Differential effects of FGFR2 mutations on syndactyly and cleft palate in Apert syndrome.
Apert syndrome is a distinctive human malformation characterized by craniosynostosis and severe syndactyly of the hands and feet. It is caused by specific missense substitutions involving adjacent amino acids (Ser252Trp or Pro253Arg) in the linker between the second and third extracellular immunoglobulin domains of fibroblast growth factor receptor 2 (FGFR2). We have developed a simple PCR assay for these mutations in genomic DNA, based on the creation of novel (SfiI) and (BstUI) restriction sites. Analysis of DNA from 70 unrelated patients with Apert syndrome showed that 45 had the Ser252Trp mutation and 25 had the Pro253Arg mutation. Phenotypic differences between these two groups of patients were investigated. Significant differences were found for severity of syndactyly and presence of cleft palate. The syndactyly was more severe with the Pro253Arg mutation, for both the hands and the feet. In contrast, cleft palate was significantly more common in the Ser252Trp patients. No convincing differences were found in the prevalence of other malformations associated with Apert syndrome. We conclude that, although the phenotype attributable to the two mutations is very similar, there are subtle differences. The opposite trends for severity of syndactyly and cleft palate in relation to the two mutations may relate to the varying patterns of temporal and tissue-specific expression of different fibroblast growth factors, the ligands for FGFR2.


Imaging polarimetry in patients with neovascular age-related macular degeneration.
Imaging polarimetry was used to examine different components of neovascular membranes in age-related macular degeneration. Retinal images were acquired with a scanning laser polarimeter. An innovative pseudocolor scale, based on cardinal directions of color, displayed two types of image information: relative phases and magnitudes of birefringence. Membranes had relative phase changes that did not correspond to anatomical structures in reflectance images. Further, membrane borders in depolarized light images had significantly higher contrasts than those in reflectance images. The retinal birefringence in neovascular membranes indicates optical activity consistent with molecular changes rather than merely geometrical changes.


Association between household triatomine density and incidence of Trypanosoma cruzi infection during a nine-year study in Castro Alves, Bahia, Brazil.
We studied the association between human incidence of Trypanosoma cruzi infection and household infestation density of Panstrongylus megistus in Castro Alves, Bahia, Brazil. During a 9-year period, 19 persons seroconverted; 17 were children, 17 lived in nonplastered houses, and 13 lived in houses infested with triatomines. Although 6 seroconverting persons lived in houses where triatomines could not be found, the risk of seroconversion was significantly greater in infested houses and 16 times greater in densely infested houses (greater than 15 bugs/person-hour of search). The highest rate of seroconversion (6/100 person-years exposure) occurred in houses containing the greatest number of bugs infected with T. cruzi (greater than 6 infected bugs/person-hour). These observations suggest that vector control measures could have a dramatic impact on transmission of T. cruzi by P. megistus.


Purine metabolism in heterozygous carriers of hypoxanthine-guanine phosphoribosyltransferase deficiency.
The urate pool and daily turnover of urate, together with the rate of incorporation of glycine into urate, were measured in three asymptomatic mothers who had sons with various degrees of deficiency of hypoxanthine-guanine phosphoribosyltransferase activity. Two of these mothers had abnormally increased values for the urate pool, urate turnover, and 24-hour urinary excretion of uric acid. These two mothers also had reduced hypoxanthine-guanine phosphoribosyltransferase activity and increased adenine phosphoribosyltransferase activity in erythrocyte lysates. All three mothers showed an abnormal increase in urate production, as judged by the rate of incorporation of glycinie into urate.


Cardiac channelopathy testing in 274 ethnically diverse sudden unexplained deaths.
Sudden unexplained deaths (SUD) in apparently healthy individuals, for which the causes of deaths remained undetermined after comprehensive forensic investigations and autopsy, present vexing challenges to medical examiners and coroners. Cardiac channelopathies, a group of inheritable diseases that primarily affect heart rhythm by altering the cardiac conduction system, have been known as one of the likely causes of SUD. Adhering to the recommendations of including molecular diagnostics of cardiac channelopathies in SUD investigation, the Molecular Genetics Laboratory of the New York City (NYC) Office of Chief Medical Examiner (OCME) has been routinely testing for six major channelopathy genes (KCNQ1, KCNH2, SCN5A, KCNE1, KCNE2, and RyR2) since 2008. Presented here are the results of cardiac channelopathy testing in 274 well-characterized autopsy negative SUD cases, all with thorough medicolegal death investigation including complete autopsy by NYC OCME between 2008 and 2012. The cohort consisted of 141 infants (92.9% younger than six-month old) and 133 non-infants (78.2% were between 19 and 58 years old). Among the ethnically diverse cohort, African American infants had the highest risks of SUD, and African American non-infants died at significantly younger age (23.7 years old, mean age-at-death) than those of other ethnicities (30.3 years old, mean age-at-death). A total of 22 previously classified cardiac channelopathy-associated variants and 24 novel putative channelopathy-associated variants were detected among the infants (13.5%) and non-infants (19.5%). Most channelopathy-associated variants involved the SCN5A gene (68.4% in infants, 50% in non-infants). We believe this is the first study assessing the role of cardiac channelopathy genes in a large and demographically diverse SUD population drawn from a single urban medical examiner's office in the United States. Our study supports that molecular testing for cardiac channelopathy is a valuable tool in SUD investigations and provides helpful information to medical examiners/coroners seeking cause of death in SUD as well as potentially life-saving information to surviving family members.


The Raman fingerprint of cyclic conjugation: the case of the stabilization of cations and dications in cycloparaphenylenes.
Radical cations and dications of [n]CPP from n = 5 to n = 12 have been studied by Raman spectroscopy and density functional theory. Small [n]CPP dications owe their stability to the closed-shell electronic structure imposed by cyclic conjugation surpassing the destabilizing effect of ring strain and of the electron deficiency of the charged states. Large [n]CPP dications mitigate cyclic strain by forming diradicals. The Raman spectra reflect the balance among cyclic conjugation, cyclic strain and biradicaloid stabilization by finding an unexpected turning point in the frequency behavior of the G vibrational modes as a function of size. These Raman data represent the vibrational fingerprint of this rare form of conjugation which is central to stabilize both cations and dications of [n]CPP macrocycles.


Recent advances in the treatment of the spondyloarthropathies.
Recently, there has been renewed interest in the spondyloarthropathy family of chronic inflammatory rheumatic conditions, which has been fueled to a large extent by the biologic era. Over the period of the past 2 years in particular, there have been several notable advances. First, there have been a number of large, high-quality randomized controlled trials evaluating the tumor necrosis factor (TNF) blockers and conservative treatments such as physiotherapy and nonsteroidal anti-inflammatory drugs for use in spondyloarthropathy. This has paved the way for the development of better tools to assess outcome in these patients both in daily practice and in the context of clinical trials. This review uses a systematic approach to outline the most recent (within the last 2 years) and the most pertinent advances in the treatments of the spondyloarthropathies, with particular emphasis on ankylosing spondylitis and psoriatic arthritis. Supervised group exercise programs maintain flexibility and posture in patients with ankylosing spondylitis, and spa therapy is a cost-effective treatment option in ankylosing spondylitis. Nonsteroidal anti-inflammatory drugs have a role in symptom modification and, more importantly, may prevent structural disease progression in patients with ankylosing spondylitis when administered continuously at a fixed dose. TNF blockers have been evaluated in a number of randomized controlled trials in ankylosing spondylitis and psoriatic arthritis and have been demonstrated to be safe and effective in the short-term management of these diseases. Longer-term trials are awaited with radiographic outcomes to comment on their disease-modifying properties and their long-term safety and efficacy profiles. There has been renewed interest in the spondyloarthropathy family of disorders, with an explosion in the number of trials evaluating outcome with the TNF blockers. To date, no cure has been found for the disease, but these agents are emerging as the best therapeutic option available for patients with ankylosing spondylitis and psoriatic arthritis to date.


Zygapophyseal Joint Orientation and Facet Tropism and Their Association with Lumbar Disc Prolapse.
Cross-sectional study. To evaluate the association between zygapophyseal joint angle (ZJA), facet tropism (FT), and lumbar intervertebral disc prolapse (IVDP). Several studies have shown that FT increases the risk of IVDP and have postulated that a more sagittally oriented zygapophyseal joint provides less mechanical resistance to axial torque, thereby exerting excessive rotational strain on the intervertebral disc, resulting in an annular tear. In contrast, other studies have found no definitive association between FT and IVDP. Therefore, conclusive evidence regarding the role of FT in the pathogenesis of disc prolapse is currently lacking. Magnetic resonance imaging scans of 426 patients with single-level lumbar IVDP were analyzed. Right and left ZJAs of the lumbar segments were measured on axial sections. The frequency and severity of FT were determined by calculating the absolute difference between the right and left ZJAs. Patients without IVDP at L4-L5 and L5-S1 served as controls for those with IVDP at L4-L5 and L5-S1, respectively. Chi-square test and t -test were used to compare the severity and frequency of FT between patients with and without IVDP. The receiver operating characteristic analysis was performed to determine the critical FT values that were predictive of IVDP. Patients with IVDP exhibited a higher frequency (L4-L5: 47% vs. 15.08%; L5-S1: 39.62% vs. 22.69%; p =0.001) and severity (L4-L5: 7.85°±3.5° vs. 4.05°±2.62°; L5-S1: 7.30°±3.07° vs. 4.82°±3.29°; p <0.001) of FT than those without IVDP. Critical FT values of 5.7° at L4-L5 and 6° at L5-S1 increased the likelihood of IVDP by a factor of 2.89 and 1.75, respectively. Our results confirm the existence of a significant association between lumbar IVDP and FT; however, a causal relationship could not be ascertained.


