Sex differences in clinical profile, management, and outcomes of patients hospitalized for atrial fibrillation in the United States.
This study aimed to investigate the impact of sex on the clinical profile, utilization of rhythm control therapies, cost of hospitalization, length of stay, and in-hospital mortality in patients admitted for atrial fibrillation (AF) in the United States. We used data from the Nationwide Inpatient Sample for the year 2018. Regression analysis was performed to investigate differences between men and women. A P-value ≤ 0.05 was considered significant. We included 82592 patients with a primary diagnosis of of AF 50.8% women. Women were significantly older (mean age 74 vs. 67 years, P < 0.001) and had a higher CHA2DS2-VASc score (median 4 vs. 2, P < 0.001) than men. Women had relatively higher in-hospital mortality (0.9% vs. 0.8%, P = 0.070); however, after adjustment for known risk factors female sex was no longer a predictor of mortality (P = 0.199). In sex-specific regression analyses, increased age, chronic obstructive pulmonary disease, previous stroke, heart failure, and chronic kidney disease were risk factors for in-hospital mortality in both sexes, vascular disease only in women, and race and alcohol abuse only in men. After adjusting for potential confounders, female sex was associated with lower likelihood of receiving catheter ablation [adjusted odds ratio (aOR) 0.69, 95% confidence interval (CI) 0.64-0.74] and electrical cardioversion (aOR 0.69, 95% CI 0.67-0.72), and with longer hospitalization (aOR 1.33, 95% CI 1.28-1.37), whereas sex had no influence on hospitalization costs (P = 0.339). There were differences in the risk profile, management, and outcomes between men and women hospitalized for AF. Further studies are needed to explore why women are treated differently regarding rhythm control procedures.


Tunable delay of Einstein-Podolsky-Rosen entanglement.
Entangled systems display correlations that are stronger than can be obtained classically. This makes entanglement an essential resource for a number of applications, such as quantum information processing, quantum computing and quantum communications. The ability to control the transfer of entanglement between different locations will play a key role in these quantum protocols and enable quantum networks. Such a transfer requires a system that can delay quantum correlations without significant degradation, effectively acting as a short-term quantum memory. An important benchmark for such systems is the ability to delay Einstein-Podolsky-Rosen (EPR) levels of entanglement and to be able to tune the delay. EPR entanglement is the basis for a number of quantum protocols, allowing the remote inference of the properties of one system (to better than its standard quantum limit) through measurements on the other correlated system. Here we show that a four-wave mixing process based on a double-lambda scheme in hot (85)Rb vapour allows us to obtain an optically tunable delay for EPR entangled beams of light. A significant maximum delay, of the order of the width of the cross-correlation function, is achieved. The four-wave mixing also preserves the quantum spatial correlations of the entangled beams. We take advantage of this property to delay entangled images, making this the first step towards a quantum memory for images.


MAOA, DBH, and SLC6A4 variants in CHARGE: a case-control study of autism spectrum disorders.
Genetic factors are established to contribute to the development of autism. We examined three loci, serotonin transporter (SLC6A4), dopamine β-hydroxylase (DBH), and the variable number of tandem repeat promoter of the monoamine oxidase A (MAOA) for association with autism in participants from the Childhood Autism Risks from Genetics and the Environment (CHARGE ) Study, the first large-scale population-based case-control investigation of both environmental and genetic contributions to autism risk. Among male children enrolled in the CHARGE study we tested associations between each of the three polymorphisms and autism (AU) (n = 119), or a combined group of autism and other autism spectrum disorders (AU+ASD, which includes an additional n = 53) as compared with typically developing controls (TD, n = 137). The case-control association analysis showed neither SLC6A4 nor DBH to be statistically significantly associated with AU or ASD. However, the male children carrying 4 tandem repeats in the promoter region of the MAOA gene showed a two-fold higher risk of AU (or AU+ASD) than those carrying allele 3, adjusted for confounders (OR = 2.02, 95% CI = 1.12, 3.65, P = 0.02 for AU vs. TD, and OR = 2.05, 95% CI = 1.19, 3.53, P = 0.01 for ASD vs. TD). In addition, children of mothers homozygous for the 4 tandem repeat allele showed at least a three-fold higher risk of AU (or AU+ASD) than those with mothers homozygous for allele 3 (OR = 3.07, 95% CI = 1.19, 7.91, P = 0.02 for AU vs. TD, and OR = 3.26, 95% CI = 1.35, 7.89, P = 0.009 for AU+ASD vs. TD). These results suggest a potential role of the functional MAOA promoter alleles in the male child, the mother, or both in ASD.


An assessment of infrared tympanic thermometers for body temperature measurement.
This article provides an experimental assessment of three commercially available clinical thermometers, using different thermal infrared sensors. This kind of thermometer measures body temperature by detecting infrared radiation from the tympanic membrane. These thermometers are growing in popularity thanks to their simplicity of use, rapid response and minimal distress to the patient. The purpose of the laboratory tests presented here was to assess the effect of varying ambient temperature and varying simulated patient temperature on the performance of the three infrared tympanic thermometers.


In Situ Gene Therapy.
Gene therapy is a technique that aims at the delivery of nucleic acids to cells, to obtain a therapeutic effect. In situ gene therapy consists of the administration of the gene product to a specific site. It possesses several advantages, such as the reduction in potential side effects, the need for a lower vector dose, and, as a consequence, reduced costs, compared to intravenous administration. Different vectors, administration routes and doses involving in situ gene transfer have been tested both in animal models and humans, with in situ gene therapy drugs already approved in the market. In this review, we present applications of in situ gene therapy for different diseases, ranging from monogenic to multifactorial diseases, focusing mainly on therapies designed for the intra-articular and intraocular compartments, as well as gene therapies for the central nervous system (CNS) and for tumors. Gene therapy finally seems to blossom as a viable therapeutic approach. The growth in the number of clinical protocols shown here is evident, and the positive outcomes observed in several clinical trials indicate that more products based on in situ gene therapy should reach the market in the next years.


Anger Rumination as a Mediator of the Relationship Between Mindfulness and Aggression: The Utility of a Multidimensional Mindfulness Model.
Mindfulness training reduces anger and aggression, but the mechanisms of these effects are unclear. Mindfulness may reduce anger expression and hostility via reductions in anger rumination, a process of thinking repetitively about angry episodes that increases anger. Previous research supports this theory but used measures of general rumination and assessed only the present-centered awareness component of mindfulness. The present study investigated associations between various aspects of mindfulness, anger rumination, and components of aggression. The present study used self-report measures of these constructs in a cross-sectional sample of 823 students. Structural equation modeling revealed that anger rumination accounts for a significant component of the relationship between mindfulness and aggression, with the largest effect sizes demonstrated for the nonjudgment of inner experiences facet of mindfulness. Nonjudgment and present-centered awareness may influence aggression via reduced anger rumination. The importance of examining mindfulness as a multidimensional construct is discussed.


Effect of prolonged neck muscle vibration on lateral head tilt in severe spasmodic torticollis.
Short term vibration of the dorsal neck muscles (10-35 s) is known to induce involuntary movements of the head in patients with spasmodic torticollis. To investigate whether neck muscle vibration might serve as a therapeutic tool when applied for a longer time interval, we compared a vibration interval of 5 seconds with a 15 minute interval in a patient with spasmodic torticollis with an extreme head tilt to the right shoulder. Head position was recorded with a two camera optoelectronic motion analyzer in six different test conditions. Vibration regularly induced a rapid change of head position that was markedly closer to a normal, upright posture. After 5 seconds of vibration, head position very quickly returned to the initial position within seconds. During the 15 minute interval, head position remained elevated. After terminating vibration in this condition, the corrected head position remained stable at first and then decreased slowly within minutes to the initial tilted position. (1) In this patient, muscle vibration was the specific sensory input that induced lengthening of the dystonic neck muscles. Neither haptic stimulation nor transcutaneous electrical stimulation had more than a marginal effect. (2) The marked difference in the change of head position after short and prolonged stimulation supports the hypothesis that spasmodic torticollis might result from a disturbance of the central processing of the afferent input conveying head position information-at least in those patients who are sensitive to sensory stimulation in the neck region. (3) Long term neck muscle vibration may provide a convenient non-invasive method for treating spasmodic torticollis at the central level by influencing the neural control of head on trunk position.


Investigation of a plasmid containing a novel immunotoxin VEGF165-PE38 gene for antiangiogenic therapy in a malignant glioma model.
Inhibition of tumor neovascularization has profound effects on the growth of solid tumors. Our previous studies have shown the effect of VEGF165-PE38 recombinant immunotoxin on proliferation and apoptosis in human umbilical vein endothelial cells in vitro. In this study, we explored the direct inhibition of angiogenesis in chick chorioallantoic membrane and antiangiogenic therapy in a malignant glioma model. HEK293 cells were transfected with the pVEGF165PE38-IRES2-EGFP plasmid. ELISA was used to confirm the expression of VEGF165-PE38 in the transfected cells. These cells released 1396 + or - 131.9 pg VEGF165-PE38/1x10(4) cells/48 h into the culture medium and the supernatant was capable of inhibiting the growth of capillary-like structures in chick chorioallantoic membrane assay. In a murine malignant glioma model, plasmid was directly administered via multiple local intratumoral delivery. After day 16 the tumor volume in mice treated with pVEGF165PE38-IRES2-EGFP was significantly lower than that in mice in the control groups. Immunohistochemistry studies showed that the treated group had decreased expression of CD31. Quantitative analysis of microvessel density in the treated group was 1.99 + or - 0.69/0.74 mm(2), and was significantly lower than that in the control groups (9.33 + or - 1.99/0.74 mm(2), 8.09 + or - 1.39/0.74 mm(2) and 8.49 + or - 1.69/0.74 mm(2)). Immunohistochemistry analysis indicated that immunotoxin VEGF165-PE38 was distributed in the treated group in malignant glioma tissue. Our findings provide evidence that the in vivo production of VEGF165-PE38 through gene therapy using a eukaryotic expression plasmid had potential antiangiogenic activity in malignant glioma in vivo.


