound (group C). Using life-table methods, the clinical course of these patients was compared between groups and was also compared to a nonrandomized surgically treated group of patients with nonstenotic ulcerative lesions in whom operation was performed for hemispheric or monocular symptoms. There were no significant (P greater than .1) differences in mortality, but the differences in stroke incidence was highly significant (P less than .001). The annual stroke rate, averaged over seven years, was 0.4% per year for group A, 1.47% per year for the surgically treated group, and 12.5% per year for groups B and C. The data indicate that group A ulcers have a benign prognosis, in noticeable contrast to group B and C ulcers which incur a high risk for subsequent stroke.


Interferons and bronchogenic carcinoma in juvenile laryngeal papillomatosis.
A squamous cell carcinoma of the bronchus developed in a patient during the course of juvenile laryngeal papillomatosis. This patient had received interferon treatment, which caused regression of the papillomas, but apparently had no influence on the progression of the bronchogenic squamous cell carcinoma. This suggests that interferons have an antiviral effect, but not an antitumor effect in the dosage used. No radiation therapy had been given in the past and no other carcinogenic factors are obvious. However, human papilloma viruses, which cause juvenile laryngeal papillomatosis, have been incriminated in the genesis of squamous cell carcinomas.


Disruption of right prefrontal cortex by low-frequency repetitive transcranial magnetic stimulation induces risk-taking behavior.
Decisions require careful weighing of the risks and benefits associated with a choice. Some people need to be offered large rewards to balance even minimal risks, whereas others take great risks in the hope for an only minimal benefit. We show here that risk-taking is a modifiable behavior that depends on right hemisphere prefrontal activity. We used low-frequency, repetitive transcranial magnetic stimulation to transiently disrupt left or right dorsolateral prefrontal cortex (DLPFC) function before applying a well known gambling paradigm that provides a measure of decision-making under risk. Individuals displayed significantly riskier decision-making after disruption of the right, but not the left, DLPFC. Our findings suggest that the right DLPFC plays a crucial role in the suppression of superficially seductive options. This confirms the asymmetric role of the prefrontal cortex in decision-making and reveals that this fundamental human capacity can be manipulated in normal subjects through cortical stimulation. The ability to modify risk-taking behavior may be translated into therapeutic interventions for disorders such as drug abuse or pathological gambling.


Nocturia: Finding an Identity.
Nocturia is a condition that has a tremendous impact on a patient's health and wellbeing. Getting up 2 or more times a night to urinate fragments sleep, preventing deep, restorative stages of the sleep cycle. With safer and more effective therapies, nocturia is a treatable condition that no longer should be overlooked. The simplicity of directly targeting the cause of nocturia, the overproduction of urine (ie, nocturnal polyuria) should be considered. Noctiva™ (desmopressin acetate) nasal spray (Avadel Pharmaceuticals plc, Chesterfield, MO), a novel FDA-approved microdose desmopressin nasal spray, can reduce nighttime urine production and potentially mitigate the potential harm of nocturia.


Premature ovarian insufficiency: an International Menopause Society White Paper.
The aim of this International Menopause Society White Paper on premature ovarian insufficiency (POI) is to provide the latest information regarding this distressing condition. The impact of POI has far-reaching consequences due to its impact on general, psychological, and sexual quality of life, fertility prospects, and long-term bone, cardiovascular, and cognitive health. Progress in fully understanding the etiology, diagnosis, and optimal management options has been slow thus far due to the complexity of the condition and fragmented research. Recent advances in epidemiological and genetic research have improved our understanding of this condition and randomized prospective trials are being planned to determine the intervention strategies, which will optimize quality of life and long-term well-being. The International Menopause Society has commissioned a number of experts at the forefront of their specialty to define the state of the art in the understanding of this condition, to advise on practical management strategies, and to propose future research strategies. It is hoped that a global task force will subsequently be convened in order to formulate a consensus statement across key societies, to accelerate date collection and analysis of a global POI registry, and to facilitate progress in the key defined areas of research.


Controlled deuterium labelling of imidazolium ionic liquids to probe the fine structure of the electrical double layer using neutron reflectometry.
We combined the deuterium labeling and neutron reflectivity techniques to determine the fine structure of the electric double layer structure in an imidazolium ionic liquid (IL). For this, a simple and large scale deuteration method for imidazolium ILs was developed, where the deuteration level can be systematically controlled.