Pathway Analysis Integrating Genome-Wide and Functional Data Identifies PLCG2 as a Candidate Gene for Age-Related Macular Degeneration.
Age-related macular degeneration (AMD) is the worldwide leading cause of blindness among the elderly. Although genome-wide association studies (GWAS) have identified AMD risk variants, their roles in disease etiology are not well-characterized, and they only explain a portion of AMD heritability. We performed pathway analyses using summary statistics from the International AMD Genomics Consortium's 2016 GWAS and multiple pathway databases to identify biological pathways wherein genetic association signals for AMD may be aggregating. We determined which genes contributed most to significant pathway signals across the databases. We characterized these genes by constructing protein-protein interaction networks and performing motif analysis. We determined that eight genes (C2, C3, LIPC, MICA, NOTCH4, PLCG2, PPARA, and RAD51B) "drive" the statistical signals observed across pathways curated in the Kyoto Encyclopedia of Genes and Genomes (KEGG), Reactome, and Gene Ontology (GO) databases. We further refined our definition of statistical driver gene to identify PLCG2 as a candidate gene for AMD due to its significant gene-level signals (P < 0.0001) across KEGG, Reactome, GO, and NetPath pathways. We performed pathway analyses on the largest available collection of advanced AMD cases and controls in the world. Eight genes strongly contributed to significant pathways from the three larger databases, and one gene (PLCG2) was central to significant pathways from all four databases. This is, to our knowledge, the first study to identify PLCG2 as a candidate gene for AMD based solely on genetic burden. Our findings reinforce the utility of integrating in silico genetic and biological pathway data to investigate the genetic architecture of AMD.


Chronic myelogenous leukemia stem and progenitor cells demonstrate chromosomal instability related to repeated breakage-fusion-bridge cycles mediated by increased nonhomologous end joining.
Chromosomal aberrations are an important consequence of genotoxic exposure and contribute to pathogenesis and progression of several malignancies. We investigated the susceptibility to chromosomal aberrations in chronic myelogenous leukemia (CML) progenitors after exposure to ionizing radiation. In normal progenitors, ionizing radiation induced both stable and unstable chromosomal lesions, but only stable aberrations persisted after multiple divisions. In contrast, radiation of chronic phase CML progenitors resulted in enhanced generation of unstable lesions that persisted after multiple divisions. CML progenitors demonstrated active cell cycle checkpoints and increased nonhomologous end joining DNA repair, suggesting that persistence of unstable aberrations was the result of continued generation of these lesions. CML progenitors demonstrated enhanced susceptibility to repeated cycles of chromosome damage, repair, and damage through a breakage-fusion-bridge mechanism. Perpetuation of breakage-fusion-bridge cycles in CML progenitors was mediated by classic nonhomologous end joining repair. These studies reveal a previously unrecognized mechanism of chromosomal instability in leukemia progenitors because of continued generation of unstable chromosomal lesions through repeated cycles of breakage and repair of such lesions.


Theoretical assessment of alternative mechanisms for non-photochemical quenching of PS II fluorescence in barley leaves.
The components of non-photochemical chlorophyll fluorescence quenching (qN) in barley leaves have been quantified by a combination of relaxation kinetics analysis and 77 K fluorescence measurements (Walters RG and Horton P 1991). Analysis of the behaviour of chlorophyll fluorescence parameters and oxygen evolution at low light (when only state transitions - measured as qNt - are present) and at high light (when only photoinhibition - measured as qNi - is increasing) showed that the parameter qNt represents quenching processes located in the antenna and that qNi measures quenching processes located in the reaction centre but which operate significantly only when those centres are closed. The theoretical predictions of a variety of models describing possible mechanisms for high-energy-state quenching, measured as the residual quenching, qNe, were then tested against the experimental data for both fluorescence quenching and quantum yield of oxygen evolution. Only one model was found to agree with these data, one in which antennae exist in two states, efficient in either energy transfer or energy dissipation, and in which those photosynthetic units in a dissipative state are unable to exchange energy with non-dissipative units.


Transvenous Embolization of Brain Arteriovenous Malformations: Up-to-Date Meta-Analysis.
To conduct an up-to-date meta-analysis to assess the success and complication rates of transvenous embolization (TVE) of brain arteriovenous malformations (BAVMs), and to determine its efficacy and safety. Relevant and potentially relevant studies from 1982 to February 2021 were searched; after which those that satisfied our eligibility criteria and reported the main outcomes (endovascular occlusion and complication rates) were included. Ultimately seven studies were selected. In total, 154 patients were comprehensively reviewed for BAVMs characteristics and endovascular TVE techniques. The weighted mean rate of immediate endovascular total occlusion, overall technical complication, and overall good functional outcome (mRs < 2) were 93% (95% confidence intervals (CI), 89.1%?96.9%, I2 = 0%, p=0.487), 10.5% (95% CI, 4.3%?16.6%, I2 = 30.8%, p=0.193), and 90.9% (95% CI, 85.3%?96.6%, I2 = 26.6%, p=0.241), respectively. TVE for BAVMs was found to be generally safe and effective in certain selected patients. However, the complementary role of TAE to TVE as a definitive endovascular treatment for BAVMs cannot be separated. More studies regarding this role need to be conducted.


TOL19-001 reduces inflammation and MMP expression in monolayer cultures of tendon cells.
Tendinopathies are tendon conditions associated with degeneration and disorganization of the matrix collagen fibers, tendon cells apoptosis and inflammation through up-regulation of proinflammatory cytokines, matrix metalloproteinase (MMP) expression, and prostaglandin E2 (PGE2) production. Currently, the pharmacological treatment is mainly based on non-steroidal anti-inflammatory drugs (NSAIDs) use and corticosteroid injections, which both can lead to numerous side effects for patients. TOL19-001 is a diet supplementary composed mostly of spirulina and glucosamine sulfate whose antioxidant properties could be helpful to treat tendinopathies while avoiding taking NSAIDs. In this study we developed an in vitro model of tendinopathy in order to evaluate the therapeutic potential of TOL19-001. Tendon cells were cultured on monolayer and treated with interleukin-1β (IL-1β) or ciprofloxacin (CIP), and then, MMPs, PGE2 and collagen expression was evaluated by RT-PCR or Elisa. In addition, a cotreatment with increased doses of TOL19-001 was done. Toxicity of TOL19-001 was evaluated using a metabolic activity assay. This study demonstrates that IL-1β mimics some aspects of tendinopathies with PGE2 induction, MMP expression (mostly MMP1 and MMP3), and increases of type III/I collagen ratio. CIP, meanwhile, leads to an increase of MMP2 and p65 mRNA, whereas it reduces TIMP1 expression. Scleraxis expression was also increased by CIP whereas it was decreased by IL-1β treatment. Besides, TOL19-001 cotreatment suppresses tendon cell inflammation in vitro, marked by the downregulation of PGE2, MMPs and type III collagen in IL-1β stimulated-cells. TOL19-001 also represses CIP induced-changes. These findings indicate that TOL19-001 exerts anti-inflammatory effects on tendon cells, which might explain why TOL19-001 diet may improve tendon function in patients with tendon injury. Future research is required to determine TOL19-001 effect on injured or overused tendons in vivo.


Effects of Pheromone Release Rate and Trap Placement on Trapping of Agrilus planipennis (Coleoptera: Buprestidae) in Canada.
The emerald ash borer, Agrilus planipennis Fairmaire (Coleoptera: Buprestidae), is a devastating insect pest in its introduced range. A trapping system that increases trap catches or detection rates in low-density populations would be beneficial for survey programs. Five trapping experiments were conducted to investigate factors influencing capture rates of male beetles on dark green traps baited with the A. planipennis pheromone, (3Z)-dodecen-12-olide ((3Z)-lactone), plus the green leaf volatile, (3Z)-hexenol. Low doses (0.001-1.0 mg) of (3Z)-lactone + (3Z)-hexenol did not consistently increase captures of male A. planipennis. In other experiments, mean captures of males were significantly higher on traps baited with a moderate dose (3.0 mg/septum) of (3Z)-lactone + (3Z)-hexenol, compared with lower doses (0.001, 0.1, and 1.0 mg) or (3Z)-hexenol alone. Next, we demonstrated that addition of (3Z)-lactone to traps baited with (3Z)-hexenol resulted in significantly greater increases in male captures when pairs of traps were placed on the same tree, than when traps were placed on adjacent trees. Moreover, significantly more A. planipennis were captured on pheromone-baited traps placed in the southern versus northern aspect of the crown. These results highlight the importance of experimental set-up for elucidating lure treatment effects and also suggests the (3Z)-lactone may be more active at close range. Our findings increase our understanding of the pheromone ecology of this species and lend support toward the use of dark green traps baited with 3.0 mg (3Z)-lactone + (3Z)-hexenol deployed in the south aspect of the canopy for detection programs for this insect.


Distinct Roles for Two Chromosome 1 Loci in Ethanol Withdrawal, Consumption, and Conditioned Place Preference.
We previously identified a region on chromosome 1 that harbor quantitative trait loci (QTLs) with large effects on alcohol withdrawal risk using both chronic and acute models in mice. Here, using newly created and existing QTL interval-specific congenic (ISC) models, we report the first evidence that this region harbors two distinct alcohol withdrawal QTLs (Alcw11and Alcw12), which underlie 13% and 3-6%, respectively, of the genetic variance in alcohol withdrawal severity measured using the handling-induced convulsion. Our results also precisely localize Alcw11 and Alcw12 to discreet chromosome regions (syntenic with human 1q23.1-23.3) that encompass a limited number of genes with validated genotype-dependent transcript expression and/or non-synonymous sequence variation that may underlie QTL phenotypic effects. ISC analyses also implicate Alcw11and Alcw12 in withdrawal-induced anxiety-like behavior, representing the first evidence for their broader roles in alcohol withdrawal beyond convulsions; but detect no evidence for Alcw12 involvement in ethanol conditioned place preference (CPP) or consumption. Our data point to high-quality candidates for Alcw12, including genes involved in mitochondrial respiration, spatial buffering, and neural plasticity, and to Kcnj9 as a high-quality candidate for Alcw11. Our studies are the first to show, using two null mutant models on different genetic backgrounds, that Kcnj9-/- mice demonstrate significantly less severe alcohol withdrawal than wildtype littermates using acute and repeated exposure paradigms. We also demonstrate that Kcnj9-/- voluntarily consume significantly more alcohol (20%, two-bottle choice) than wildtype littermates. Taken together with evidence implicating Kcnj9 in ethanol CPP, our results support a broad role for this locus in ethanol reward and withdrawal phenotypes. In summary, our results demonstrate two distinct chromosome 1 QTLs that significantly affect risk for ethanol withdrawal, and point to their distinct unique roles in alcohol reward phenotypes.