Genetic interactions among regulators of septin organization.
Septins form a cortical scaffold at the yeast mother-bud neck that restricts the diffusion of cortical proteins between the mother and bud and serves as a signaling center that is important for governing various cell functions. After cell cycle commitment in late G(1), septins are assembled into a narrow ring at the future bud site, which spreads to form a mature septin hourglass immediately after bud emergence. Although several septin regulators have been identified, it is unclear how they cooperate to assemble the septin scaffold. We have examined septin localization in isogenic strains containing single or multiple mutations in eight septin organization genes (CDC42, RGA1, RGA2, BEM3, CLA4, GIN4, NAP1, and ELM1). Our results suggest that these regulators act largely in parallel to promote either the initial assembly of the septin ring (CDC42, RGA1, RGA2, BEM3, and CLA4) or the conversion of the ring to a stable hourglass structure at the neck (GIN4, NAP1, and ELM1). Aberrant septin localization patterns in mutant strains could be divided into apparently discrete categories, but individual strains displayed heterogeneous defects, and there was no clear-cut correspondence between the specific mutations and specific categories of defect. These findings suggest that when they are deprived of their normal regulators, septin scaffolds collapse into a limited repertoire of aberrant states in which the nature of the mutant regulators influences the probability of a given aberrant state.


A phase II study of VP-16-fosfamide-cisplatin combination chemotherapy plus early concurrent thoracic irradiation for previously untreated limited small cell lung cancer.
At present the addition of thoracic irradiation to combination chemotherapy is a standard treatment for limited staged small cell lung cancer. However, there is still controversy about the optimum timing of chest irradiation. We conducted a phase II study of etoposide (VP-16)-ifosfamide-cisplatin (VIP) combination chemotherapy plus early concurrent thoracic irradiation for the patients with previously untreated limited small cell lung cancer in order to assess if the treatment modality could improve the response rate and the toxicity. Forty-four patients with limited small cell lung cancer were treated with etoposide-ifosfamide-cisplatin and concurrent thoracic irradiation. Combination chemotherapy consisted of etoposide 100 mg/m2 (on days 1-3), ifosfamide 1000 mg/m2 (on days 1 and 2) and cisplatin 100 mg/m2 (on day 1). Concurrent thoracic irradiation consisted of a total of 4000 cGy over 4 weeks starting on the first day of the first chemotherapy. All patients who showed a complete response were given prophylactic cranial irradiation for 2.5 weeks. Forty-four of the 49 patients who entered the study from May 1994 to August 1998 were evaluable. The median age was 59 years and 40 patients had a performance status of 0 or 1. The median survival time was 22.5 months. Twenty-eight patients (62%) showed a complete response and 16 (38%) a partial response. Twenty-four patients (54%) developed grade 3 or 4 neutropenia; there was a 9% RTOG score 3 or 4 esophagitis. VIP combination chemotherapy and early concurrent thoracic irradiation for patients with limited stage small cell lung cancer revealed excellent antitumor response with tolerable toxicity.


Prognostic significance of KLF4 expression in gastric cancer.
To understand the roles of pluripotent stem cell-inducing genes in gastric cancer, the expression of Krüppel-like factor 4 (KLF4), Nanog, octamer-binding transcription factor 4 (Oct4), avian myelocytomatosis viral oncogene homolog (c-Myc) and sex-determining region Y-box 2 (SOX2) was examined using the newly developed gastric carcinoma tissue microarray. The associations between the immunohistochemical expression levels of the pluripotency-inducing factors and the clinicopathological data of 108 patients with gastric cancer were analyzed. No associations were identified between the expression levels of the five pluripotency-inducing factors and the tumor-node-metastasis (TNM) classification or clinicopathological characteristics of the patients. In addition, multivariate analysis revealed no association of Nanog, Oct4, SOX2 or c-Myc with the prognosis of the gastric cancer patients; however, low expression of KLF4 was determined to be an independent negative prognostic factor (P=0.0331), particularly in patients who underwent R0 resection (TNM stages 2 and 3; P=0.0048). In summary, low KLF4 expression was found to be negatively associated with overall survival, and may therefore be a useful prognostic marker in gastric cancer patients.


Do Perineuronal Net Elements Contribute to Pathophysiology of Spinal Muscular Atrophy? In Vitro and Transcriptomics Insights.
Spinal muscular atrophy (SMA) is one of the most common childhood onset neurodegenerative disorders in global health whereby novel biomarkers and therapeutic targets are sorely needed. SMA is an autosomal recessive genetic disorder resulting in degeneration of α-motor neurons in the brain stem and spinal cord that leads to mortality in infants worldwide. In majority of the patients, SMA is caused by homozygous deletion of the SMN1 gene. The clinical spectrum of the SMA displays, however, large person-to-person variations where the underlying mechanisms are poorly understood. We report in this study transcriptomics insights gleaned from patients with the severe type I (GM03813 and GM09677) and the mild type III. Pathway enrichment and functional analysis showed that especially extracellular matrix (ECM), synapse organization, and ECM receptor interaction pathways were affected. Among the neural ECM components, hyaluronan and proteoglycan link protein (HAPLN1), which is a key triggering molecule of the perineuronal net (PNN), was significantly downregulated in type I fibroblasts compared to type III. PNN is a specialized form of neural ECM around the neuronal cell bodies and dendrites in the central nervous system. In addition, we evaluated the PNN expression in vitro in a model established by SMN silencing in the PC12 rat pheochromocytoma cell line which can be differentiated into neurons with nerve growth factor treatment. In this neuronal in vitro model, we found that HAPLN1 showed a significant 50% decrease. Our results describe the association between PNN elements, especially HAPLN1, and SMA pathophysiology for the first time. These observations collectively inform future translational research on SMA for discovery of novel molecular targets for diagnostics and precision medicine innovation.


Relationships between daily stress responses in everyday life and nightly sleep.
Stress and sleep are related, but the nature and time course of this relation is not well understood. We explored the within-person associations of three components of emotional responses to everyday stressors, indexed by negative affect, reactivity (initial response to a stressor), recovery (persistence of the post-stressor response), and pile-up (accumulation of stress episodes), with sleep indicators. We conducted coordinated analyses of data in several studies employing ecological momentary assessments, which captured naturally occurring, self-reported stress and sleep. We defined proximal reactivity as the emotional response to the stressor moment in question compared to an immediate pre-stressor state, and distal reactivity as the emotional response to the stressor moment in question compared to a typical stressor-free state for that person. Results in two of three studies showed that people reported significantly lower sleep quality following days on which they experienced higher levels of distal reactivity to stressors. Days with greater distal reactivity also predicted significantly more difficulty falling asleep in one of two studies. There was no clear association between proximal reactivity and subsequent sleep. Associations of recovery or pile-up with subsequent sleep emerged only in single studies. Poorer sleep quality was significantly related to higher next day levels of negative affect in all three studies, but there were no consistent relations between sleep and next day stress reactivity, recovery, or pile-up. These exploratory analyses suggest that distal reactivity is associated with a heightened risk of experiencing poor sleep quality the following night, and as such the former may serve as a candidate for potential targets for the remediation of the negative effects of stress on sleep.


Antiproliferative effects of S-allylmercaptocysteine on colon cancer cells when tested alone or in combination with sulindac sulfide.
Epidemiological studies link increased garlic (Allium sativum) consumption with a reduced incidence of colon cancer in various human populations. Experimental carcinogenesis studies in animal models and in cell culture systems indicate that several allium-derived compounds exhibit inhibitory effects and that the underlying mechanisms may involve both the initiation and promotion phases of carcinogenesis. To provide a better understanding of the effects of allium derivatives on the prevention of colon cancer, we examined two water-soluble derivatives of garlic, S-allylcysteine (SAC) and S-allylmercaptocysteine (SAMC), for their effects on proliferation and cell cycle progression in two human colon cancer cell lines, SW-480 and HT-29. For comparison, we included the compound sulindac sulfide (SS), because sulindac compounds are well-established colon cancer chemopreventive agents. We found that SAMC, but not SAC, inhibited the growth of both cell lines at doses similar to that of SS. SAMC also induced apoptosis, and this was associated with an increase in caspase3-like activity. These affects of SAMC were accompanied by induction of jun kinase activity and a marked increase in endogenous levels of reduced glutathione. Although SS caused inhibition of cell cycle progression from G1 to S, SAMC inhibited progression at G2-M, and a fraction of the SW-480 and HT-29 cells were specifically arrested in mitosis. Coadministration of SS with SAMC enhanced the growth inhibitory and apoptotic effects of SS. These findings suggest that SAMC may be useful in colon cancer prevention when used alone or in combination with SS or other chemopreventive agents.