Genetic parameters for measures of the efficiency of gain of boars and the genetic relationships with its component traits in Duroc pigs.
Genetic parameters for the efficiency of gain traits on 380 boars and the genetic relationships with component traits were estimated in 1,642 pigs (380 boars, 868 gilts, and 394 barrows) in 7 generations of a Duroc population. The efficiency of gain traits included the feed conversion ratio (FCR) and residual feed intake (RFI) and their component traits, ADG, metabolic BW (MWT), and daily feed intake (FI). The RFI was calculated as the difference between the actual and expected FI. The expected FI was predicted by the nutritional requirement and by the residual of phenotypic (RFI(phe)) and genetic (RFI(gen)) regressions from the multivariate analysis for FI on MWT and ADG. The means for RFI(phe) and RFI(gen) were close to zero, and the mean for nutritional RFI was negative (-0.11 kg/d). The traits studied were moderately heritable (ranging from 0.27 to 0.53). The genetic and phenotypic correlations between ADG and FI were moderate to high, whereas the genetic correlation between MWT and FI was moderate, and the phenotypic correlation between them was low. The corresponding correlations between RFI(phe) and RFI(gen) were > 0.95, implying that they can be regarded as the same trait. The genetic and phenotypic correlations of FCR with measures of RFI were high but lower than unity. The RFI(phe) was phenotypically independent of its component traits, MWT (r(p) = 0.01) and ADG (r(p) = 0.03). The RFI(gen) was genetically independent of MWT (r(g) = -0.04), whereas there was a weak genetic relationship (r(g) = 0.15) between RFI(gen) and ADG. Residual FI was more heritable than FCR, and the genetic and phenotypic correlations of RFI(phe) and RFI(gen) with FI were positive and stronger than that of FCR with FI. These results provide evidence that RFI(phe) or RFI(gen) should be included in breeding programs for Duroc pigs to make genetic improvement in the efficiency of gain.


[Antimicrobial agents in pediatric cancer patients with hepatic or renal impairment].
Antimicrobial agents are among the most frequently prescribed therapeutics in the supportive care of children and adolescents with cancer or following hematopoietic stem cell transplantation. Most of these agents are cleared from the body by elimination of unchanged drug by the kidney and/or metabolism by the liver. Impaired renal and hepatic function may have profound effects on the pharmacokinetics and pharmacodynamics of antimicrobial agents, necessitating modification of the dosage regimen in order to avoid toxicity through accumulation of the parent and/or its metabolites. Key to minimize such toxicities is a thorough understanding of the antimicrobial drug armamentarium and a careful evaluation of benefits and risks of antimicrobial interventions. This article reviews the mechanisms of renal and hepatic drug clearance in the normal state and in the state of functional impairment, their implications for antimicrobial therapy and dosage recommendations for pediatric cancer patients with impaired renal or hepatic function.


Disease burden of stroke in rural South Africa: an estimate of incidence, mortality and disability adjusted life years.
In the context of an epidemiologic transition in South Africa, in which cardiovascular disease is increasing, little is known about the stroke burden, particularly morbidity in rural populations. Risk factors for stroke are high, with hypertension prevalence of more than 50%. Accurate, up-to-date information on disease burden is essential in planning health services for stroke management. This study estimates the burden of stroke in rural South Africa using the epidemiological parameters of incidence, mortality and disability adjusted life year (DALY) metric, a time-based measure that incorporates both mortality and morbidity. Data from the Agincourt health and socio-demographic surveillance system was utilised to calculate stroke mortality for the period 2007-2011. Dismod, an incidence-prevalence-mortality model, was used to estimate incidence and duration of disability in Agincourt sub-district and 'mostly rural' municipalities of South Africa. Using these values, burden of disease in years of life lost (YLL), years lived with disability (YLD) and DALYs was calculated for Agincourt sub-district. Over 5 years, there were an estimated 842 incident cases of stroke in Agincourt sub-district, a crude stroke incidence rate of 244 per 100,000 person years. We estimate that 1,070 DALYs are lost due to stroke yearly. Of this, YLDs contributed 8.7% (3.5 - 10.5%) in sensitivity analysis). Crude stroke mortality was 114 per 100,000 person-years in 2007-11 in Agincourt sub-district. Burden of stroke in entire rural South Africa, a population of some 13,000,000 people, was high, with an estimated 33, 500 strokes occurring in 2011. This study provides the first estimates of stroke burden in terms of incidence, and disability in rural South Africa. High YLL and DALYs lost amongst the rural populations demand urgent measures for preventing and mitigating impacts of stroke. Longitudinal surveillance sites provide a platform through which a changing stroke burden can be monitored in rural South Africa.