Anatomic relationship between the spinal accessory nerve and internal jugular vein in the upper neck.
The goal of this study was to precisely detail the relationship between the spinal accessory nerve (SAN) and the internal jugular vein (IJV) in the upper neck, specifically at the level of the posterior belly of the digastric muscle. Case series with planned data collection. University hospital. This information was prospectively gathered intraoperatively in patients undergoing a neck dissection. The neck dissections were performed for the treatment or diagnosis of cancer, independent of the research goals. Eighty-six subjects underwent neck dissections, 56 unilateral and 30 bilateral. The position of the SAN was determined to be oriented lateral to the IJV, medial to the IJV, posterior to the IJV, or directly through the IJV at the level of the posterior belly of the digastric muscle. Of 116 neck dissections, 112 (96%) were oriented lateral to the IJV at the level of the superior border of the posterior belly of the digastric muscle. In three necks (3%), the SAN was positioned medial to the IJV, and one (1%) traveled directly through the IJV. The SAN has an intimate anatomic relationship with the IJV as it travels through the neck. The SAN is nearly always oriented lateral to the IJV, and the IJV and SAN are likely at some increased risk of injury during neck dissection in cases where the nerve travels medial to or through the IJV.


Alterations in myocyte shape and basement membrane attachment with tachycardia-induced heart failure.
Chronic supraventricular tachycardia (SVT) results in left ventricular (LV) dilatation and dysfunction. However, the underlying mechanisms responsible for LV failure in this setting are not known. LV force production is dependent on the coupling of myocytes to the extracellular matrix, which is mediated through the basement membrane. This study was designed to determine whether alterations in myocyte geometry and basement membrane attachment are associated with LV failure in a pacing-induced model of cardiomyopathy. Echocardiographic measurement of LV function was performed in six pigs after 3 weeks of pacing-induced SVT (240 beats/min) and in eight sham-operated controls. Myocytes from these hearts were isolated, and attachment studies to specific components of the basement membrane were performed using laminin, fibronectin, and collagen IV. The SVT group when compared with the control group showed a significant reduction of LV fractional shortening (14 +/- 2% versus 31 +/- 2%, respectively; p less than 0.05), increased end-diastolic dimension (50 +/- 1 versus 35 +/- 1 mm, respectively; p less than 0.05), and lengthening of isolated myocytes (196 +/- 18 versus 142 +/- 9 microns, respectively; p less than 0.05). Myocyte attachment to laminin (50 micrograms/ml) was significantly decreased at 60 minutes in the SVT group compared with the control group (18.2 +/- 4.5 versus 60.9 +/- 4.5 cells/mm2, respectively; p less than 0.05). Similar reductions in myocyte attachment to fibronectin and collagen IV were observed. Ultrastructural examination of LV sections revealed focal disruptions of the basement membrane-sarcolemmal interface and a reduced number of sarcolemmal festoons in SVT hearts compared with control hearts (0.8 +/- 0.6 versus 2.8 +/- 0.8/4 microns, respectively; p less than 0.05). These alterations in myocyte morphology and basement membrane attachment may contribute to the LV failure associated with chronic SVT. Further, these structural changes may play a significant role in the progression of ventricular dysfunction as well as recovery from chronic SVT.


Contrast-enhanced three-dimensional fast imaging with steady-state precession (FISP) MR angiography of supraaortic vessels: preliminary results.
The purpose of this study was to assess the effectiveness of contrast-enhanced fast three-dimensional (3D) MR angiography in depicting both the carotid and vertebral arteries in their cervical portions and to compare MR angiography with conventional angiography for the evaluation of arteriosclerotic disease. Twenty-seven patients with ischemic cerebral events in the anterior (n = 18) and posterior (n = 9) circulation underwent contrast-enhanced 3D MR angiography in the coronal plane. MR angiograms were examined in a blinded fashion by two observers independently. Stenosis was classified according to the appearance of the residual lumen (no stenosis, mild stenosis, moderate stenosis, severe stenosis, occlusion). Conventional angiography was used as the standard of reference. Proximal great vessels and carotid siphons were not assessable on MR angiograms in 35% of cases owing to limited coverage. All cervical and petrous segments of the internal carotid arteries (ICAs) and 93% of the extracranial vertebral arteries were assessable. Flow-related artifacts were observed in seven cases of severe stenosis, including three with signal void at the site of narrowing and four with signal loss in the distal ICA. Interobserver agreement was good and significant. Overall agreement between 3D MR angiography and conventional angiography was good for the anterior and posterior circulations despite a tendency toward overestimation of stenoses on MR angiograms. Clinically relevant stenoses and occlusions were correctly identified on 3D MR angiograms, providing good sensitivity and specificity. Contrast-enhanced 3D MR angiography is a promising tool for assessing arteriosclerotic lesions of supraaortic vessels. Further studies with larger groups are required to determine its value for patient care.


Overexpression of Angiotensin-Converting Enzyme 2 Ameliorates Amyloid β-Induced Inflammatory Response in Human Primary Retinal Pigment Epithelium.
Amyloid-β (Aβ) is a major constituent of drusen, which is a hallmark of early AMD. The purpose of this study was to investigate whether enhancement of ACE2, an important component of the protective angiotensin-converting enzyme 2 (ACE2)/Ang-(1-7)/Mas axis of the renin angiotensin system (RAS), ameliorates Aβ-induced inflammatory response in human RPE cells. Annexin-V FITC/propidium iodide assay for detecting apoptosis rate was used to determine the optimum concentration and incubation time of Aβ1-42. ACE2 plasmid was transfected into primary cultured human RPE (hRPE) and ARPE-19 cells for 6 hours followed by stimulation with Aβ1-42 at the concentration of 1 μM for 48 hours. Gene expression was detected by real-time PCR and protein levels were determined by Western blotting or ELISA. A779, an antagonist of Ang-(1-7), was used to further confirm the involvement of ACE2/Ang-(1-7)/Mas axis. Flow cytometry showed that the optimal concentration of Aβ1-42 was 1 μM and the optimal incubation time was 48 hours. Aβ1-42 upregulated the expression of IL-1β and monocyte chemoattractant protein-1. ACE2 plasmid significantly upregulated the expression of ACE2 and Ang-(1-7) in hRPE and ARPE-19 cells. Activation of ACE2 reduced the overproduction of inflammatory cytokines at both mRNA and protein levels in hRPE and ARPE-19 cells stimulated with Aβ1-42. Furthermore, an antagonist of Ang-(1-7), A779 reversed the anti-inflammatory effect of ACE2. Overexpression of ACE2 ameliorates Aβ-induced inflammatory response by activating the ACE2/Ang-(1-7)/Mas axis in human RPE cells. Our data suggest that ACE2/Ang-(1-7)/Mas axis may be a promising target for developing novel therapies for inflammation response in AMD.


A specific mix of generalists: bacterial symbionts in Mediterranean Ircinia spp.
Microbial symbionts form abundant and diverse components of marine sponge holobionts, yet the ecological and evolutionary factors that dictate their community structure are unresolved. Here, we characterized the bacterial symbiont communities of three sympatric host species in the genus Ircinia from the NW Mediterranean Sea, using electron microscopy and replicated 16S rRNA gene sequence clone libraries. All Ircinia host species harbored abundant and phylogenetically diverse symbiont consortia, comprised primarily of sequences related to other sponge-derived microorganisms. Community-level analyses of bacterial symbionts revealed host species-specific genetic differentiation and structuring of Ircinia-associated microbiota. Phylogenetic analyses of host sponges showed a close evolutionary relationship between Ircinia fasciculata and Ircinia variabilis, the two host species exhibiting more similar symbiont communities. In addition, several bacterial operational taxonomic units were shared between I. variabilis and Ircinia oros, the two host species inhabiting semi-sciophilous communities in more cryptic benthic habitats, and absent in I. fasciculata, which occurs in exposed, high-irradiance habitats. The generalist nature of individual symbionts and host-specific structure of entire communities suggest that: (1) a 'specific mix of generalists' framework applies to bacterial symbionts in Ircinia hosts and (2) factors specific to each host species contribute to the distinct symbiont mix observed in Ircinia hosts.


Reverse Takotsubo Pattern in the Setting of Undiagnosed Pheochromocytoma and Pulmonary Embolism: A Rare Presentation.
BACKGROUND Takotsubo cardiomyopathy is a rare acute cardiac event with varied manifestations characterized by abrupt onset of transient regional dysfunction in a characteristic pattern. A reverse Takotsubo pattern is also well recognized but can also be seen in non-Takotsubo cardiomyopathies. CASE REPORT A 23-year-old woman with history of migraines and palpitations presented with nausea, vomiting, pleuritic chest pain, and dyspnea. On initial presentation her vitals were stable and her physical exam was unremarkable. Lab test results were significant for an elevated troponin and D-dimer. An initial CXR was unremarkable. The differential was concerning for pulmonary embolism. Prior to getting a CTA to establish diagnosis, she quickly decompensated. She was emergently intubated due to hypoxia and altered mental status. A repeat CXR showed acute pulmonary edema and repeat lab work showed increasing troponin and creatinine. EKG showed lateral ST depressions the lateral leads and ST elevations in aVL. ECHO showed akinesia of ½ to 2/3rd of proximal LV with a hyperdynamic functioning distal 1/3 LV and an estimated LVEF of 31%, a pattern consistent with reverse Takotsubo. She quickly developed multi-organ failure and, despite aggressive measures, underwent a PEA arrest and was unable to be successfully resuscitated. The autopsy showed hemorrhagic rupture of pheochromocytoma and bilateral thromboemboli of the main pulmonary arteries. CONCLUSIONS Reverse Takotsubo variant pattern can be seen in non-Takotsubo cardiomyopathies, and in our patient was noted in the presence of pheochromocytoma and pulmonary embolism. In this scenario, the presence of both would have significantly affected management, if she had not decompensated so quickly.


Modeling NAFLD disease burden in China, France, Germany, Italy, Japan, Spain, United Kingdom, and United States for the period 2016-2030.
Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) are increasingly a cause of cirrhosis and hepatocellular carcinoma globally. This burden is expected to increase as epidemics of obesity, diabetes and metabolic syndrome continue to grow. The goal of this analysis was to use a Markov model to forecast NAFLD disease burden using currently available data. A model was used to estimate NAFLD and NASH disease progression in eight countries based on data for adult prevalence of obesity and type 2 diabetes mellitus (DM). Published estimates and expert consensus were used to build and validate the model projections. If obesity and DM level off in the future, we project a modest growth in total NAFLD cases (0-30%), between 2016-2030, with the highest growth in China as a result of urbanization and the lowest growth in Japan as a result of a shrinking population. However, at the same time, NASH prevalence will increase 15-56%, while liver mortality and advanced liver disease will more than double as a result of an aging/increasing population. NAFLD and NASH represent a large and growing public health problem and efforts to understand this epidemic and to mitigate the disease burden are needed. If obesity and DM continue to increase at current and historical rates, both NAFLD and NASH prevalence are expected to increase. Since both are reversible, public health campaigns to increase awareness and diagnosis, and to promote diet and exercise can help manage the growth in future disease burden. Non-alcoholic fatty liver disease and non-alcoholic steatohepatitis can lead to advanced liver disease. Both conditions are becoming increasingly prevalent as the epidemics of obesity and diabetes continue to increase. A mathematical model was built to understand how the disease burden associated with non-alcoholic fatty liver disease and non-alcoholic steatohepatitis will change over time. Results suggest increasing cases of advanced liver disease and liver-related mortality in the coming years.