Turkish health field periodical editors' Views on publication process and ethical problems.
We aimed in this study to investigate views and suggestions of health field editors about the publication process and ethical problems. The study involved 42 journal editors who accepted to participate in the study. The data were collected through 70-item "Editor Views Questionnaire" which was developed by the researchers in line with the related literature. The editors who participated in the study were asked about their views about the most common problems they encountered related to publication ethics; the top three problems indicated by the editors included unjustified authorship (40.5%), duplicate publication (33.3%), and falsification (26.2%). An analysis of the problems encountered in the initial evaluation stage revealed the top three issues as articles that did not follow the writing rules of the journal (33.3%), unqualified articles (30.1%), and negligence of the author(s) (14.3%). Views in relation to the problems about the referee evaluation stage included evaluations that were not completed within the time given (28.6%), insufficient importance attached to the evaluation (23.9%), and inability to find sufficient number of referees (16.7%). some editors were found to encounter violation of publication ethics, to experience problems in the revision stage, and not to feel fully independent in their contribution to article publication and thus the improvement of the journal quality. Identification of journal editors' views and problems is an important step for the solution to these problems; it could thus contribute to improving the quality of publication process and journal quality.


Protection against tuberculosis with homologous or heterologous protein/vector vaccine approaches is not dependent on CD8+ T cells.
Considerable effort has been directed to develop Mycobacterium tuberculosis vaccines to boost bacille Calmette-Guérin or for those who cannot be immunized with bacille Calmette-Guérin. We hypothesized that CD4(+) and CD8(+) T cell responses with a heterologous prime/boost vaccine approach could induce long-lived vaccine efficacy against M. tuberculosis in C57BL/6 mice. We produced an adenovirus vector expressing ID93 (Ad5-ID93) for induction of CD8 T cells to use with our candidate tuberculosis vaccine, ID93/glucopyranosyl lipid adjuvant (GLA)-stable emulsion (SE), which induces potent Th1 CD4 T cells. Ad5-ID93 generates ID93-specific CD8(+) T cell responses and induces protection against M. tuberculosis. When Ad5-ID93 is administered in a prime-boost strategy with ID93/GLA-SE, both CD4(+) and CD8(+) T cells are generated and provide protection against M. tuberculosis. In a MHC class I-deficient mouse model, all groups including the Ad5-ID93 group elicited an Ag-specific CD4(+) T cell response and significantly fewer Ag-specific CD8(+) T cells, but were still protected against M. tuberculosis, suggesting that CD4(+) Th1 T cells could compensate for the loss of CD8(+) T cells. Lastly, the order of the heterologous immunizations was critical. Long-lived vaccine protection was observed only when Ad5-ID93 was given as the boost following an ID93/GLA-SE prime. The homologous ID93/GLA-SE prime/boost regimen also induced long-lived protection. One of the correlates of protection between these two approaches was an increase in the total number of ID93-specific IFN-γ-producing CD4(+) T cells 6 mo following the last immunization. Our findings provide insight into the development of vaccines not only for tuberculosis, but other diseases requiring T cell immunity.


[Screening of Human Immunodeficiency Virus and Other Sexually Transmitted Infections in a Group of Sex Workers in Indoor Settings in the Porto Metropolitan Area].
Early diagnosis is a crucial tool for containing the human immunodeficiency virus and other sexually transmitted infections, particularly in key populations such as sex workers. Despite its relevance, there is a gap considering epidemiological studies and interventions aimed at the monitoring and diagnosis of sexually transmitted infections in Portugal. The objectives of this study are: (i) to contribute to a better understanding of the epidemiology of sexually transmitted infections; and (ii) to evaluate the transfer of screening methods from clinical settings to the outreach context in hidden populations such as sex workers. The screening of sexually transmitted infections (human immunodeficiency virus 1/2, hepatitis B virus, hepatitis C virus, syphilis, chlamydia and gonorrhea) were carried out in a sample of 100 sex workers during the Porto G outreach intervention in the Metropolitan area of Porto, from September 2015 to September 2016. Six reactive cases for human immunodeficiency virus were identified, five of syphilis, eight of chlamydia and two of gonorrhea. No positive results were detected for hepatitis B virus and hepatitis C virus. The results were discussed considering the risk gradient and sexually transmitted infections vulnerability in the different sex workers' subgroups. The results of this study corroborate the need to promote comprehensive responses to populations most affected by the human immunodeficiency virus and other sexually transmitted infections, such as sex workers. Also, in this group, men who have sex with men and trans women have a higher prevalence than cis women. Intervention strategies should be informed by rigorous epidemiological studies. The adaptation of the screening methodology performed in a clinical setting to the proximity context has shown to be an innovative response in Portugal, especially in sentinel populations.


The involvement of the major surface glycoprotein (gp63) of Leishmania promastigotes in attachment to macrophages.
The interaction between the macrophage and the parasite plays a central role in the continued success of Leishmania infection. The promastigote surface ligand, and its complementary macrophage membrane receptor, involved in attachment and phagocytosis are likely to exert considerable influence over the outcome of a new infection. In this study, we report experiments pertaining to one such parasite membrane protein. Initial examination of promastigote surface proteins by radiolabeling and two-dimensional-polyacrylamide gel electrophoresis revealed an abundant polypeptide with an apparent m.w. of 63,000. Lectin-binding studies indicated that it was a glycoprotein containing mannose, N-acetyl glucosamine, and N-acetyl galactosamine residues. Monospecific antiserum raised against this glycoprotein, gp63, decorated the entire promastigote plasmalemma. Univalent antibody fragments from this antiserum blocked the interaction between promastigotes and macrophages by inhibiting attachment. Anti-gp63-inhibition reduced parasite/macrophage binding to 30 to 35% of the control binding level. Additional evidence of the involvement of gp63 in attachment to macrophages was provided by studies that made use of gp63-containing proteoliposomes. These vesicles were avidly phagocytosed by macrophages. Uptake of the gp63-containing liposomes was suppressed by greater than 90% by both anti-gp63 F(ab) fragments and the oligosaccharide mannan, indicating that their phagocytosis was receptor dependent. These results demonstrate that the abundant glycoprotein gp63 plays an important role in attachment of promastigotes to macrophages, and attachment via this parasite ligand is sufficient to trigger phagocytosis.


Identification of verotoxin type 2 variant B subunit genes in Escherichia coli by the polymerase chain reaction and restriction fragment length polymorphism analysis.
A set of synthetic oligonucleotide primers was designed for use in a polymerase chain reaction protocol to specifically detect the B subunit genes in vtx2ha and vtx2hb, which code for the production of the VT2 (Shiga-like toxin II) variant cytotoxins VT2v-a and VT2v-b, respectively. An additional set of primers amplified a fragment common to the B subunits of the VT2 and the VT2 variant genes. Subsequent restriction endonuclease digestion of this amplicon permitted prediction of specific VT2 and variant genotypes on the basis of predetermined restriction fragment length polymorphisms. Genotypes of 21 VT2-producing strains of Escherichia coli were determined using this polymerase chain reaction-restriction fragment length polymorphism procedure. Four strains contained B subunit target sequences only for VT2 genes, 9 strains contained sequences only for VT2v-a genes, and 3 strains contained sequences only for VT2v-b. For genes in combination, one strain contained B subunit genes for both VT2 and VT2v-a and two strains contained B subunit genes for VT2 and VT2v-b. Two strains of E. coli O91:H21 contained both VT2v-a and VT2v-b B subunit genes. The VT2 reference strain of E. coli, E32511, was found to contain the targeted sequences from both VT2 and VT2v-a genes, whereas the recombinant E. coli, pEB1, possessed only that of the VT2 gene. The specific activities of extracellular VT2 determined in HeLa cells ranged from 0.3 to 41.7 TCD50 per microgram of protein in strains carrying the VT2 gene target and from 0 to 50.0 TCD50 per microgram of protein in strains carrying only the VT2 variant target (TCD50 is the tissue culture dose by which 50% of the cells were affected), suggesting that phenotypic expression does not correlate with genotype.


Protein H, an antiphagocytic surface protein in Streptococcus pyogenes.
Surface-associated M protein is a major virulence factor in Streptococcus pyogenes which confers bacterial resistance to phagocytosis. However, many S. pyogenes strains also express additional structurally related so-called M-like proteins. The strain studied here is of the clinically important M1 serotype and expresses two structurally related surface proteins, the M1 protein and protein H. Mutants were generated that expressed only one or none of these proteins at the bacterial surface. For survival in human blood either protein H or M1 protein was sufficient, whereas the double mutant was rapidly killed. The protein-binding properties of protein H, M1 protein, and the mutants suggest that bacterial binding of immunoglobulin G and factor H or factor H-like protein 1, which are regulatory proteins in the complement system, contribute to the antiphagocytic property.