IL-35-producing B cells in gastric cancer patients.
A significant characteristic of advanced gastric cancer (GC) is immune suppression, which can promote the progression of GC. Interleukin 35 (IL-35) is an immune-suppressing cytokine, and it is generally recognized that this cytokine is secreted by regulatory T (Treg) cells. Recently, studies have found that IL-35 can also be produced by B cells in mice. However, scientific studies reporting that IL-35 is secreted by B cells in humans, specifically in cancer patients, are very rare.Blood samples were collected from 30 healthy controls (HCs) and 50 untreated GC patients, and IL-35-producing B cells in the peripheral blood were investigated. Moreover, Treg cells (CD4CD25CD127), myeloid-derived suppressor cells (MDSCs) (CD14HLA-DR) and other lymphocyte subsets (CD3, CD4, CD8 T cells, activated and memory CD4 T cells, activated CD8 T cells, CD14 monocytes, and IL-10-producing B cells) were also examined.IL-35-producing B cells were significantly upregulated in patients with advanced GC. Furthermore, the frequency of IL-35-producing B cells was positively correlated with the frequencies of Treg cells (CD4CD25CD127), MDSCs (CD14HLA-DR), IL-10-producing B cells, and CD14 monocytes in these GC patients.In summary, the frequency of IL-35-producing B cells is significantly elevated in advanced GC; this outcome implies that this group of B cells may participate in GC progression.


Loss of transcriptional repression of three sterol-regulated genes in mutant hamster cells.
Two genes that encode enzymes in cholesterol biosynthesis, 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase and HMG-CoA synthase, and the gene encoding the low density lipoprotein (LDL) receptor are repressed when sterols accumulate in animal cells. Their 5'-flanking regions contain a common element, designated sterol regulatory element-1 (SRE-1). In the HMG-CoA synthase and LDL receptor promoters, the SRE-1 enhances transcription in the absence of sterols and is inactivated in the presence of sterols. In the HMG-CoA reductase promoter, the region containing the SRE-1 represses transcription when sterols are present. In the current studies, we show that the SRE-1 retains enhancer function but loses sterol sensitivity in mutant Chinese hamster ovary cells that are resistant to the repressor, 25-hydroxycholesterol. In the absence of sterols, the mutant cells produced high levels of all three sterol-regulated mRNAs, and there was no repression by 25-hydroxycholesterol. When transfected with plasmids containing each of the regulated promoters fused to a bacterial reporter gene, the mutant cells showed high levels of transcription in the absence of sterols and no significant repression by sterols. When the SRE-1 in the LDL receptor and HMG-CoA synthase promoters was mutated prior to transfection into the mutant cells, transcription was markedly reduced. Thus, the 25-hydroxycholesterol-resistant cells retain a protein that enhances transcription by binding to the SRE-1 in the absence of sterols, but they have lost the function of a protein that abolishes this enhancement in the presence of sterols. Mutation of a 30-base pair segment of the HMG-CoA reductase promoter that contains the SRE-1 did not reduce transcription in the mutant cells, indicating that this promoter is driven by elements other than the SRE-1. Nevertheless, this promoter failed to be repressed by sterols in the mutant cells. These data suggest that a common factor mediates the effects of sterols on the SRE-1 in all three promoters and that this factor has been functionally lost in the 25-hydroxycholesterol-resistant cells.


Potential applications of differential permeability membranes in the control of gas composition in closed circuit atmospheres.
Long hyperbaric exposures of humans, at pressures in excess of 2.5 atmospheres, require that the oxygen concentration of the breathing gas be maintained at levels less than atmospheric air, in order to prevent pulmonary oxygen toxicity. Carbon dioxide produced by humans must be removed from the breathing gas of closed environments. Differential permeability gas separation devices can be used to reduce the concentrations of carbon dioxide and oxygen in recirculating nitrogen/oxygen atmospheres. The application of these devices can eliminate the requirement for nitrogen to dilute oxygen, and reduce, or eliminate, the requirement for carbon dioxide absorbents. The use of differential permeability gas separation devices for the production of nitrogen/oxygen breathing gas mixtures for divers, using air as a source gas, can produce mixtures with unacceptably high levels of carbon dioxide.