[The immunohistochemical determination of hormonal receptors in breast cancer. A retrospective study in 322 cases].
A study of 322 patients with infiltrating ductal carcinoma of the breast, followed from 6 to 20 years, is presented. Pathological characteristics including immunohistochemical determinations of estrogen and progesterone receptors are shown, as well as interrelations of the different factors between themselves and with the follow up. Results showed significant relations between positive estrogen receptors and low nuclear grade (p < 0.001), histological low grade (p = 0.06) and positive progesterone receptors (p = 0.001). In addition, progesterone receptors were associated with stage I (p = 0.02); tumors with less than 2 cm in diameter (p = 0.01); low nuclear grade (p < 0.001) and positive estrogen receptors (p < 0.001). The univariate Cox regression analysis of prognostic factors revealed an association between positive lymph nodes and high nuclear grade with a more frequent tumoral recurrence. On the other hand, overall survival was significantly affected by cases in stage II, positive lymph nodes, tumors with diameter greater than 2 cm, and high nuclear grade. Stepwise Cox regression analysis showed that a high nuclear grade, positive lymph nodes and absence of estrogen receptor, were associated with a higher risk for recurrence and that tumor size and the state of lymph nodes were predictive for overall survival. This paper demonstrates that histochemical determination of hormonal receptors is useful because together with other known prognostic factors it contributes to a better management of patients with breast carcinoma.


Understanding of alkaline pretreatment parameters for corn stover enzymatic saccharification.
Previous research on alkaline pretreatment has mainly focused on optimization of the process parameters to improve substrate digestibility. To achieve satisfactory sugar yield, extremely high chemical loading and enzyme dosages were typically used. Relatively little attention has been paid to reduction of chemical consumption and process waste management, which has proven to be an indispensable component of the bio-refineries. To indicate alkali strength, both alkali concentration in pretreatment solution (g alkali/g pretreatment liquor or g alkali/L pretreatment liquor) and alkali loading based on biomass solids (g alkali/g dry biomass) have been widely used. The dual approaches make it difficult to compare the chemical consumption in different process scenarios while evaluating the cost effectiveness of this pretreatment technology. The current work addresses these issues through pretreatment of corn stover at various combinations of pretreatment conditions. Enzymatic hydrolysis with different enzyme blends was subsequently performed to identify the effects of pretreatment parameters on substrate digestibility as well as process operational and capital costs. The results showed that sodium hydroxide loading is the most dominant variable for enzymatic digestibility. To reach 70% glucan conversion while avoiding extensive degradation of hemicellulose, approximately 0.08 g NaOH/g corn stover was required. It was also concluded that alkali loading based on total solids (g NaOH/g dry biomass) governs the pretreatment efficiency. Supplementing cellulase with accessory enzymes such as α-arabinofuranosidase and β-xylosidase significantly improved the conversion of the hemicellulose by 6-17%. The current work presents the impact of alkaline pretreatment parameters on the enzymatic hydrolysis of corn stover as well as the process operational and capital investment costs. The high chemical consumption for alkaline pretreatment technology indicates that the main challenge for commercialization is chemical recovery. However, repurposing or co-locating a biorefinery with a paper mill would be advantageous from an economic point of view.


Genetically controlled total deficiency of the fourth component of complement in the guinea pig.
Guinea pigs with a total deficiency of the fourth component of complement (C4) have been discovered. There was no evidence for the presence of a C4 inhibitor in the serum of these animals. Mating studies indicate that C4 deficiency is transmitted as a simple autosomal recessive trait. A colony of these animals is being established at the National Institutes of Health. They will provide an opportunity to more precisely define the role of complement in immune phenomena and the defense against disease.


Potential Therapeutic Benefit of Low Dose Naltrexone in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Role of Transient Receptor Potential Melastatin 3 Ion Channels in Pathophysiology and Treatment.
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a debilitating multi-systemic chronic condition of unknown aetiology classified as an immune dysfunction syndrome and neurological disorder. The discovery of the widely expressed Transient Receptor Potential Melastatin 3 (TRPM3) as a nociceptor channel substantially targeted by certain opioid receptors, and its implication in calcium (Ca2+)-dependent Natural Killer (NK) cell immune functions has raised the possibility that TRPM3 may be pharmacologically targeted to treat characteristic symptoms of ME/CFS. Naltrexone hydrochloride (NTX) acts as an antagonist to the mu (μ)-opioid receptor thus negating its inhibitory function on TRPM3. Based on the benefits reported by patients on their symptoms, low dose NTX (LDN, 3.0-5.0 mg/day) treatment seems to offer some potential benefit suggesting that its effect may be targeted towards the pathomechanism of ME/CFS. As there is no literature confirming the efficacy of LDN for ME/CFS patients in vitro, this study investigates the potential therapeutic effect of LDN in ME/CFS patients. TRPM3 ion channel activity was measured after modulation with Pregnenolone sulfate (PregS) and ononetin in NK cells on 9 ME/CFS patients taking LDN and 9 age- and sex-matched healthy controls using whole-cell patch-clamp technique. We report that ME/CFS patients taking LDN have restored TRPM3-like ionic currents in NK cells. Small ionic currents with a typical TRPM3-like outward rectification were measured after application of PregS, a TRPM3-agonist, in NK cells from patients taking LDN. Additionally, PregS-evoked ionic currents through TRPM3 were significantly modulated by ononetin, a TRPM3-antagonist, in NK cells from ME/CFS patients taking LDN. These data support the hypothesis that LDN may have potential as a treatment for ME/CFS by characterising the underlying regulatory mechanisms of LDN treatment involving TRPM3 and opioid receptors in NK cells. Finally, this study may serve for the repurpose of marketed drugs, as well as support the approval of prospective randomized clinical studies on the role and dose of NTX in treating ME/CFS patients.


Cell-context dependent TCF/LEF expression and function: alternative tales of repression, de-repression and activation potentials.
Wnt signaling controls cell specification and fate during development and adult tissue homeostasis by converging on a small family of DNA binding factors, the T-cell factor/lymphoid enhancer factor (TCF/LEF) family. In response to Wnt signals, TCF/LEF members undergo a transcriptional switch from repression to activation mediated in part by nuclear β-catenin binding and recruitment of co-activator complexes. In mammals, the specificity and fine tuning of this transcriptional switch is also achieved by the cell-context-dependent expression of four members (TCF7, TCF7L1, TCF7L2, and LEF1) and numerous variants, which display differential DNA binding affinity and specificity, repression strength, activation potential, and regulators. TCF7/LEF1 variants are generated by alternative promoters, alternative exon cassettes, and alternative donor/acceptor splicing sites, allowing combinatorial insertion/exclusion of modular functional and regulatory domains. In this review we present mounting evidence for the interdependency of TCF7/LEF1 variant expression and functions with cell lineage and cell state. We also illustrate how the p53 and nuclear receptor family of transcription factors, known to control cell fate and to inhibit Wnt signaling, may participate in the fine tuning of TCF7/LEF1 repression/activation potentials.


Laser Treatments for Postinflammatory Hyperpigmentation: A Systematic Review.
Lasers are gaining interest as a treatment option for postinflammatory hyperpigmentation (PIH) but can pose a clinical dilemma given the risk for laser-induced or exacerbated PIH. To assess the clinical evidence for the use of lasers in the treatment of PIH. A systematic review was performed by searching PubMed databases from January 1, 1990, through May 31, 2016. Included studies involved laser treatment for PIH with the degree of pigmentation as a measure of outcome. The search was filtered to include only clinical studies written in the English language. Study methods were analyzed and the reproducibility of the studies was graded. Outcome measures varied from study to study and included concentration of melanin and hemoglobin, patient satisfaction questionnaires, clinical photography, subjective clinical improvement, light microscopy, melanin index, reflectance spectroscopy, and/or skin biopsy evaluated by a blinded dermatopathologist. Of 1295 results, 20 unique studies with 224 patients met the inclusion criteria. These studies included 1 randomized clinical observer-blinded study (6 patients), 4 nonrandomized clinical trials (133 patients), 1 cohort study (34 patients), 7 case series (44 patients), and 7 case reports (7 patients). Multiple lasers were studied; however, most of the studies were not methodologically rigorous. Some studies showed no improvement or worsening of PIH after laser treatment. The most extensively studied device was the Q-switched Nd:YAG laser, which has shown promising results based on multiple outcome measures as listed above. Some lasers may be beneficial in the treatment of PIH. The evidence suggests that additional studies would be required to determine the benefit of laser treatment of PIH.


Cognitive neuropsychological theory of antidepressant action: a modern-day approach to depression and its treatment.
Depression is a leading cause of disability worldwide and improving its treatment is a core research priority for future programmes. A change in the view of psychological and biological processes, from seeing them as separate to complementing one another, has introduced new perspectives on pathological mechanisms of depression and treatment mode of action. This review presents a theoretical model that incorporated this novel approach, the cognitive neuropsychological hypothesis of antidepressant action. This model proposes that antidepressant treatments decrease the negative bias in the processing of emotionally salient information early in the course of antidepressant treatment, which leads to the clinically significant mood improvement later in treatment. The paper discusses the role of negative affective biases in the development of depression and response to antidepressant treatments. It also discusses whether the model can be applied to other antidepressant interventions and its potential translational value, including treatment choice, prediction of response and drug development.