Baseline neuropsychiatric symptoms and psychotropic medication use midway through data collection of the Longitudinal Early-Onset Alzheimer's Disease Study (LEADS) cohort.
We examined neuropsychiatric symptoms (NPS) and psychotropic medication use in a large sample of individuals with early-onset Alzheimer's disease (EOAD; onset 40-64 years) at the midway point of data collection for the Longitudinal Early-onset Alzheimer's Disease Study (LEADS). Baseline NPS (Neuropsychiatric Inventory - Questionnaire; Geriatric Depression Scale) and psychotropic medication use from 282 participants enrolled in LEADS were compared across diagnostic groups - amyloid-positive EOAD (n = 212) and amyloid negative early-onset non-Alzheimer's disease (EOnonAD; n = 70). Affective behaviors were the most common NPS in EOAD at similar frequencies to EOnonAD. Tension and impulse control behaviors were more common in EOnonAD. A minority of participants were using psychotropic medications, and use was higher in EOnonAD. Overall NPS burden and psychotropic medication use were higher in EOnonAD than EOAD participants. Future research will investigate moderators and etiological drivers of NPS, and NPS differences in EOAD versus late-onset AD.


Evaluating Utility Measurement from Recurrent Marker Processes in the Presence of Competing Terminal Events.
In follow-up studies, utility marker measurements are usually collected upon the occurrence of recurrent events until a terminal event such as death takes place. In this article, we define the recurrent marker process to characterize utility accumulation over time. For example, with medical cost and repeated hospitalizations being treated as marker and recurrent events respectively, the recurrent marker process is the trajectory of cumulative cost, which stops to increase after death. In many applications, competing risks arise as subjects are at risk of more than one mutually exclusive terminal event, such as death from different causes, and modeling the recurrent marker process for each failure type is often of interest. However, censoring creates challenges in the methodological development, because for censored subjects, both failure type and recurrent marker process after censoring are unobserved. To circumvent this problem, we propose a nonparametric framework for recurrent marker process with competing terminal events. In the presence of competing risks, we start with an estimator by using marker information from uncensored subjects. As a result, the estimator can be inefficient under heavy censoring. To improve efficiency, we propose a second estimator by combining the first estimator with auxiliary information from the estimate under non-competing risks model. The large sample properties and optimality of the second estimator is established. Simulation studies and an application to the SEER-Medicare linked data are presented to illustrate the proposed methods. Supplemental materials are available online.


Analysis of copper-induced protein precipitation across the E. coli proteome.
Metal cations have been exploited for their precipitation properties in a wide variety of studies, ranging from differentiating proteins from serum and blood to identifying the protein targets of drugs. Despite widespread recognition of this phenomenon, the mechanisms of metal-induced protein aggregation have not been fully elucidated. Recent studies have suggested that copper's (Cu) ability to induce protein aggregation may be a main contributor to Cu-induced cell death. Here, we provide the first proteome-wide analysis of the relative sensitivities of proteins across the Escherichia coli proteome to Cu-induced aggregation. We utilize a metal-induced protein precipitation (MiPP) methodology that relies on quantitative bottom-up proteomics to define the metal concentration-dependent precipitation properties of proteins on a proteomic scale. Our results establish that Cu far surpasses other metals in promoting protein aggregation and that the protein aggregation is reversible upon metal chelation. The bulk of the Cu bound in the protein aggregates is Cu1+, regardless of the Cu2+ source. Analysis of our MiPP data allows us to investigate underlying biophysical characteristics that determine a protein's sensitivity to Cu-induced aggregation, which is independent of the relative concentration of protein in the lysate. Overall, this analysis provides new insights into the mechanism behind Cu cytotoxicity, as well as metal cation-induced protein aggregation.


Determination of enantiomeric excess in samples of chiral molecules using fourier transform vibrational circular dichroism spectroscopy: simulation of real-time reaction monitoring.
The first use of Fourier transform vibrational circular dichroism (FT-VCD) to follow changes in the percent enantiomeric excess (% EE) of chiral molecules in time using a flow cell sampling apparatus is reported. FT-VCD, as opposed to dispersive scanning VCD, eliminates the need to scan the VCD spectrum in time to monitor the % EE at more than one spectral location. The first use of partial least-squares chemometric analysis to determine % EE values from kinetic sets of VCD spectral data is also reported. These two advances have been used to monitor simultaneously changes in the fractional composition and the % EE of a mixture of two different chiral molecules. This simulates the progress of the chemical reaction from a chiral reactant to a chiral product where the % EE of both molecules can change with time. For the molecules studied, alpha-pinene, camphor, and borneol, the accuracy of following % EE changes for one species alone is approximately 1%, while for simultaneously following % EE changes in two species is approximately 2% for 10-20-min sampling periods at 4 cm(-)(1) spectral resolution. This accuracy can be increased for the same collection times or maintained for shorter periods of collection by lowering the spectral resolution. These findings demonstrate the potential for VCD to be used for real-time monitoring of the composition and % EE of chemical reactions involving the synthesis chiral molecules.


Influence of nopal intake upon fasting glycemia in type II diabetics and healthy subjects.
To assess if the acute hypoglycemic effect of nopal which occurs in diabetic patients also appears in healthy individuals, 500 g of nopal stems (O. streptacantha Lem.) were given orally to 14 healthy volunteers and to 14 patients with NIDDM. Serum glucose and insulin levels were measured at 0, 60, 120 and 180 minutes after nopal ingestion. A control test was performed with the intake of 400 ml of water. The intake of nopal by the NIDDM group was followed by a significant reduction of serum glucose and insulin concentration reaching 40.8 + 4.6 mg/dl (n = 14) (mean+SEM) and 7.8 + 1.5 uU/ml (n = 7) less than basal value, respectively, at 180 minutes. (P less than 0.001 vs control test). No significant changes were noticed in the healthy group as compared with the control test (P greater than 0.05). Acute hypoglycemic effect of nopal was observed in patients with NIDDM but not in healthy subjects, thus the mechanisms of this effect differs from current hypoglycemic agents.


Neuroprotective effects of melatonin and celecoxib against ethanol-induced neurodegeneration: a computational and pharmacological approach.
Melatonin and celecoxib are antioxidants and anti-inflammatory agents that exert protective effects in different experimental models. In this study, the neuroprotective effects of melatonin and celecoxib were demonstrated against ethanol-induced neuronal injury by in silico, morphological, and biochemical approaches. For the in silico study, 3-D structures were constructed and docking analysis performed. For in vivo studies, rats were treated with ethanol, melatonin, and celecoxib. Brain samples were collected for biochemical and morphological analysis. Homology modeling was performed to build 3-D structures for IL1β), TNFα, TLR4, and inducible nitric oxide synthase. Structural refinement was achieved via molecular dynamic simulation and processed for docking and postdocking analysis. Further in vivo experiments showed that ethanol induced marked neuronal injury characterized by downregulated glutathione, glutathione S-transferase, and upregulated inducible nitric oxide synthase. Additionally, ethanol increased the expression of TNFα and IL1β. Finally, neuronal apoptosis was demonstrated in ethanol-intoxicated animals using caspase 3 and activated JNK staining. On the other hand, melatonin and celecoxib treatment ameliorated the biochemical and immunohistochemical alterations induced by ethanol. These results demonstrated that ethanol induced neurodegeneration by activating inflammatory and apoptotic proteins in rat brain, while melatonin and celecoxib may protect rat brain by downregulating inflammatory and apoptotic markers.


Neural pathways mediating adrenocortical responses.
The effects of hypothalamic deafferentations and brain lesions on adrenocorticotropin (ACTH) and corticosterone (CS) responses after neural stimuli were studied in rats. It was found that the various modalities are mediated by different neural pathways. Photic and acoustic stimuli utilize a posterior input, whereas the sciatic and olfactory modalities are mediated by anterior afferents and forebrain limbic structures. The effects of limbic extrahypothalamic structures on the hypothalamus are transmitted by both anterior and posterior inputs. The medial forebrain bundle (MFB) was found to have a differential role in the mediation of ACTH and CS responses. To identify the neurotransmitters involved, rats were injected with 6-hydroxydopamine in the MFB and 5,7-dihydroxytryptamine in the raphe nuclei. The depletion of hypothalamic norepinephrine and serotonin caused inhibition of the adrenocortical responses only after photic stimulation, and only of responses to limbic stimuli in the former group. In view of the location of corticotropin-releasing factor in the paraventricular nucleus, responses to afferent stimuli were studied in this region in identified neurons projecting to the median eminence. Stimuli that increased or decreased CS secretion facilitated or inhibited cell firing, respectively, thus demonstrating a possible electrophysiological correlate of neuroendocrine regulation.


Two distinct attachment sites for vimentin along the plasma membrane and the nuclear envelope in avian erythrocytes: a basis for a vectorial assembly of intermediate filaments.
In vitro binding studies with isolated bovine lens vimentin and avian erythrocyte membranes reveal the existence of two functionally distinct sets of intermediate filament attachment sites. One population of such receptors is located along the nuclear envelope and comprises polypeptides recognizing the carboxy-terminal tail domain of vimentin. Vimentin associates with these nuclear surface receptors in a cooperative manner and forms extensive 10-nm filaments in a concentration-dependent fashion. Conversely, the plasma membrane contains binding sites that interact in a noncooperative, saturable fashion with vimentin, recognizing its amino-terminal head domain. The functional dichotomy of the vimentin-binding sites under in vitro conditions may reflect a vectorial assembly process whereby 10-nm filaments, although structurally apolar, acquire polar features brought about by the differential attachment to specific receptors arranged along the plasma membrane and the nuclear envelope.