Histiocytic sarcoma in an aging gerbil.
A histiocytic sarcoma in an aging female gerbil is described. The neoplasm primarily involved the spleen and liver, and these organs were considered the primary sites of neoplastic origin. No neoplastic infiltration was noted in the uterus or ovaries as is commonly seen in the female mouse. This is the first report of histiocytic sarcoma in gerbils.


Technical assessment of a cone-beam CT scanner for otolaryngology imaging: image quality, dose, and technique protocols.
As cone-beam CT (CBCT) systems dedicated to various imaging specialties proliferate, technical assessment grounded in imaging physics is important to ensuring that image quality and radiation dose are quantified, understood, and justified. This paper involves technical assessment of a new CBCT scanner (CS 9300, Carestream Health, Rochester, NY) dedicated to imaging of the ear and sinuses for applications in otolaryngology-head and neck surgery (OHNS). The results guided evaluation of technique protocols to minimize radiation dose in a manner sufficient for OHNS imaging tasks. The technical assessment focused on the imaging performance and radiation dose for each of seven technique protocols recommended by the manufacturer: three sinus protocols and four ear (temporal bone) protocols. Absolute dose was measured using techniques adapted from AAPM Task Group Report No. 111, involving three stacked 16 cm diameter acrylic cylinders (CTDI phantoms) and a 0.6 cm(3) Farmer ionization chamber to measure central and peripheral dose. The central dose (D(o)) was also measured as a function of longitudinal position (z) within and beyond the primary radiation field to assess, for example, out-of-field dose to the neck. Signal-difference-to-noise ratio (SDNR) and Hounsfield unit (HU) accuracy were assessed in a commercially available quality assurance phantom (CATPHAN module CTP404, The Phantom Laboratory, Greenwich, NY) and a custom phantom with soft-tissue-simulating plastic inserts (Gammex RMI, Madison, WI). Spatial resolution was assessed both qualitatively (a line-pair pattern, CATPHAN module CTP528) and quantitatively (modulation transfer function, MTF, measured with a wire phantom). Imaging performance pertinent to various OHNS imaging tasks was qualitatively assessed using an anthropomorphic phantom as evaluated by two experienced OHNS specialists. The technical assessment motivated a variety of modifications to the manufacturer-specified protocols to provide reduced radiation dose without compromising pertinent task-based imaging performance. The revised protocols yielded D(o) ranging 2.9-5.7 mGy, representing a ∼30% reduction in dose from the original technique chart. Out-of-field dose was ∼10% of D(o) at a distance of ∼8 cm from the field edge. Soft-tissue contrast resolution was fairly limited (water-brain SDNR ∼0.4-0.7) while high-contrast performance was reasonably good (SDNR ∼2-4 for a polystyrene insert in the CATPHAN). The scanner does not demonstrate (or claim to provide) accurate HU and exhibits a systematic error in CT number that could potentially be addressed by further calibration. The spatial resolution is ∼10-16 lp∕cm as assessed in a line-pair phantom, with MTF exceeding 10% out to ∼20 lp∕cm. Qualitative assessment by expert readers suggested limited soft-tissue visibility but excellent high-contrast (bone) visualization with isotropic spatial resolution suitable to a broad spectrum of pertinent sinus and temporal bone imaging tasks. The CBCT scanner provided spatial and contrast resolution suitable to visualization of high-contrast morphology in sinus, maxillofacial, and otologic imaging applications. Rigorous technical assessment guided revision of technique protocols to reduce radiation dose while maintaining image quality sufficient for pertinent imaging tasks. The scanner appears well suited to high-contrast sinus and temporal bone imaging at doses comparable to or less than that reported for conventional diagnostic CT of the head.