[Evaluation of utilization of preventive services for infants in Israel--personal and organizational determinants].
Preventive services for prenatal and child health care were established 85 years ago by Henrietta Szold, president of the Women's Zionist Organization of America. A network of 1200 Mother and Child-Care clinics (known as "Tipat Halav") has developed as a result of this initiative. Preventive services are provided by the Ministry of Health, municipalities and recently, by all four Health Maintenance Organizations (HMO's) in Israel. To assess the utilization and satisfaction of preventive health services during infancy. The sample consisted of Jewish and Arab women who gave birth during March 2000. A total of 667 Jewish and 211 Arab mothers were interviewed after their infants reached the age of 15-19 months. The response rate was 92% and 88% respectively. It was found that 96% of the Jewish women and 100% of the Arab women utilized "Tipat Halav" services. Preventive services were provided mainly by the Ministry of Health and municipalities, while HMO's provided service to 15% of the Jewish infants and 19% of the Arab infants. Nine percent of the infants were not, examined by a physician within the framework of the preventive service, but all infants had health supervision by a nurse. Overall, 25% of the Jewish infants and 32% of the Arab infants had 11 or more visits with the nurse. It was observed that mothers with a higher educational level and those with many children began the process of health supervision at a later stage and visited the clinic less frequently. The number of visits to all health services combined, from birth to 15-19 months, was 26 for Jewish and 28 for Arab infants, indicating over-utilization and dependence. However, the performance of hearing and vision tests was inadequate. Referral to orthopedics was 41% for Jewish and 11% for Arab infants. The level of satisfaction with the service was high, with scores mostly above 3.0 out of a maximum of a total of 4.0 points. The preventive services provided by the different agencies do not differ significantly except in the case of private physicians and voluntary organizations in East Jerusalem, which do not comply with the recommended routines. Our recommendations include raising the compliance and performance of screening tests and defining the policy of referral to orthopedic services. Furthermore, the clinics should provide more outreach to high-risk families in order to optimize their utilization of services and compliance.


Ultraviolet B activated 1,25(OH)(2)D affects the level of fibroblast growth factor-23 in human.
Fibroblast growth factor 23 (FGF-23) is known as a phosphaturic factor regulating phosphate homeostasis. Several studies suggest that dietary phosphate, serum phosphate and 1,25-dihydroxyvitamin D [1,25(OH)(2)D] are candidate regulators of FGF-23. While the human studies, which modulated the dietary or serum phosphate showed in rather controversial results, manipulation of the active vitamin D definitely affected FGF-23 in animals. This study was conducted to elucidate the relationship between active vitamin D directly stimulated by ultraviolet B (UVB) exposure and FGF-23 level in human. Ten healthy young adults were recruited to get the UVB exposure thrice a week at sub-minimal erythemal dose with gradual increment by 10% only for 4 weeks. Serum calcium, phosphate, mineral-related hormones and bone turnover markers were analyzed before and after the UVB exposure every 4 week for 12 whole weeks. Twenty five-hydroxyvitamin D [25(OH)D] increased by 115% (19.8 ng/mL to 40.5 ng/mL, p < 0.001) after 4 weeks of UVB exposure. While 1,25(OH)(2)D increased by 75% (49.9 pg/mL to 64.4 pg/mL, p < 0.001) then both level decreased after 4 weeks of withdrawal. C-telopeptide peaked at 2nd week then decreased, while osteocalcin increased gradually. FGF-23 started to increase from the 4th week of UVB exposure then significantly at the 4th week after withdrawal of UVB (27.8 pg/mL to 41.4 pg/mL, p < 0.05). UVB exposure effectively increased 1,25(OH)(2)D with delayed stimulatory effect on FGF-23. This result could support the regulatory loop of 1,25(OH)(2)D and FGF-23 in human, FGF-23 regulation by 1,25(OH)(2)D.


Comparison of age-related, site-specific muscle loss between young and old active and inactive Japanese women.
To compare the effect of habitual recreational sports and exercise activity on age-related, site-specific muscle loss in young and old women in Japan. Participants included 152 young (aged 20-35 years) and 157 old (aged 60-85 years) women who were classified into 4 subgroups on the basis of their habitual (more than once a week) sports and exercise activity: young active (n = 86), young inactive (n = 66), old active (n = 43), and old inactive (n [SUPERSCRIPT EQUALS SIGN] 114). Muscle thickness (MTH) and fat thickness (FTH) were measured by ultrasonography at 8 sites, with MTH expressed in terms relative to limb length (MTH/L) or height (MTH/Ht). Percent fat was estimated from FTH, and fat-free mass was calculated. Fat-free mass was similar between younger and older women and between active and inactive women. MTH/L in the quadriceps (P < .001), abdomen (P < .001), and triceps surae (P < .05) was lower in the older women than in the younger women. In contrast, MTH/L in the hamstrings, subscapula, and biceps was higher (P < .01) in the older women than in the younger women. Compared with the MTH of the young inactive women, the MTH of the young active women was greater (P < .05) in 5 sites. Similarly, MTH/L in the quadriceps and triceps was higher (P < .05) in the old active women than in the old inactive women. However, quadriceps MTH/L and abdomen MTH/Ht were still lower (P < .001) in the old active women than in the young inactive women. Age-related muscle loss remains site-specific in both active and inactive young and old women, even when habitual physical activity has an effect on muscle size.


The gut microbiota influences blood-brain barrier permeability in mice.
Pivotal to brain development and function is an intact blood-brain barrier (BBB), which acts as a gatekeeper to control the passage and exchange of molecules and nutrients between the circulatory system and the brain parenchyma. The BBB also ensures homeostasis of the central nervous system (CNS). We report that germ-free mice, beginning with intrauterine life, displayed increased BBB permeability compared to pathogen-free mice with a normal gut flora. The increased BBB permeability was maintained in germ-free mice after birth and during adulthood and was associated with reduced expression of the tight junction proteins occludin and claudin-5, which are known to regulate barrier function in endothelial tissues. Exposure of germ-free adult mice to a pathogen-free gut microbiota decreased BBB permeability and up-regulated the expression of tight junction proteins. Our results suggest that gut microbiota-BBB communication is initiated during gestation and propagated throughout life.


Case Report of Percutaneous Retrograde Transcollateral Recanalization of the Superior Mesenteric Artery via the Celiac Artery for Acute Mesenteric Ischemia.
Revascularization for acute mesenteric ischemia (AMI) can be achieved through a bypass from the aorta or iliac arteries, embolectomy, open exposure of SMA and retrograde recanalization and stent, or percutaneous antegrade stenting. Flush occlusion of the SMA can make antegrade recanalization very challenging and is usually unsuccessful. We present a novel approach for recanalization of superior mesenteric artery (SMA) via the celiac artery for acute mesenteric ischemia. A 69-year-old lady with previous endarterectomy of SMA and extensive small bowel resection presented with severe abdominal pain, emesis, leukocytosis, and imaging finding of new SMA flush occlusion. She refused to consent for a laparotomy. Percutaneous retrograde transcollateral recanalization of SMA was performed via the celiac artery through the pancreaticoduodenal arcade, and the SMA then stented. This resulted in subsequent resolution of patient's symptoms and discharge. SMA revascularization with retrograde transcollateral wiring technique is an important tool in the armamentarium of the vascular care specialist when antegrade percutaneous approach and open exposure via laparotomy are not an option.


Persistent microbial translocation and immune activation in HIV-1-infected South Africans receiving combination antiretroviral therapy.
Microbial translocation contributes to immune activation and disease progression during chronic human immunodeficiency virus type 1 (HIV-1) infection. However, its role in the African AIDS epidemic remains controversial. Here, we investigated the relationship between markers of monocyte activation, plasma lipopolysaccharide (LPS), and HIV-1 RNA in South Africans prioritized to receive combination antiretroviral therapy (cART). Ten HIV-1-negative African controls and 80 HIV-1-infected patients with CD4 T cell counts <200 cells/microL were sampled prior to (n=60) or during (n=20) receipt of effective cART. Viral load was measured by Nuclisens; LPS by the Limulus amoebocyte lysate assay; monocyte and T cell subsets by flow cytometry; and soluble CD14, cytokines, and chemokines by enzyme-linked immunosorbent assay and customized Bio-Plex plates. Three distinct sets of markers were identified. CCL2, CXCL10, and CD14(+)CD16(+) monocyte levels were positively correlated with HIV-1 viremia. This finding, together with cART-induced normalization of these markers, suggests that their upregulation was driven by HIV-1. Plasma interleukin-6 was associated with the presence of opportunistic coinfections. Soluble CD14 and tumor necrosis factor were linked to plasma LPS levels and, as observed for LPS, remained elevated in patients receiving effective cART. Microbial translocation is a major force driving chronic inflammation in HIV-infected Africans receiving cART. Prevention of monocyte activation may be especially effective at enhancing therapeutic outcomes.


The endothelial nitric oxide synthase Glu298Asp polymorphism is not a risk factor for endometriosis in south Indian women.
To investigate whether the eNOS gene influences the risk of developing endometriosis in south Indian women. The single nucleotide polymorphism, Glu298Asp, in exon7 of the eNOS gene was tested for association in a case-control study of 232 affected women and 210 women with no evidence of disease. All the women were infertile, ascertained from the same infertility clinic. The genotype frequencies of the polymorphism were compared, using polymerase chain reaction and sequencing analysis. The localization and expression of eNOS in the eutopic endometrium of five cases and four controls was also analyzed using immunohistochemistry and western blotting. No statistically significant differences were observed in the genotype distributions and allele frequencies (p=0.3) between the cases and controls according to codominant, dominant and recessive genotype models. The localization and expression of this protein were similar in the endometrium of cases and controls. In the present study we could neither observe a difference in the eNOS expression nor establish an association between the eNOS Glu298Asp exon 7 polymorphism in south Indian women with endometriosis.


Organocatalytic asymmetric synthesis of benzazepinoindole derivatives with trifluoromethylated quaternary stereocenters by chiral phosphoric acid catalysts.
An enantioselective aza-Friedel-Crafts reaction of trifluoromethyl dihydrobenzoazepinoindoles with pyrroles catalyzed by a chiral spirocyclic phosphoric acid was developed. This methodology provides a facile route to CF3- and pyrrole-containing benzazepinoindoles bearing quaternary stereocenters in good yields and with moderate to excellent enantioselectivities (up to 93% ee). Indoles were also investigated as electron-rich aromatic substrates to afford the corresponding chiral heterocycles with good yields and considerable enantioselectivities. The introduction of CF3 shows a remarkable fluorine effect and increases the activation and stereoinduction.