An unnamed branch of the lingual nerve: gingival branch.
Our main aim was to study the mylohyoid nerve, but during cadaveric dissections an unnamed branch of the lingual nerve was encountered incidentally. Dissections of sublingual and pterygomandibular spaces on 13 cadavers preserved in formalin showed an unnamed branch present bilaterally in 11 specimens, which had not been identified before in any of the anatomical textbooks. The branch extended horizontally from the medial mandibular cortex at the level of the retromolar pad to mesial of the lower first molars-second premolars. It was supplying the lingual periosteum, gingiva, and mucosa that were overlying the medial alveolar process. The mean (SD) diameter of the left and right branches was 0.66 (0.1) mm at the branching side. The mean (SD) length of the right and left sides was 28.7 (4.4) mm. The mean (SD) distance from the alveolar crest was 5.8 (0. 9) mm. The lingual nerve supplies the lingual soft tissues; however, none of the anatomical textbooks mention such a subdivision or a branch supplying that part of the oral cavity. We describe the site and the morphological characteristics of this unnamed branch, and recommend that it be named "the gingival branch of the lingual nerve".


Poverty and health disparities for American Indian and Alaska Native children: current knowledge and future prospects.
This report explores the current state of knowledge regarding inequalities and their effect on American Indian and Alaska Native children, underscoring gaps in our current knowledge and the opportunities for early intervention to begin to address persistent challenges in young American Indian and Alaska Native children's development. This overview documents demographic, social, health, and health care disparities as they affect American Indian and Alaska Native children, the persistent cultural strengths that must form the basis for any conscientious intervention effort, and the exciting possibilities for early childhood interventions.


Adult hepatic retransplantation. UCL experience.
Retransplantation is a rescue operation in orthotopic liver transplantation. Its appropriateness has been questioned on medical, economical and also on ethical grounds. During the period february 1984-december 1997, 54 (14.5%) of 372 adult patients were retransplanted; three (0.8%) of them had two retransplantations. Indications were graft dysfunction [(primary non function (8x) and early dysfunction (14x in 13 patients)], immunological failure [acute (9x in 8 patients) and chronic (9x) rejection], technical failure [(hepatic artery thrombosis (5x in four patients), allograft decapsulation (1x), ischaemic biliary tract lesions (6x)] and recurrent viral allograft disease [HBV (4x) and HCV (1x)]. Five year actuarial patient survival after retransplantation was 70.8%, which was identical to this of non retransplanted patients (72%). Early (< 3 mo) mortality was significantly lower in elective procedures (9.1%--2/22 pat. vs 34.4%--11/32 pat. in urgent procedures--p < 0.05). Mortality was highest in the graft dysfunction (23.8%, 5/21 pat.) and immunological failure (41%, 7/17 pat.) groups. Five of six patients retransplanted for rejection, whilst being on renal support, and two of three patients retransplanted urgently twice died of infectious complications. All patients retransplanted because of recurrent allograft disease were long-term (> 3 mo) survivors. Both HBV-infected patients died of allograft reinfection 7 months later; the two HBV-Delta infected patients were, free of infection, 44 and 6 months after retransplantation under HBV-immunoprophylaxis. Length of hospitalisation after primary transplantation and retransplantation were identical (median of 16 days--range 11 to 40 vs 14 days (range 7 to 110). Economical study during the period 1990-1995 showed that costs of the first hospitalization of primary transplantation and of retransplantation could be equalized during the period 1994-1995 as a consequence of the more frequent use of elective retransplantation (median 1.3 million BF, range 720,988 to 8,887,145 vs 1.1 million BF, range 943,685 to 1,940,409). Hepatic retransplantation is a successful safety net for many liver transplant patients. Every effort should be made to do this intervention electively under minimal immunosuppression. In case of immunological graft failure and hepatic artery thrombosis retransplantation must be done early in order to avoid infectious complications; the same holds for ischaemic biliary tract lesions which cannot be cured by interventional radiology. Retransplantation for recurrent benign disease should be restricted to those diseases which can be effectively treated by (neo- and) adjuvant antiviral therapy.


Metastatic and nonmetastatic models of retinoblastoma.
To generate animal models of retinoblastoma that closely resemble metastatic and nonmetastatic human disease for the purposes of examining tumor biology and developing alternate treatments, human retinoblastoma cell lines were injected into the vitreal cavities of immunodeficient mice. Two reproducible animal models with contrasting biological behaviors analogous to human retinoblastoma have been developed. The Y79 retinoblastoma model demonstrated specific tumor evolution similar to that seen in human invasive and metastatic disease. Y79 retinoblastoma cells formed intraocular tumors that were initially confined to the vitreal cavity. Tumors progressively invaded the retina, subretinal space, choroid, optic nerve head, and anterior chamber of the eye. Tumors progressed into the subarachnoid space and focally invaded the brain. Metastases were detected in the contralateral optic nerve. Large tumors developed extraocular extensions. The histology of the tumors showed a poorly differentiated pattern with high mitotic rate, foci of necrosis, and calcification. The WERI-Rb model more closely resembled nonmetastatic human retinoblastoma. WERI- Rb tumors were localized in the eye with only anterior choroidal invasion at late stages. To examine potential biological differences in vitro, the retinoblastoma cell lines were cocultured with adherent choroid cells or adherent glioma cells which represent the targets of invasive retinoblastoma in vivo. Consistent with the in vivo observations, Y79 cells but not WERI-Rb cells adhere specifically to both the choroidal and the glioma cell lines.


Retrieval of foreign-broadened water vapor continuum coefficients from emitted spectral radiance in the H2O rotational band from 240 to 590 cm(-1).
The paper presents a novel methodology to retrieve the foreign-broadened water vapor continuum absorption coefficients in the spectral range 240 to 590 cm(-1) and is the first estimation of the continuum coefficient at wave numbers smaller than 400 cm(-1) under atmospheric conditions. The derivation has been accomplished by processing a suitable set of atmospheric emitted spectral radiance observations obtained during the March 2007 Alps campaign of the ECOWAR project (Earth Cooling by WAter vapor Radiation). It is shown that, in the range 450 to 600 cm(-1), our findings are in good agreement with the widely used Mlawer, Tobin-Clough, Kneizys-Davies (MT CKD) continuum. Below 450 cm(-1) however the MT CKD model overestimates the magnitude of the continuum coefficient.


Absolute phase measurement in fringe projection using multiple perspectives.
A technique for absolute phase measurement in fringe projection for shape measurement is presented. A standard fringe projection system is used, comprising a camera and a projector fixed relative to each other. The test object is moved to different orientations relative to the fringe projection system. Using the system calibration parameters, the technique identifies homologous surface areas imaged from different perspectives and resolves the 2 π phase ambiguity between them simultaneously. The technique is also used to identify regions of the phase maps corresponding to discrete surfaces on the object. The methods described are suitable for automatic shape measurement with a lightweight fringe projection probe mounted to a coordinate measuring machine.


[Gasometric arterial extraction].
Gasometric arterial extraction comprises a simple, painful and invasive technique through which a nurse obtains arterial blood by a direct puncture of an artery be it radial, brachial or femoral, or to insert a cannula in a radial artery This method serves to evaluate the pulmonary gas interchange and to study alterations in acid-base balances. The authors' objective is to unify criteria for extraction, conservation and transfer of samples to laboratory. To carry out our study, the authors made a wide bibliographical review on the subject and arrived at the following conclusions: All the articles reviewed counseled medical personnel to follow the "SEPAR" (Spanish Association of Lung and Thoracic Surgery) norm, but there is no unanimous recommendation regarding the type of local anesthetics to use before making the puncture. Nursing personnel are those responsible for extracting arterial blood. The majority of authors coincide stating that the conservation of the sample, the time which lapses after its extraction and the extraction conditions affect the reliability of the results.


Distribution of drb genes coding for Dr binding adhesins among uropathogenic and fecal Escherichia coli isolates and identification of new subtypes.
The Dr family of related adherence structures, some fimbriated and others afimbriated, bind to decay-accelerating factor molecules on human cells. Dr is associated with recurring urinary tract infection (UTI), but the distribution of Dr subtypes among uropathogenic Escherichia coli causing UTI among otherwise healthy women has yet to be described. A total of 787 UTI and fecal E. coli isolates from college women were screened for the presence of Dr sequences (drb). Fifteen percent of UTI strains were drb positive, compared to 5% of fecal strains. The adhesin (E gene) subtype of each drb-positive strain was determined by type-specific PCR followed by restriction enzyme analysis. Among 78 drb-positive strains, we found 14 (18%) afaE1, 1 (1.3%) afaE2, 1 (1.3%) afaE3, 9 (12%) draE, 9 (12%) draE-afaE3 hybrid, 1 (1.3%) daaE, 32 (41%) afaE5, 4 (5.1%) F131 E gene-like, and 7 untypeable strains. All untypeable E genes were cloned and sequenced, revealing four additional new classes of E genes, including two similar to the previously identified nonfimbrial E series. While a great range of diversity exists among the E genes, restriction fragment length polymorphism analysis demonstrated that all of these drb operons share a highly conserved gene structure. The most common subtype, afaE5, occurred three times as often among UTI than fecal strains. Over half of the drb-positive strains and 80% of those positive for afaE5 have the same virulence signature (positive for aer, kpsMT, ompT, and fim), suggesting an association of this profile with UTI pathogenesis.