Pore texture analysis in automated 3D breast ultrasound images for implanted lightweight hernia mesh identification: a preliminary study.
Precise visualization of meshes and their position would greatly aid in mesh shrinkage evaluation, hernia recurrence risk assessment, and the preoperative planning of salvage repair. Lightweight (LW) meshes are able to preserve abdominal wall compliance by generating less post-implantation fibrosis and rigidity. However, conventional 3D imaging techniques such as computed tomography (CT) and magnetic resonance imaging (MRI) cannot visualize the LW meshes. Patients sometimes have to undergo a second-look operation for visualizing the mesh implants. The goal of this work is to investigate the potential advantages of Automated 3D breast ultrasound (ABUS) pore texture analysis for implanted LW hernia mesh identification. In vitro, the appearances of four different flat meshes in both ABUS and 2D hand-held ultrasound (HHUS) images were evaluated and compared. In vivo, pore texture patterns of 87 hernia regions were analyzed both in ABUS images and their corresponding HHUS images. In vitro studies, the imaging results of ABUS for implanted LW meshes are much more visualized and effective in comparison to HHUS. In vivo, the inter-class distance of 40 texture features was calculated. The texture features of 2D sectional plans (axial and sagittal plane) have no significant contribution to implanted LW mesh identification. Significant contribution was observed in coronal plane. However, since the mesh may have spatial variation such as shrinkage after implantation surgery, the inter-class distance of 3D coronal plane pore texture features are bigger than 2D coronal plane, so the contribution of 3D coronal plane pore texture features are more valuable than 2D coronal plane for implanted LW mesh identification. The use of 3D pore texture features significantly improved the robustness of the identification method in distinguishing between LW mesh and fascia. An innovative new ABUS provides additional pore texture visualization, by separating the LW mesh from the fascia tissues. Therefore, ABUS has the potential to provides more accurate features to characterize pore texture patterns, and ultimately provide more accurate measures for implanted LW mesh identification.


Cerebrospinal Fluid Neurofilament Light Predicts Risk of Dementia Onset in Cognitively Healthy Individuals and Rate of Cognitive Decline in Mild Cognitive Impairment: A Prospective Longitudinal Study.
Background: Biomarkers that are indicative of early biochemical aberrations are needed to predict the risk of dementia onset and progression in Alzheimer's disease (AD). We assessed the utility of cerebrospinal fluid (CSF) neurofilament light (NfL) chain for screening preclinical AD, predicting dementia onset among cognitively healthy (CH) individuals, and the rate of cognitive decline amongst individuals with mild cognitive impairment (MCI). Methods: Neurofilament light levels were measured in CSF samples of participants (CH, n = 154 and MCI, n = 32) from the Australian Imaging, Biomarkers and Lifestyle study of ageing (AIBL). Cases of preclinical AD were identified using biomarker-guided classification (CH, amyloid-β [Aβ]+, phosphorylated-tau [P-tau]+ and total-tau [T-tau]±; A+T+/N±). The prediction of dementia onset (questionable dementia) among CH participants was assessed as the risk of conversion from Clinical Dementia Rating [CDR = 0] to CDR ≥ 0.5 over 6 years. Mixed linear models were used to assess the utility of baseline CSF NfL levels for predicting the rate of cognitive decline among participants with MCI over 4.5 years. Results: Neurofilament light levels were significantly higher in preclinical AD participants (CH, A+T+/N±) as compared to A-T-N- (p < 0.001). Baseline levels of CSF NfL were higher in CH participants who converted to CDR ≥ 0.5 over 6 years (p = 0.045) and the risk of conversion to CDR ≥ 0.5 was predicted (hazard ratio [HR] 1.60, CI 1.03−2.48, p = 0.038). CH participants with CSF NfL > cut-off were at a higher risk of developing dementia (HR 4.77, CI 1.31−17.29, p = 0.018). Participants with MCI and with higher baseline levels of CSF NfL (>median) had a higher rate of decline in cognition over 4.5 years. Conclusion: An assessment of CSF NfL levels can help to predict dementia onset among CH vulnerable individuals and cognitive decline among those with MCI.