Subcutaneous C1-esterase inhibitor to prevent hereditary angioedema attacks: Safety findings from the COMPACT trial.
The first subcutaneous (SC) C1-esterase inhibitor concentrate (C1-INH) was approved by the U.S. Food and Drug Administration in June 2017 as routine prophylaxis to prevent hereditary angioedema attacks in adolescents and adults at a dose of 60 IU/kg twice weekly based on the phase III Clinical Study for Optimal Management of Preventing Angioedema With Low-volume Subcutaneous C1-Inhibitor Replacement Therapy (COMPACT) trial. This article aimed to evaluate the relationship of the C1-INH (SC) dose regimens tested in the COMPACT trial (40 IU/kg and 60 IU/kg twice weekly) and the occurrence of adverse events (AEs). Patients were instructed to record any AEs in their e-diary daily. Safety and tolerability were assessed based on reported AEs, including injection-site reactions (ISRs); unsolicited AEs (AEs other than ISRs); serious AEs; thrombotic, thromboembolic, anaphylactic, hypersensitivity, sepsis, and bacteremia events; inhibitory antibodies to C1-INH; and clinically significant abnormalities in laboratory assessments. Information on ISRs was specifically solicited. No relationship between the dose of C1-INH (SC) and the incidence of ISRs or unsolicited AEs was observed. The proportion of injections followed by at least one ISR was 12% with C1-INH (SC) 40 IU/kg versus 5% with 60 IU/kg and 6% with placebo. No ISRs were serious or led to treatment discontinuation, and all resolved. There were no anaphylaxis, thromboembolic, sepsis, or bacteremia events reported during treatment with C1-INH (SC). All hypersensitivity AEs were nonserious, and the majority were assessed as being unrelated to treatment. No inhibitory antibodies to C1-INH were observed. C1-INH (SC) is safe and well tolerated with no dose-dependent safety concerns, as demonstrated in the COMPACT trial.Clinical trial NCT01912456, <ext-link xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="uri" xlink:href="http://www.clinicaltrials.gov">www.clinicaltrials.gov</ext-link>.


A randomized, placebo-controlled trial of combined insulin-like growth factor I and low dose growth hormone therapy for wasting associated with human immunodeficiency virus infection.
Loss of body mass, or wasting, is a major cause of morbidity and a contributor to mortality in human immunodeficiency virus-1 (HIV-1) infection. Dietary supplements and appetite adjuvants have had limited effectiveness in treating this condition. GH and insulin-like growth factor I (IGF-I) have been shown to be anabolic in many catabolic conditions, and limited data suggest similar efficacy in HIV wasting. In addition, it appears that GH and IGF-I may have complementary anabolic effects with opposing glucoregulatory effects. We report results from a 12-week randomized, placebo-controlled trial of combination recombinant human GH (rhGH; Nutropin; 0.34 mg, sc, twice daily) and rhIGF-I (5.0 mg, sc, twice daily) in individuals with HIV wasting and without active opportunistic infection, cancer, or gastrointestinal disease. A total of 142 subjects (140 males and 2 females) were randomized using a 2:1, double blind treatment scheme and assigned to receive either active treatment or placebo injections. Eighty subjects completed the 12-week protocol. Nutritional intake and demographic and clinical characteristics did not differ between the groups at any study time point. At 3 weeks, the treatment group had a significantly larger weight increase (P = 0.0003), but this difference was not observed at any later time point. Similarly, fat-free mass, calculated from skinfold measurements, increased transiently in the treatment group at 6 weeks (P = 0.002). No significant differences in isokinetic muscle strength or endurance testing or in quality of life were observed between the groups. Resting heart rate was significantly higher in the treatment group at each time point post-baseline. GH and IGF-binding protein-3 levels did not change; however, IGF-I levels were higher in the treatment group at 6 and 12 weeks. There were no significant between-group differences in any of the measured biochemical or immunological parameters. rhGH plus rhIGF-I treatment was associated with an increased incidence of peripheral edema and other side-effects, possibly related to fluid retention. We conclude that the combination of rhIGF-I and low dose rhGH used in this study had no significant anabolic effect in HIV wasting.


Monitoring the reaction of carbachol with acetylcholinesterase by thioflavin T fluorescence and acetylthiocholine hydrolysis.
Acetylcholinesterase (AChE) contains a narrow and deep active site gorge with two sites of ligand binding, an acylation site (or A-site) at the base of the gorge and a peripheral site (or P-site) near the gorge entrance. The P-site contributes to catalytic efficiency by transiently binding substrates on their way to the acylation site, where a short-lived acyl enzyme intermediate is produced. Carbamates are very poor substrates that, like other AChE substrates, form an initial enzyme-substrate complex and proceed to an acylated enzyme intermediate which is then hydrolyzed. However, the hydrolysis of the carbamoylated enzyme is slow enough to resolve the acylation and deacylation steps on the catalytic pathway. Here we show that the reaction of carbachol (carbamoylcholine) with AChE can be monitored both with acetylthiocholine as a reporter substrate and with thioflavin T as a fluorescent reporter group. The fluorescence of thioflavin T is strongly enhanced when it binds to the P-site of AChE, and this fluorescence is partially quenched when a second ligand binds to the A-site to form a ternary complex. These fluorescence changes allow not only the monitoring of the course of the carbamoylation reaction but also the determination of carbachol affinities for the A- and P-sites.


Flexammina islandica gen. nov. sp. nov. and some new phylotypes of monothalamous foraminifera from the coast of Iceland.
Monothalamous (single-chambered) foraminifera comprise a poorly known group, the diversity of which is strongly underestimated according to environmental DNA surveys. The gross morphology of monothalamids offers few distinguishing features; their organic-walled or agglutinated tests are often very delicate and make isolation difficult. Here, we use an integrated taxonomic approach, including morphological and molecular analysis, to examine the diversity of monothalamids in a shallow subtidal area on the coast of Iceland. We report nine new phylotypes of single-chambered foraminifera distinguished by SSU rDNA sequences. Among them, we establish a new genus Flexammina and a new species Flexammina islandica, possessing a very pliable, finely agglutinated test capable of extreme shape transformations. According to molecular data, F. islandica belongs to the monothalamid clade M, which also includes the well-known genus Allogromia. In addition, we provide brief descriptions and illustrations of nine other monothalamous foraminifera isolated from the same area. Three of them are closely related to some unidentified environmental sequences and serve as the first microscopic documentation of these anonymous lineages.


Features associated with hematologic abnormalities and their impact in patients with systemic lupus erythematosus: Data from a multiethnic Latin American cohort.
To examine hematological manifestations' correlates and their impact on damage accrual and mortality in SLE patients from the multiethnic, Latin American, GLADEL cohort. In patients with recent SLE diagnosis (≤2 years), the association between follow-up hematological manifestations (per ACR criteria) and socio-demographic and clinical variables was examined by univariable and multivariable logistic regressions; their impact on damage accrual and mortality was examined by Poisson and Cox proportional-hazards regression analyses, respectively. Of 1437 patients, 948 (66.0%) developed ≥1 hematological manifestation [5.5% hemolytic anemia (AHA), 16.3% thrombocytopenia, and 56.4% lymphopenia] over 4.3 (3.3) follow-up years. Younger age, Mestizo ethnicity, hematologic disorder (at/or before SLE diagnosis), and first damage recorded were associated with hematological manifestations while antimalarials were negatively associated. AHA (at/or before SLE diagnosis), anti-Sm, and anti-RNP antibodies were associated with subsequent AHA occurrence while musculoskeletal involvement was negatively associated. Thrombocytopenia (at/or before SLE diagnosis), AHA, anti-phospholipid antibodies (aPLs), anti-SSA/Ro, anti-SSB/La antibodies, and first damage recorded were associated with later thrombocytopenia occurrence. Lymphopenia (at/or before SLE diagnosis), younger age at diagnosis, Mestizo ethnicity, having medical insurance, and first damage recorded were associated with subsequent lymphopenia occurrence while antimalarials and azathioprine treatment were negatively associated. AHA was associated with damage accrual and mortality after adjusting for variables known to affect these outcomes. Mestizo ethnicity and early hematological manifestations are risk factors for their subsequent occurrence while antimalarials have a protective effect. The associations between AHA and aPLs and thrombocytopenia were corroborated. AHA contributes independently to damage accrual and diminished survival.


Efficient transcriptional silencing in Saccharomyces cerevisiae requires a heterochromatin histone acetylation pattern.
Heterochromatin in metazoans induces transcriptional silencing, as exemplified by position effect variegation in Drosophila melanogaster and X-chromosome inactivation in mammals. Heterochromatic DNA is packaged in nucleosomes that are distinct in their acetylation pattern from those present in euchromatin, although the role these differences play in the structure of heterochromatin or in the effects of heterochromatin on transcriptional activity is unclear. Here we report that, as observed in the facultative heterochromatin of the inactive X chromosome in female mammalian cells, histones H3 and H4 in chromatin spanning the transcriptionally silenced mating-type cassettes of the yeast Saccharomyces cerevisiae are hypoacetylated relative to histones H3 and H4 of transcriptionally active regions of the genome. By immunoprecipitation of chromatin fragments with antibodies specific for H4 acetylated at particular lysine residues, we found that only three of the four lysine residues in the amino-terminal domain of histone H4 spanning the silent cassettes are hypoacetylated. Lysine 12 shows significant acetylation levels. This is identical to the pattern of histone H4 acetylation observed in centric heterochromatin of D. melanogaster. These two observations provide additional evidence that the silent cassettes are encompassed in the yeast equivalent of metazoan heterochromatin. Further, mutational analysis of the amino-terminal domain of histone H4 in S. cerevisiae demonstrated that this observed pattern of histone H4 acetylation is required for transcriptional silencing. This result, in conjunction with prior mutational analyses of yeast histones H3 and H4, indicates that the particular pattern of nucleosome acetylation found in heterochromatin is required for its effects on transcription and is not simply a side effect of heterochromatin formation.


Long term mortality after a single treatment course with X-rays in patients treated for ankylosing spondylitis.
Mortality up to 1 January 1983 has been studied in 14,106 patients with ankylosing spondylitis given a single course of X-ray treatment during 1935-54. For neoplasms other than leukaemia or colon cancer, mortality was 28% greater than that of members of the general population of England and Wales, and this increase is likely to have been a direct consequence of the treatment. The proportional increase reached a maximum of 71% between 10.0 and 12.4 years after irradiation and then declined. There was only a 7% increase in mortality from these tumours more than 25.0 years after irradiation and only for cancer of the oesophagus was the relative risk significantly raised in this period. Neither the magnitude of the relative risk, nor its temporal pattern following treatment, were greatly influenced by the age of the patient at first treatment. For leukaemia there was a threefold increase in mortality that is also likely to have been due to the radiotherapy. The relative risk was at its highest between 2.5 and 4.9 years after the treatment and then declined, but the increase did not disappear completely, and the risk was still nearly twice that of the general population more than 25.0 years after treatment. There was some evidence that the risks of acute myeloid, acute lymphatic, and chronic myeloid leukaemia were all increased, but no evidence of any increase in chronic lymphatic leukaemia. The relative risk appeared to be greatest for acute myeloid leukaemia. For colon cancer, which is associated with spondylitis through a common association with ulcerative colitis, mortality was increased by 30%. For non-neoplastic conditions there was a 51% increase in mortality that was likely to be associated with the disease itself rather than its treatment. The increase was apparent for a wide range of diseases and was not confined to diseases that have been associated clinically with ankylosing spondylitis.