Mechanotransduction in epidermal Merkel cells.
The cellular and molecular basis of vertebrate touch reception remains least understood among the traditional five senses. Somatosensory afferents that innervate the skin encode distinct tactile qualities, such as flutter, slip, and pressure. Gentle touch is thought to be transduced by somatosensory afferents whose tactile end organs selectively filter mechanical stimuli. These tactile end organs comprise afferent terminals in association with non-neuronal cell types such as Merkel cells, keratinocytes, and Schwann cells. An open question is whether these non-neuronal cells serve primarily as passive mechanical filters or whether they actively participate in mechanosensory transduction. This question has been most extensively studied in Merkel cells, which are epidermal cells that complex with sensory afferents in regions of high tactile acuity such as fingertips, whisker follicles, and touch domes. Merkel cell-neurite complexes mediate slowly adapting type I (SAI) responses, which encode sustained pressure and represent object features with high fidelity. How Merkel cells contribute to unique SAI firing patterns has been debated for decades; however, three recent studies in rodent models provide some direct answers. First, whole-cell recordings demonstrate that Merkel cells are touch-sensitive cells with fast, mechanically activated currents that require Piezo2. Second, optogenetics and intact recordings show that Merkel cells mediate sustained SAI firing. Finally, loss-of-function studies in transgenic mouse models reveal that SAI afferents are also touch sensitive. Together, these studies identify molecular mechanisms of mechanotransduction in Merkel cells, reveal unexpected functions for these cells in touch, and support a revised, two-receptor site model of mechanosensory transduction.


BPTF Drives Gastric Cancer Resistance to EGFR Inhibitor by Epigenetically Regulating the C-MYC/PLCG1/Perk Axis.
Erlotinib, an EGFR tyrosine kinase inhibitor, is used for treating patients with cancer exhibiting EGFR overexpression or mutation. However, the response rate of erlotinib is low among patients with gastric cancer (GC). The findings of this study illustrated that the overexpression of bromodomain PHD finger transcription factor (BPTF) is partially responsible for erlotinib resistance in GC, and the combination of the BPTF inhibitor AU-1 with erlotinib synergistically inhibited tumor growth both in vivo and in vitro. AU-1 inhibited the epigenetic function of BPTF and decreased the transcriptional activity of c-MYC on PLCG1 by attenuating chromosome accessibility of the PLCG1 promoter region, thus decreasing the expression of p-PLCG1 and p-Erk and eventually improving the sensitivity of GC cells to erlotinib. In patient-derived xenograft (PDX) models, AU-1 monotherapy exhibited remarkable tumor-inhibiting activity and is synergistic anti-tumor effects when combined with erlotinib. Altogether, the findings illustrate that BPTF affects the responsiveness of GC to erlotinib by epigenetically regulating the c-MYC/PLCG1/pErk axis, and the combination of BPTF inhibitors and erlotinib is a viable therapeutic approach for GC.


Hidden sources of infection in unapproachable areas.
The population living in the hilly terrains of Panvel taluka, District Raigad of Maharashtra State was examined in a special campaign carried out during a time when the majority of the population will be stationed at the hills. Examination of 10499 persons revealed 108 leprosy cases (PR 10.3/1000) of which 72 were paucibacillary (PB) and 29 were multibacillary (MB) cases. Among the PB cases, only two had single lesion type and among the 29 MB cases, 14 were smear-positive, having BI more than 4. These untreated advanced leprosy cases, in view of their frequent migrations in order to earn their livelihood, may be responsible for transmitting the infection in the plains areas where multidrug therapy is practiced since 1990. In order to achieve early leprosy elimination, it is necessary to cover populations in difficult areas like the one mentioned by special action programmes.


A comparison of patient-reported outcome measures after spinal surgery.
Minimal clinically important differences (MCID) in the scores of patient-reported outcome measures allow clinicians to assess the outcome of intervention from the perspective of the patient. There has been significant variation in their absolute values in previous publications and a lack of consistency in their calculation. The purpose of this study was first, to establish whether these values, following spinal surgery, vary depending on the surgical intervention and their method of calculation and secondly, to assess whether there is any correlation between the two external anchors most frequently used to calculate the MCID. We carried out a retrospective analysis of prospectively gathered data of adult patients who underwent elective spinal surgery between 1994 and 2009. A total of 244 patients were included. There were 125 men and 119 women with a mean age of 54 years (16 to 84); the mean follow-up was 62 months (6 to 199) The MCID was calculated using three previously published methods. Our results show that the value of the MCID varies considerably with the operation and its method of calculation. There was good correlation between the two external anchors. The global outcome tool correlated significantly better. We conclude that consensus needs to be reached on the best method of calculating the MCID. This then needs to be defined for each spinal procedure. Using a blanket value for the MCID for all spinal procedures should be avoided.


Identifying poor-quality hospitals. Can hospital mortality rates detect quality problems for medical diagnoses?
Many groups involved in health care are very interested in using external quality indices, such as risk-adjusted mortality rates, to examine hospital quality. The authors evaluated the feasibility of using mortality rates for medical diagnoses to identify poor-quality hospitals. The Monte Carlo simulation model was used to examine whether mortality rates could distinguish 172 average-quality hospitals from 19 poor-quality hospitals (5% versus 25% of deaths being preventable, respectively), using the largest diagnosis-related groups (DRGs) for cardiac, gastrointestinal, cerebrovascular, and pulmonary diseases as well as an aggregate of all medical DRGs. Discharge counts and observed death rates for all 191 Michigan hospitals were obtained from the Michigan Inpatient Database. Positive predictive value (PPV), sensitivity, and area under the receiver operating characteristic curve were calculated for mortality outlier status as an indicator of poor-quality hospitals. Sensitivity analysis was performed under varying assumptions about the time period of evaluation, quality differences between hospitals, and unmeasured variability in hospital casemix. For individual DRG groups, mortality rates were a poor measure of quality, even using the optimistic assumption of perfect casemix adjustment. For acute myocardial infarction, high mortality rate outlier status (using 2 years of data and a 0.05 probability cutoff) had a PPV of only 24%, thus, more than three fourths of those labeled poor-quality hospitals (high mortality rate outliers) actually would have average quality. If we aggregate all medical DRGs and continue to assume very large quality differences and perfect casemix adjustment, the sensitivity for detecting poor-quality hospitals is 35% and PPV is 52%. Even for this extreme case, the PPV is very sensitive to introduction of small amounts of unmeasured casemix differences between hospitals. Although they may be useful for some surgical diagnoses, DRG-specific hospital mortality rates probably cannot accurately detect poor-quality outliers for medical diagnoses. Even collapsing to all medical DRGs, hospital mortality rates seem unlikely to be accurate predictors of poor quality, and punitive measures based on high mortality rates frequently would penalize good or average hospitals.


Chemotherapy with or without selective internal radiation therapy for intrahepatic cholangiocarcinoma: Data from clinical trials.
In advanced, liver-only intrahepatic cholangiocarcinoma (iCCA), selective internal radiation therapy (SIRT) has been suggested as promising in nonrandomized studies. We aimed to compare data from patients with advanced, liver-only iCCA treated in the first line in clinical trials with either chemotherapy alone or the combination with SIRT. We collected individual patients' data from the ABC-01, ABC-02, ABC-03, BINGO, AMEBICA, and MISPHEC prospective trials. Data from patients with liver-only iCCA treated in chemotherapy-only arms of the first 5 trials were compared with data from patients treated with SIRT and chemotherapy in MISPHEC. Emulated target trial paradigm and Inverse Probability of Treatment Weighting (IPTW methods) using the propensity score were used to minimize biases. We compared 41 patients treated with the combination with 73 patients treated with chemotherapy alone, the main analysis being in 43 patients treated with cisplatin-gemcitabine or gemcitabine-oxaliplatin. After weighting, overall survival was significantly higher in patients treated with SIRT: median 21.7 months (95% CI: 14.1; not reached) versus 15.9 months(95% CI: 9.8; 18.9), HR = 0.59 (95% CI: 0.34; 0.99), p = 0.049. Progression-free survival was significantly improved: median 14.3 months (95% CI: 7.8; not reached) versus 8.4 months (95% CI: 5.9; 12.1), HR = 0.52 (95% CI: 0.31; 0.89), p < 0.001. Results were confirmed in most sensitivity analyses. This analysis derived from prospective clinical trials suggests that SIRT combined with chemotherapy might improve outcomes over chemotherapy alone in patients with advanced, liver-only iCCA. Randomized controlled evidence is needed to confirm these findings.