Noninvasive Detection of ctDNA Reveals Intratumor Heterogeneity and Is Associated with Tumor Burden in Gastrointestinal Stromal Tumor.
Molecular analysis of circulating tumor DNA (ctDNA) has a large potential for clinical application by capturing tumor-specific aberrations through noninvasive sampling. In gastrointestinal stromal tumor (GIST), analysis of KIT and PDGFRA mutations is important for therapeutic decisions, but the invasiveness of traditional biopsies limits the possibilities for repeated sampling. Using targeted next-generation sequencing, we have analyzed circulating cell-free DNA from 50 GIST patients. Tumor-specific mutations were detected in 16 of 44 plasma samples (36%) from treatment-naïve patients and in three of six (50%) patients treated with tyrosine kinase inhibitors. A significant association between detection of ctDNA and the modified National Institutes of Health risk classification was found. All patients with metastatic disease had detectable ctDNA, and tumor burden was the most important detection determinant. Median tumor size was 13.4 cm for patients with detectable mutation in plasma compared with 4.4 cm in patients without detectable mutation (P = 0.006). ctDNA analysis of a patient with disease progression on imatinib revealed that multiple resistance mutations were synchronously present, and detailed analysis of tumor tissue showed that these were spatially distributed in the primary tumor. Plasma samples taken throughout the course of treatment demonstrated that clonal evolution can be monitored over time. In conclusion, we have shown that detection of GIST-specific mutations in plasma is particularly feasible for patients with high tumor burden. In such cases, we have demonstrated that mutational analysis by use of liquid biopsies can capture the molecular heterogeneity of the whole tumor, and may guide treatment decisions during progression. Mol Cancer Ther; 17(11); 2473-80. ©2018 AACR.


Attitudes of Florida pharmacists toward implementing a state prescription drug monitoring program for controlled substances.
As of May 23, 2011, 35 states had an operational prescription drug monitoring program (PDMP), and 13 additional states, including Florida in 2009, had passed legislation to implement a PDMP. PDMPs, electronic databases that collect and track designated data on controlled substances and other commonly abused medications, are intended to serve as a tool for health care practitioners when prescribing and dispensing controlled substances to reduce drug abuse and diversion. In an analysis of 1,268 drug-caused deaths from January through June 2010 in Florida, the top 3 prescription drugs included the controlled substances oxycodone (56%), alprazolam (35%), and methadone (26%), all of which would be subject to reporting in Florida's PDMP when implemented. Because pharmacists are the health care professionals most affected by PDMP reporting requirements, evaluating their attitudes about PDMP implementation is important. To assess Florida pharmacists' attitudes toward implementing a PDMP in the state. This was a cross-sectional study conducted in Florida between February 2010 and June 2010 prior to the implementation of the proposed PDMP. A random sample of 5,000 of approximately 26,000 pharmacists licensed in Florida was invited to participate in a voluntary and anonymous 10-question self-administered mail survey of which 4 survey items assessed pharmacists' attitudes towards implementing a PDMP in the state. Of the 5,000 pharmacists contacted by mail, 911 (18.2%) completed the survey, of whom 836 responded to the items assessing opinions about PDMPs and provided practice site information. A majority of pharmacists across all practice settings agreed or strongly agreed with the statements that a PDMP "should be implemented in Florida" (chain 84.0%, hospital 74.2%, independent 77.9%, and other 71.1%) and that a PDMP would decrease "the incidence of doctor shopping" if implemented (chain 80.8%, hospital 67.2%, independent 71.7%, and other 63.3%). A majority of pharmacists across all practice settings disagreed or strongly disagreed with the statements that they would be "discouraged to dispense controlled substances" by the PDMP (chain 61.4%, hospital 50.0%, independent 60.2%, and other 63.8%) and that PDMP implementation would be "an invasion of patients' privacy" (chain 80.3%, hospital 67.7%, independent 67.3%, and other 69.3%). In a small-sample survey, a majority of Florida pharmacists across all practice settings were in favor of implementing a PDMP in Florida. This is the first study to examine Florida pharmacists' attitudes toward PDMP implementation, and the results should prompt future analyses of relevant outcomes, such as drug abuse, drug-related mortality, and doctor shopping.


Properties and modulation of If in newborn versus adult cardiac SA node.
The hearts in newborn mammals have greater intrinsic beating rates, rates of diastolic depolarization, and sensitivity to autonomic stimulation than those in adults. The differences could be explained partly by altered properties of the hyperpolarization-activated current (If). To test this possibility, sinoatrial node myocytes from the hearts of newborn (9- to 10-day) and adult (>30-day) rabbits were isolated, and the If was examined with the perforated-patch-clamp technique. The fully activated current-voltage relationship yielded a larger slope conductance of If in newborn SA node myocytes (0.244 +/- 0.020 vs. 0.158 +/- 0.012 pS/pF), compatible with the more rapid diastolic depolarization. Activation curves of the If had similar midactivation voltages (newborn, -66.71 +/- 1.94 mV; adult, -66.33 +/- 2.60 mV), but the slope was significantly greater in newborns (inverse slope factor: newborn, -9.57 +/- 0.35 mV; adult, -11.34 +/- 0.54 mV). No differences in shifts of the If activation curve in response to maximal concentrations of acetylcholine (newborn, -9.70 +/- 1.8 mV; adult, -12.60 +/- 2.10 mV) and isoproterenol (newborn, 6.90 +/- 2.5 mV; adult, 5.3 +/- 1.5 mV) or in the total shift in response to these agonists (newborn, 16.60 +/- 3.30 mV; adult, 18.00 +/- 1.00 mV) were observed. The greater If density and steeper voltage dependence can contribute to both the greater heart rate and the greater sensitivity of the SA node to autonomic modulation in newborn animals.