Resources in women's social networks for food shopping are more strongly associated with better dietary quality than people: A cross-sectional study.
When healthy people are part of an individual's social network, those individuals will have better dietary quality. Little, however, is known about whether social networks for food shopping, including both people and resources (e.g. recipes, weight loss programmes and food advertisements) are associated with dietary quality. The aim of this study was to explore the relationship between social networks for food shopping and dietary quality, and whether this differs for people and resources, among women aged 18-45 years. A total of 129 participants completed a cross-sectional questionnaire including an ego-centric Social Network Exposure tool and short Food Frequency Questionnaire. Associations between dietary quality and type of network member, perceived healthiness and support for healthy shopping choices were explored using linear regression models. Analyses revealed that participants who nominated people in their food shopping social network that eat healthily or support healthy food shopping had better dietary quality (β = 0.16 SD per 1-point change on a 4-point scale, 95%CI -0.06, 0.39; β = 0.20, 95%CI -0.07, 0.46, respectively). Resources in participants' food shopping social networks which promote healthy eating or support healthy shopping were associated with better dietary quality. These associations remained robust after adjustment for confounding variables identified using a directed acyclic graph (β = 0.31 SD per 1-point change on a 4-point scale, 95%CI 0.03, 0.58; β = 0.44, 95%CI 0.09, 0.79 respectively). The results were strengthened when the outcome was multiplied by frequency of contact (β = 0.33, 95%CI 0.05, 0.61; β = 0.47, 95%CI 0.11, 0.83 respectively). This study suggests that resources which promote healthy eating and healthy food shopping have a stronger association with dietary quality than social support from people. Further research is required in a larger sample, including multiple time-points, to confirm these findings.


Modality exclusivity norms for 423 object properties.
Recent work has shown that people routinely use perceptual information during language comprehension and conceptual processing, from single-word recognition to modality-switching costs in property verification. In investigating such links between perceptual and conceptual representations, the use of modality-specific stimuli plays a central role. To aid researchers working in this area, we provide a set of norms for 423 adjectives, each describing an object property, with mean ratings of how strongly that property is experienced through each of five perceptual modalities (visual, haptic, auditory, olfactory, and gustatory). The data set also contains estimates of modality exclusivity--that is, a measure of the extent to which a particular property may be considered unimodal (i.e., perceived through one sense alone). Although there already exists a number of sets of word and object norms, we provide the first set to categorize words describing object properties along the dimensions of the five perceptual modalities. We hope that the norms will be of use to researchers working at the interface between linguistic, conceptual, and perceptual systems. The modality exclusivity norms may be downloaded as supplemental materials for this article from brm.psychonomic-journals.org/content/supplemental.


Fisetin Confers Cardioprotection against Myocardial Ischemia Reperfusion Injury by Suppressing Mitochondrial Oxidative Stress and Mitochondrial Dysfunction and Inhibiting Glycogen Synthase Kinase 3β Activity.
Acute myocardial infarction (AMI) is the leading cause of morbidity and mortality worldwide. Timely reperfusion is considered an optimal treatment for AMI. Paradoxically, the procedure of reperfusion can itself cause myocardial tissue injury. Therefore, a strategy to minimize the reperfusion-induced myocardial tissue injury is vital for salvaging the healthy myocardium. Herein, we investigated the cardioprotective effects of fisetin, a natural flavonoid, against ischemia/reperfusion (I/R) injury (IRI) using a Langendorff isolated heart perfusion system. I/R produced significant myocardial tissue injury, which was characterized by elevated levels of lactate dehydrogenase and creatine kinase in the perfusate and decreased indices of hemodynamic parameters. Furthermore, I/R resulted in elevated oxidative stress, uncoupling of the mitochondrial electron transport chain, increased mitochondrial swelling, a decrease of the mitochondrial membrane potential, and induction of apoptosis. Moreover, IRI was associated with a loss of the mitochondrial structure and decreased mitochondrial biogenesis. However, when the animals were pretreated with fisetin, it significantly attenuated the I/R-induced myocardial tissue injury, blunted the oxidative stress, and restored the structure and function of mitochondria. Mechanistically, the fisetin effects were found to be mediated via inhibition of glycogen synthase kinase 3β (GSK3β), which was confirmed by a biochemical assay and molecular docking studies.


Female gender and other factors predictive of a limited screening flexible sigmoidoscopy examination for colorectal cancer.
Flexible sigmoidoscopy (FS) screening for colorectal cancer (CRC) is associated with reduced mortality from CRC. It is unknown whether FS is equally effective in men and women, but differences in anatomy and perception of pain may increase the difficulty of performing FS in women. The aim of this study was to determine factors associated with a shorter or limited screening FS. Patients referred by their primary care provider were eligible for screening sigmoidoscopy if they were 50 yr or older with negative fecal occult blood tests and no first-degree relative with colorectal cancer at age 55 yr or younger. A detailed questionnaire regarding demographic characteristics and risk factors for CRC, aspirin and multivitamin use, and previous abdominal surgery was completed by the patient on a standardized form before their procedure. The histologic type (hyperplastic, adenoma, normal mucosa, or carcinoma) of each polyp was recorded. Depth of examination (in cm) was recorded based on the standardized markings on the shaft of the sigmoidoscope when it was thought to be in a straight position. Limitations to the examination (angulation, pain, and poor preparation), other mucosal findings, and complications were also noted. A total of 3980 patients (52% female) were prospectively enrolled in a screening program over a 22-month period. Women were more likely than men to report previous pelvic or abdominal surgery (OR = 2.64, 95% CI = 2.29-3.05) and were less likely to have had a previous sigmoidoscopy (OR = 0.71, 95% CI = 0.61-0.83). Females were almost twice as likely as males to have a procedure limited in some way (angulation, spasm, or pain) (OR = 1.86, 95% CI = 1.63-2.13). When defined by depth of examination, females were significantly more likely than males to have a procedure of <50 cm (OR = 1.93, 95% CI = 1.63, 2.29) and were less likely to have an adenomatous polyp or cancer detected (OR = 0.55, 95% CI = 0.42-0.71). The average endoscopy distance for women was 52.3 cm, compared with 55.2 cm in men (p < 0.0001), and the average number of polyps detected in women was 1.4, compared with 1.56 in men (p = 0.003) among patients with at least one polyp. Using multivariable analysis, females were more likely to have an examination of <50 cm compared with men, controlling for age, spasm or pain on examination, previous surgery, angulation of the colon, and type of endoscopist-MD or nonphysician endoscopist (OR = 1.67, 95% CI = 1.41-1.99). Women are more likely than men to have a shorter and more limited FS. This is partly owing to increased colonic angulation and pain during the examination. Methods aimed at reducing pain and improving maneuverability in an angulated colon during FS may improve the effectiveness of CRC screening in women.


To do or not to do? Prospective memory versus response inhibition in autism spectrum disorder and attention-deficit/hyperactivity disorder.
In the present research, event-based prospective memory and response inhibition (RI) abilities were investigated in children with ASD (Study 1), with ADHD (Study 2), and their matched neurotypical controls. Children engaged in a categorisation (ongoing) task and, concurrently, in either an event-based prospective memory (PM) or a Go/No-Go secondary task. Results showed that, as compared to their matched controls, ASD children's performance was more impaired in the PM task than in the Go/No-Go task, while the performance pattern of ADHD children was reversed. In the ongoing task, ASD children were as accurate as, but significantly slower than, controls, independently of conditions. ADHD children did not differ from controls in the presence of a concurrent PM task, while they were less accurate than controls in the presence of the go/no-go task. Overall, the two patterns of findings suggest important differences in the way ASD and ADHD children remember and realise intentions requiring opposite behaviours (acting vs stopping).


State-dependent valuation learning in fish: banded tetras prefer stimuli associated with greater past deprivation.
Humans and some birds and insects sometimes prefer alternatives associated with greater past cost or need, sometimes affording losses. It has been proposed that this is widespread because learning may include knowledge about both the physical properties of alternatives and state-dependent fitness gains. We examine the phenomenon for the first time in a fish, the banded tetra (Astyanax fasciatus). During training we paired two different color cues to identical food rewards, one under greater deprivation than the other. We then tested preference between these cues under both deprivation states. Consistent with previous results in other taxa, the fish preferred the cue associated with previous greater deprivation regardless of the condition under which they were tested. These results provide further support to the view that organisms assign value using state-dependent increments in fitness during learning. Although generally adaptive, under experimental conditions state-dependent valuation learning can lead to paradoxical choices.


Projected gradient methods for nonnegative matrix factorization.
Nonnegative matrix factorization (NMF) can be formulated as a minimization problem with bound constraints. Although bound-constrained optimization has been studied extensively in both theory and practice, so far no study has formally applied its techniques to NMF. In this letter, we propose two projected gradient methods for NMF, both of which exhibit strong optimization properties. We discuss efficient implementations and demonstrate that one of the proposed methods converges faster than the popular multiplicative update approach. A simple Matlab code is also provided.


Massive transfusion experience, current practice and decision support: A survey of Australian and New Zealand anaesthetists.
Massive transfusions guided by massive transfusion protocols are commonly used to manage critical bleeding, when the patient is at significant risk of morbidity and mortality, and multiple timely decisions must be made by clinicians. Clinical decision support systems are increasingly used to provide patient-specific recommendations by comparing patient information to a knowledge base, and have been shown to improve patient outcomes. To investigate current massive transfusion practice and the experiences and attitudes of anaesthetists towards massive transfusion and clinical decision support systems, we anonymously surveyed 1000 anaesthetists and anaesthesia trainees across Australia and New Zealand. A total of 228 surveys (23.6%) were successfully completed and 227 were analysed for a 23.3% response rate. Most respondents were involved in massive transfusions infrequently (88.1% managed five or fewer massive transfusion protocols per year) and worked at hospitals which have massive transfusion protocols (89.4%). Massive transfusion management was predominantly limited by timely access to point-of-care coagulation assessment and by competition with other tasks, with trainees reporting more significant limitations compared to specialists. The majority of respondents reported that they were likely, or very likely, both to use (73.1%) and to trust (85%) a clinical decision support system for massive transfusions, with no significant difference between anaesthesia trainees and specialists (P = 0.375 and P = 0.73, respectively). While the response rate to our survey was poor, there was still a wide range of massive transfusion experience among respondents, with multiple subjective factors identified limiting massive transfusion practice. We identified several potential design features and barriers to implementation to assist with the future development of a clinical decision support system for massive transfusion, and overall wide support for a clinical decision support system for massive transfusion among respondents.