Is real-time elastography helpful to differentiate acute from subacute deep venous thrombosis? A preliminary study.
To detect and characterize changes in stiffness of thrombus in patients with acute and subacute deep venous thrombosis (DVT) by using real-time elastography (RTE). Fifty-eight patients with acute or subacute DVT were prospectively evaluated by B-mode sonography (US), color Doppler US (CDUS), and RTE. Two radiologists evaluated the thrombus echogenicity, compressibility, and recanalization of the affected vein, and thrombus stiffness in consensus. The thrombi were classified into 3 groups as soft, intermediate, and hard on RTE images. The final study group consisted of 30 patients with acute DVT, among whom 10 were women (33%), and 19 patients with subacute DVT, among whom 6 were women (32%). The presence of hypoechoic thrombus, incompressible vein, and absence of recanalization on US and CDUS were significantly associated with acute DVT (P < .001 for all variables). The differences in elasticity pattern of the thrombi between acute and subacute DVT were not significant (P = .202). Venous thrombus hardens with age; however, elastography pattern on RTE, in its present form, may not be able to differentiate acute DVT from subacute DVT.


Timescale halo: average-speed targets elicit more positive and less negative attributions than slow or fast targets.
Research on the timescale bias has found that observers perceive more capacity for mind in targets moving at an average speed, relative to slow or fast moving targets. The present research revisited the timescale bias as a type of halo effect, where normal-speed people elicit positive evaluations and abnormal-speed (slow and fast) people elicit negative evaluations. In two studies, participants viewed videos of people walking at a slow, average, or fast speed. We find evidence for a timescale halo effect: people walking at an average-speed were attributed more positive mental traits, but fewer negative mental traits, relative to slow or fast moving people. These effects held across both cognitive and emotional dimensions of mind and were mediated by overall positive/negative ratings of the person. These results suggest that, rather than eliciting greater perceptions of general mind, the timescale bias may reflect a generalized positivity toward average speed people relative to slow or fast moving people.


Executive function skills are associated with reading and parent-rated child function in children born prematurely.
Preterm children are at risk for executive function (EF) problems, which have been linked to behavior and learning problems in full term children. In this study, we examine the relationship between EF and functional outcomes in preterm children. To evaluate (1) EF skills of 9- to 16-year-old children born across the spectrum of gestational age (GA), (2) relationship of degree of prematurity to EF skills, and (3) contributions of EF skills to two functional outcomes - reading scores and parent-rated child function. Preterm children <36 weeks gestation (n=72) were compared to full term children (n=42) of similar age, gender and SES, on measures of EF, reading, and parent-ratings of child function. Multiple regression models evaluated contributions to EF skills and functional outcomes. Compared to full term controls, preterm children had poorer EF performance on a complex planning and organization task and did not increase planning time as task difficulty increased. Their spatial memory capacity was not different. GA contributed to EF skills, but was mediated by IQ. EF contributed to the variance in reading skills but did not add to the variance in reading when IQ was considered. EF skills significantly contributed to the variance in parent-rated child function, but IQ did not. EF skills contribute to measures of functional outcome in this high-risk population. The use of EF skills as an early marker for learning and functional problems and as a target for intervention in children born preterm warrants future study.


Beta cell expression of IGF-I leads to recovery from type 1 diabetes.
Patients with type 1 diabetes are identified after the onset of the disease, when beta cell destruction is almost complete. beta cell regeneration from islet cell precursors might reverse this disease, but factors that can induce beta cell neogenesis and replication and prevent a new round of autoimmune destruction remain to be identified. Here we show that expression of IGF-I in beta cells of transgenic mice (in both C57BL/6-SJL and CD-1 genetic backgrounds) counteracts cytotoxicity and insulitis after treatment with multiple low doses of streptozotocin (STZ). STZ-treated nontransgenic mice developed high hyperglycemia and hypoinsulinemia, lost body weight, and died. In contrast, STZ-treated C57BL/6-SJL transgenic mice showed mild hyperglycemia for about 1 month, after which they normalized glycemia and survived. After STZ treatment, all CD-1 mice developed high hyperglycemia, hypoinsulinemia, polydipsia, and polyphagia. However, STZ-treated CD-1 transgenic mice gradually normalized all metabolic parameters and survived. beta cell mass increased in parallel as a result of neogenesis and beta cell replication. Thus, our results indicate that local expression of IGF-I in beta cells regenerates pancreatic islets and counteracts type 1 diabetes, suggesting that IGF-I gene transfer to the pancreas might be a suitable therapy for this disease.


Effect of fucoidan on ethanol-induced liver injury and steatosis in mice and the underlying mechanism.
Alcoholic liver disease is caused as a result of chronic alcohol consumption. In this study, we used an alcoholic liver injury mouse model to investigate the effect of fucoidan on ethanol-induced liver injury and steatosis and the underlying mechanisms. All mice were randomly divided into four groups: 1) control group, 2) model group, 3) diammonium glycyrrhizinate treatment group (200 mg/kg body weight), and 4) fucoidan treatment group (300 mg/kg body weight). Administration of ethanol for 8 weeks induced liver injury and steatosis in mice. Fucoidan treatment decreased serum alanine aminotransferase activity, serum total cholesterol levels, and hepatic triglyceride levels, and improved the morphology of hepatic cells. Fucoidan treatment upregulated the expression of AMPKα1, SIRT1, and PGC-1α and inhibited the expression of ChREBP and HNF-1α. The levels of hepatic IL-6 and IL-18 were significantly decreased in the fucoidan group. Further, the levels of cytochrome P450-2E1 (CYP2E1), glucose-regulated protein (GRP) 78, and 3-nitrotyrosine (3-NT) in hepatic tissues were reduced in the fucoidan group as compared to the model group. Fucoidan significantly reversed the reduction of ileac Farnesoid X receptor (FXR) and fibroblast growth factor 15 (FGF15) levels induced by alcohol-feeding and reduced CYP7A1 (cholesterol 7α-hydroxylase) expression and total bile acid levels in the liver tissue. In addition, fucoidan regulated the structure of gut flora, with increased abundance of Prevotella and decreased abundance of Paraprevotella and Romboutsia as detected by 16S rDNA high-throughput sequencing. Fucoidan inhibited alcohol-induced steatosis and disorders of bile acid metabolism in mice through the AMPKα1/SIRT1 pathway and the gut microbiota-bile acid-liver axis and protected against alcohol-induced liver injury in vivo.


Differential partition of virulent Aeromonas salmonicida and attenuated derivatives possessing specific cell surface alterations in polymer aqueous-phase systems.
Two-polymer aqueous-phase systems were used to compare via partitioning the surface properties of strains of the fish pathogen Aeromonas salmonicida which differed in their ability to produce the surface protein array known as the A layer and in their ability to produce smooth lipopolysaccharide. In these two-phase systems, biological particles are known to partition between the phases in a manner related to a variety of surface properties, including hydrophobicity, charge, and lipid composition. Both the presence of the superficial protein layer and the O polysaccharide chains of lipopolysaccharide were shown to play an important role in the partitioning behavior of A. salmonicida cells. The presence of the A layer, which is crucial to the virulence of A. salmonicida, appeared to decrease the surface hydrophilicity of this pathogen and to increase, in a somewhat specific manner, its surface affinity for fatty acid esters of polyethylene glycol. The ability of two-polymer aqueous-phase systems to differentially partition A. salmonicida cells on the basis of differences in surface architecture suggests their general usefulness for the analysis of surface properties important in bacterial virulence and should permit their use in the selection of strains and mutants exhibiting specific surface characteristics.


Genetics of Bladder-Exstrophy-Epispadias Complex (BEEC): Systematic Elucidation of Mendelian and Multifactorial Phenotypes.
The Bladder-Exstrophy-Epispadias Complex (BEEC) represents the severe end of the uro-rectal malformation spectrum, and has a profound impact on continence, and on sexual and renal function. While previous reports of familial occurrence, in-creased recurrence among first-degree relatives, high concordance rates among monozygotic twins, and chromosomal aberra-tions were suggestive of causative genetic factors, the recent identification of copy number variations (CNVs), susceptibility regions and genes through the systematic application of array based analysis, candidate gene and genome-wide association studies (GWAS) provide strong evidence. These findings in human BEEC cohorts are underscored by the recent description of BEEC(-like) murine knock-out models. Here, we discuss the current knowledge of the potential molecular mechanisms, mediating abnormal uro-rectal development leading to the BEEC, demonstrating the importance of ISL1-pathway in human and mouse and propose SLC20A1 and CELSR3 as the first BEEC candidate genes, identified through systematic whole-exome sequencing (WES) in BEEC patients.


Implementation of the presence of companions during hospital admission for childbirth: data from the Birth in Brazil national survey.
Robust evidence of the benefits of continuous support during childbirth led to the recommendation that it should be offered for all women. In Brazil, it has been guaranteed by law since 2005, but scarce data on implementation is available. We aimed to estimate the frequency and associated socio-demographic, obstetric and institutional predictors of women having companionship during childbirth in the Birth in Brazil survey. Descriptive statistical analysis was done for the characterization of companions (at different moments of hospital stay), maternal and institutional factors; associations were investigated in bivariate and multivariate models. We found that 24.5% of women had no companion at all, 18.8% had continuous companionship and 56.7% had partial companionship. Independent predictors of having no or partial companionship at birth were: lower income and education, brown color of skin, using the public sector, multiparity, and vaginal delivery. Implementation of companionship was associated with having an appropriate environment, and clear institution al rules about women's rights to companionship.