Field observations of mating behavior in the neck-banded snake Scaphiodontophis annulatus (Serpentes: Colubridae).
We observed the mating behavior of the neck-banded snake Scaphiodontophis annulatus (a common species of colubrid in the South Pacific of Costa Rica) in the pre-montane wet forest of Las Cruces Biological Station (San Vito de Java, Costa Rica). Three S. annulatus were observed during courtship between 10-12 AM in a patch of primary forest. The two males were observed to interact with the female, but not signs of male-male agonistic interactions were observed. Their behavior includes grabbing and holding the female, copula, and biting during the copula.


Sequence heterogeneity of heron hepatitis B virus genomes determined by full-length DNA amplification and direct sequencing reveals novel and unique features.
So far, only a single heron hepatitis B virus genome (HHBV-4) has been cloned and sequenced. Therefore, neither the significance of its sequence divergence from other avian hepadnaviruses nor the sequence variability of HHBV genomes in general are known. Here we have analysed the sequence heterogeneity of HHBV genome populations in several sera from naturally infected herons. A highly sensitive PCR method for full-length HHBV genome amplification was established which allowed direct sequencing of entire HHBV populations without prior cloning. Sequences of HHBV genomes from four sera were thus obtained which differed from those of HHBV-4 by up to 7%. Some of the divergent nucleotides and the corresponding amino acids of the predicted viral proteins were conserved in all four new HHBV isolates and varied only in HHBV-4. This indicates that the HHBV-4 genome is not in all aspects representative of this class of viruses. Interestingly, a highly conserved ORF upstream of the C-gene present in a position analogous to that of the mammalian hepadnavirus X-gene became apparent in all HHBV genomes. In contrast to the duck hepadnaviruses, the small (sAg-S) instead of the largest (sAg-L) envelope protein of all HHBVs has a myristylation site. These data confirm the significant sequence divergence of HHBV from other avian hepadnaviruses. Moreover, they show that HHBV has low sequence variability and indicate two new and unique features not evident in other avihepadnaviruses: an additional, highly conserved gene and potential myristylation of the sAg-S instead of the sAg-L envelope protein.


Developing an Open Access, Competency-Based Global Oral Health Curriculum: A Global Health Starter Kit.
Dental education has seen increases in global health and international educational experiences in many dental schools' curricula. In response, the Consortium of Universities for Global Health's Global Oral Health Interest Group aims to develop readily available, open access resources for competency-based global oral health teaching and learning. The aim of this study was to develop and evaluate a Global Health Starter Kit (GHSK), an interdisciplinary, competency-based, open access curriculum for dental faculty members who wish to teach global oral health in their courses. Phase I (2012-17) evaluated longitudinal outcomes from two Harvard School of Dental Medicine pilot global health courses with 32 advanced and 34 predoctoral dental students. In Phase II (2018), the Phase I outcomes informed development, implementation, and evaluation of the open access GHSK (45 enrollees) written by an interdisciplinary, international team of 13 content experts and consisting of five modules: Global Trends, Global Goals, Back to Basics: Primary Care, Social Determinants and Risks, and Ethics and Sustainability. In Phase III (summer and fall 2018), five additional pilot institutions (two U.S. dental schools, one U.S. dental hygiene program, and two dental schools in low- and middle-income countries) participated in an early adoption of the GHSK curriculum. The increase in perceived knowledge scores of students enrolled in the pilot global health courses was similar to those enrolled in the GHSK, suggesting the kit educated students as well or better in nearly all categories than prior course materials. This study found the GHSK led to improvements in learning in the short term and may also contribute to long-term career planning and decision making by providing competency-based global health education.