Establishment of an in vitro RNA polymerase transcription system: a new tool to study transcriptional activation in Borrelia burgdorferi.
The Lyme disease spirochete Borrelia burgdorferi exhibits dramatic changes in gene expression as it transits between its tick vector and vertebrate host. A major hurdle to understanding the mechanisms underlying gene regulation in B. burgdorferi has been the lack of a functional assay to test how gene regulatory proteins and sigma factors interact with RNA polymerase to direct transcription. To gain mechanistic insight into transcriptional control in B. burgdorferi, and address sigma factor function and specificity, we developed an in vitro transcription assay using the B. burgdorferi RNA polymerase holoenzyme. We established reaction conditions for maximal RNA polymerase activity by optimizing pH, temperature, and the requirement for divalent metals. Using this assay system, we analyzed the promoter specificity of the housekeeping sigma factor RpoD to promoters encoding previously identified RpoD consensus sequences in B. burgdorferi. Collectively, this study established an in vitro transcription assay that revealed RpoD-dependent promoter selectivity by RNA polymerase and the requirement of specific metal cofactors for maximal RNA polymerase activity. The establishment of this functional assay will facilitate molecular and biochemical studies on how gene regulatory proteins and sigma factors exert control of gene expression in B. burgdorferi required for the completion of its enzootic cycle.


Feature selection for ordinal text classification.
Ordinal classification (also known as ordinal regression) is a supervised learning task that consists of estimating the rating of a data item on a fixed, discrete rating scale. This problem is receiving increased attention from the sentiment analysis and opinion mining community due to the importance of automatically rating large amounts of product review data in digital form. As in other supervised learning tasks such as binary or multiclass classification, feature selection is often needed in order to improve efficiency and avoid overfitting. However, although feature selection has been extensively studied for other classification tasks, it has not for ordinal classification. In this letter, we present six novel feature selection methods that we have specifically devised for ordinal classification and test them on two data sets of product review data against three methods previously known from the literature, using two learning algorithms from the support vector regression tradition. The experimental results show that all six proposed metrics largely outperform all three baseline techniques (and are more stable than these others by an order of magnitude), on both data sets and for both learning algorithms.


Distribution of human papillomavirus genotypes in sardinian patients with oral squamous cell carcinoma.
Human papillomaviruses (HPVs) seem to play an important role in the pathogenesis of gynecological carcinomas and in head and neck carcinomas. The aim of this study was to detect and genotype HPVs in fresh oral squamous cell carcinoma (OSCC) from a Sardinian population, and to determine whether HPV presence was significantly associated with the development of OSCC.The oral mucosa tissues were obtained from 120 samples (68 OSCC and 52 control samples) taken from a Sardinian population seen at the Dental Clinic of the Department of Surgery and Odontostomatological Sciences, University of Cagliari (Italy) and the " Ospedale SS Trinità", Cagliari (A.S.L. 8) between 2007 and 2008. PCR was used for the detection of HPV DNA and the genotype was determined by DNA sequencing. The frequency of HPV infection was evaluated in relation to age, sex, smoking and alcohol use. Statistical analysis was performed using the SPSS 11.5 software.The results showed the presence of HPV-DNA in 60.3% of OSCC with HPV-16 (51.2%) being the most frequent genotype. In these Sardinian OSCC patients, HPV-DNA was detected more in males (65.8%) than in females (34.1%) while controls show a 0% of HPV presence. HPV positive was highly associated with OSCC among subjects with a history of heavy tobacco and alcohol use and among those with no such history.A greater frequency of high risk HPV presence was observed in patients with OSCC compared to health control patients. In addition these results suggested that oral HPV presence could be associated in OSCC subjects. Our results need more analyses to detect the HPV-DNA integration into tumoral cells.


Validation of a hierarchical algorithm to define chronic liver disease and cirrhosis etiology in administrative healthcare data.
Chronic liver disease (CLD) and cirrhosis are leading causes of death globally with the burden of disease rising significantly over the past several decades. Defining the etiology of liver disease is important for understanding liver disease epidemiology, healthcare planning, and outcomes. The aim of this study was to validate a hierarchical algorithm for CLD and cirrhosis etiology in administrative healthcare data. Consecutive patients with CLD or cirrhosis attending an outpatient hepatology clinic in Ontario, Canada from 05/01/2013-08/31/2013 underwent detailed chart abstraction. Gold standard liver disease etiology was determined by an attending hepatologist as hepatitis C (HCV), hepatitis B (HBV), alcohol-related, non-alcoholic fatty liver disease (NAFLD)/cryptogenic, autoimmune or hemochromatosis. Individual data was linked to routinely collected administrative healthcare data at ICES. Diagnostic accuracy of a hierarchical algorithm incorporating both laboratory and administrative codes to define etiology was evaluated by calculating sensitivity, specificity, positive (PPV) and negative predictive values (NPV), and kappa's agreement. 442 individuals underwent chart abstraction (median age 53 years, 53% cirrhosis, 45% HCV, 26% NAFLD, 10% alcohol-related). In patients with cirrhosis, the algorithm had adequate sensitivity/PPV (>75%) and excellent specificity/NPV (>90%) for all etiologies. In those without cirrhosis, the algorithm was excellent for all etiologies except for hemochromatosis and autoimmune diseases. A hierarchical algorithm incorporating laboratory and administrative coding can accurately define cirrhosis etiology in routinely collected healthcare data. These results should facilitate health services research in this growing patient population.


Role of clinical evaluation in academic medical centers: results of a national survey.
It is widely acknowledged that academic medical centers (AMCs) must be committed to appropriate resource use and to the clinical evaluation research needed to accomplish this goal. The authors report the results of a national survey and series of site visits to further elucidate the role of centralized mechanisms for evaluating clinical practice, called clinical evaluation units (CEUs). A CEU is characterized by a separate operating unit with a physician director on at least a half-time basis complemented by data analysts, information system specialists, or other technical staff. In April 1993, the authors mailed a survey instrument to the 60 hospitals that were members of the University Hospital Consortium (UHC) and to 28 non-UHC teaching hospitals. After four follow-up mailings and telephone reminders, a 69% response rate (61 responses) was achieved. The survey instrument highlighted areas such as the environment in which the hospitals operated, the structure and organization of clinical evaluation, the process of how these activities were carried out, and the outcomes from the CEUs. Twenty-two respondents had centralized mechanisms that met the authors' definition of a CEU. Support for most CEUs came from hospital administrations and not from medical school deans. An alternative structure emerged from the analysis: 18 respondents indicated that they did not have CEUs but that clinical evaluation activities were integrated into the medical staff hierarchy and dispersed throughout departments that reported to a physician executive. The discipline of clinical evaluation is in its infancy in teaching institutions. Many AMCs do not have a coordinated program of clinical evaluation; others are just starting. Clinical evaluation must become integrated into medical education and hospital operations to serve as one aspect of academic medicine's response to health care reform.


How do the psychosocial consequences of ageing affect asthma management?
WHAT WE NEED TO KNOW: How do social, physical and psychological factors affect asthma and asthma management in older people? How can we minimise their impact and enhance quality of life for older people with asthma? Does inequity based on age, sex, socioeconomic status and/or area of residence affect accessibility, quality and effectiveness of care for older people with asthma? What is the extent of undiagnosed and undertreated asthma among older people, and what are the barriers to symptom reporting, diagnosis and treatment? WHAT WE NEED TO DO: Promote equity of access to diagnosis, investigation and treatment across age, sociodemographic and geographic groups. Encourage older people to seek help for symptoms and exacerbations. Encourage quality use of medicines among older people with asthma and comorbid conditions and disabilities. Promote healthy behaviours for older people with asthma (eg, smoking cessation, exercise, vaccination, better nutrition). Develop guidelines that account for complexities of older age and that are framed to achieve optimal quality of life for people with asthma.


Correction for Ion Recombination in a Built-in Monitor Chamber of a Clinical Linear Accelerator at Ultra-High Dose Rates.
In the novel and promising radiotherapy technique known as FLASH, ultra-high dose-rate electron beams are used. As a step towards clinical trials, dosimetric advances will be required for accurate dose delivery of FLASH. The purpose of this study was to determine whether a built-in transmission chamber of a clinical linear accelerator can be used as a real-time dosimeter to monitor the delivery of ultra-high-dose-rate electron beams. This was done by modeling the drop-in ion-collection efficiency of the chamber with increasing dose-per-pulse values, so that the ion recombination effect could be considered. The raw transmission chamber signal was extracted from the linear accelerator and its response was measured using radiochromic film at different dose rates/dose-per-pulse values, at a source-to-surface distance of 100 cm. An increase of the polarizing voltage, applied over the transmission chamber, by a factor of 2 and 3, improved the ion-collection efficiency, with corresponding increased efficiency at the highest dose-per-pulse values by a factor 1.4 and 2.2, respectively. The drop-in ion-collection efficiency with increasing dose-per-pulse was accurately modeled using a logistic function fitted to the transmission chamber data. The performance of the model was compared to that of the general theoretical Boag models of ion recombination in ionization chambers. The logistic model was subsequently used to correct for ion recombination at dose rates ranging from conventional to ultra-high, making the transmission chamber useful as a real-time monitor for the dose delivery of FLASH electron beams in a clinical setup.


The Choice Between Total Hip Arthroplasty and Arthrodesis in Adolescent Patients: A Survey of Orthopedic Surgeons.
For adolescent patients with end-stage hip disease, the choice between total hip arthroplasty (THA) and arthrodesis is complex; the clinical evidence is not definitive, and there are difficult trade-offs between clear short-term benefits from THA and uncertain long-term risks. We surveyed nearly 700 members of the Pediatric Orthopedic Society of North America and the American Association of Hip and Knee Surgeons. Respondents chose between a recommendation of THA or arthrodesis in four clinical vignettes. A clear majority of surgeons recommended THA in two of the vignettes, however opinion was somewhat divided in one vignette (overweight adolescent) and deeply divided in another (adolescent destined for manual labor job). Across all vignettes, recommendations varied systematically according to surgeons' age and their attitudes regarding tradeoffs between life stages.