First-episode genital herpes: interventions for men and women.
The mission of the Cochrane Nursing Care Field (CNCF) is to improve health outcomes through increasing the use of the Cochrane Library and supporting Cochrane's role by providing an evidence base for nurses and healthcare professionals who deliver, lead or research nursing care. The CNCF produces Cochrane Corner columns, summaries of recent nursing-care-relevant Cochrane Reviews that are regularly published in collaborating nursing-related journals. Information on the processes CNCF has developed can be accessed at: cncf.cochrane.org/evidence-transfer-program-review-summaries. This is a Cochrane review summary of: Heslop R, Roberts H, Flower D et al ( 2016 ) Interventions for men and women with their first episode of genital herpes. Cochrane Database of Systematic Reviews. Issue 8. CD010684. doi: 10.1002/14651858.CD010684.pub2.


Assessing the Validity and Cover Rate of the National Swedish Hernia Register.
To assess the validity and cover rate of the Swedish hernia register. Since the start of the Swedish Hernia register an annual review of randomly selected hospitals has been carried out, and since 2013 in a more standardized form to allow a systematic data collection and evaluation. 10% of all clinics were randomly selected each year in a specific region of Sweden, ensuring a systematic validation of all regions from north to south. Data from 2013 to 2018 were analyzed regarding data quality and from 2014 to 2018 regarding cover rate. All operations registered at the validated clinics were compared with the Swedish Hernia Register to assess cover rate. Fifty operations were randomly selected at each clinic and data in the Swedish Hernia register were compared with the medical records to evaluate data quality. Fifty-five clinics was evaluated and a total of 73,764 variables were compared with the medical records. Cover rate between 2014 and 2018 was 97%. The proportion of correct variables was 98% between 2013 and 2018. Most frequent errors were ASA score, date at which the patient was put on the waiting list and postoperative complications. This unique validation of a national hernia register shows a high cover rate and good quality of data. Efforts to maintain and improve national registers are of great importance. Research with data from the Swedish hernia register should be evaluated on the basis of the results presented in this study.


Assessment of analytical bias in ferritin assays and impact on functional reference limits.
Serum ferritin is currently the recommended laboratory test to investigate iron deficiency. There have been efforts to standardise serum ferritin assays with implementation of traceability to the World Health Organization reference standard. We evaluate the analytical bias among five widely used commercial ferritin assays in Australia. The relationship between serum ferritin and erythrocyte parameters was recently explored to derive functional reference limits. Residual patient serum specimens were analysed by five participating laboratories that utilised a different ferritin assay, Abbott, Beckman Coulter, Roche, Siemens, and Ortho. Using data mining approach, functional reference limits for Siemens, Abbott, and Ortho serum ferritin methods were derived and compared. At clinically relevant ferritin decision points, compared to the Beckman method, the Roche assay showed higher results ranging from 6 μg/L (31%) at the lowest decision point to 575 μg/L (57%) at the highest decision point. In contrast, the Ortho method underestimated ferritin results at lower decision points of 20 and 30 μg/L, with estimated ferritin results of 16 μg/L (-19%) and 27 μg/L (-12%), respectively. The Abbott and Siemens assays showed a positive bias which was introduced at differing decision points. The comparison of the Siemens and Ortho methods presents similar inflection points between the two assays in the establishment of functional reference limits for serum ferritin. There remain significant biases among some of the commonly used commercial ferritin assays in Australia. More studies are needed to assess if functional reference limits are a way to overcome method commutability issues.


Learning enhancement with neuropeptides.
Previous work has demonstrated that two synthetic peptides can prevent prenatal alcohol-induced damage as assessed by prevention of learning abnormalities in adult offspring as well as improve outcome from traumatic brain damage. The current studies were undertaken to evaluate whether these peptides could enhance performance in a learning and memory paradigm when administered either prenatally or to aged mice. For prenatal treatment, C57Bl6/J mice were treated on gestational day 8 with 1 oral administration of D-NAP or D-SAL alone or D-NAP+D-SAL or a double dose of D-SAL. Control groups were same-regimen treated with vehicle alone. Learning was assessed in adult male offspring (35-50 days) by using the Morris water maze. To evaluate aged animals, 12-month-old mice were treated with D-NAP and D-SAL or vehicle alone daily and tested on the Morris water maze. Offspring exposed prenatally to D-NAP+D-SAL learned significantly faster than controls, with an earlier onset of learning and an overall decreased latency to find the hidden platform (P < .05). Animals exposed prenatally to either D-NAP or D-SAL alone learned similar to control, with a trend toward faster latencies. Aged animals who received D-NAP+D-SAL learned significantly faster than age-matched controls, with an earlier onset of learning (P < .05). Combined D-NAP+D-SAL enhanced learning in healthy young mice and aged mice. These findings suggest potential therapeutic interventions not only during a critical developmental period, but also in aged animals.


The formation of exchangeable sulphite from adenosine 3'-phosphate 5'-sulphatophosphate in yeast.
A new low-molecular-weight bound sulphite was found in yeast enzyme reaction systems which convert the sulphur of 35S-labelled adenosine 3'-phosphate 5'-sulphatophosphate into exchangeable radioactive sulphite. This bound sulphite was separated from other components by paper electrophoresis and Sephadex G-25 chromatography, and shown to be a peptide with multiple thiol groups and an estimated mol.wt. of 1400. The labelled sulphur in this peptide is highly exchangeable with unlabelled sulphite, but exchangeability decreases with time and freeze-drying. The low-molecular-weight acceptor is tightly bound to enzyme B of the yeast system and, apparently, accepts the sulpho group of adenosine 3'-phosphate 5'-sulphatophosphate and is released as bound sulphite only in the presence of enzymically or chemically reduced fraction C. It is proposed that the low-molecular-weight acceptor is a carrier peptide which, after release of the reduced sulphur, becomes re-oxidized and returns to enzyme B. Fraction C appears to function as an obligatory reductant of the oxidized acceptor before it can accept another-SO-3-moiety from adenosine 3'-phosphate 5'-sulphatophosphate. These findings are consistent with mechanisms proposed for sulphate reduction in spinach and Chlorella, and suggest that fraction C is the natural thiol required in these systems. An improved column technique for the preparation of adenosine 3'-phosphate 5'-sulphatophosphate is described.


hnRNP H and hnRNP F complex with Fox2 to silence fibroblast growth factor receptor 2 exon IIIc.
The heterogeneous nuclear ribonucleoprotein H (hnRNP) family of proteins has been shown to activate exon inclusion by binding intronic G triplets. Much less is known, however, about how hnRNP H and hnRNP F silence exons. In this study, we identify hnRNP H and hnRNP F proteins as being novel silencers of fibroblast growth factor receptor 2 exon IIIc. In cells that normally include this exon, we show that the overexpression of either hnRNP H1 or hnRNP F resulted in the dramatic silencing of exon IIIc. In cells that normally skip exon IIIc, skipping was disrupted when RNA interference was used to knock down both hnRNP H and hnRNP F. We show that an exonic GGG motif overlapped a critical exonic splicing enhancer, which was predicted to bind the SR protein ASF/SF2. Furthermore, the expression of ASF/SF2 reversed the silencing of exon IIIc caused by the expression of hnRNP H1. We show that hnRNP H and hnRNP F proteins are present in a complex with Fox2 and that the presence of Fox allows hnRNP H1 to better compete with ASF/SF2 for binding to exon IIIc. These results establish hnRNP H and hnRNP F as being repressors of exon inclusion and suggest that Fox proteins enhance their ability to antagonize ASF/SF2.


Inhibition of aflatoxin B1-hepatocarcinogenesis in rats by beta-naphthoflavone.
Effects of beta-naphthoflavone (beta NF) on the activity of hepatic microsomal aflatoxin B1 (AFB1)-4-hydroxylase - the cytochrome P-450-dependent enzyme system which catalyzes the metabolism of AFB1 to AFM1 - and on AFB1-induced in vivo hepatocarcinogenesis were investigated in weanling male Fischer rats. A single i.p. injection of beta NF in doses of 20 mg/kg and 150 mg/kg induced AFB1-4-hydroxylase 3- and 4-fold, respectively, 48 h post injection. Feeding of diet containing 0.01% beta NF for a period of 9-weeks induced AFB1-4-hydroxylase approximately 2-fold. AFB1, given by intubation in a dose of 25 micrograms five times/week for 8 weeks, produced 42 weeks later a 100% incidence of liver lesions (neoplastic foci, nodules or tumors), but feeding beta-NF in diet at a concentration of 0.015% for one week prior to and during the 8 weeks of AFB1 treatment inhibited AFB1 hepatocarcinogenesis by approximately 75%. These results are in accord with the suggestion that AFB1-4-hydroxylase induction may be associated with the inhibition of AFB1 carcinogenesis, possibly occurring as a consequence of accelerated detoxification of AFB1 via its conversion to AFM1.


Accurate adventitia reconstruction; significant or not in atherosclerotic plaque growth simulationsƒ A comparative study.
A reform in the diagnosis and treatment process is urgently required as carotid artery disease remains a leading cause of death in the world. To this purpose, all computational techniques are now being applied to enhancing the most cutting-edge diagnosis techniques. Computational modeling of plaque generation and evolution is being refined over the past years to forecast the atherosclerotic progression and the corresponding risk in patient-specific carotid arteries. A prerequisite to their implementation is the reconstruction of the precise three-dimensional models of patient-specific main carotid arteries. Even with the most sophisticated algorithms, accurate reconstruction of the arterial vessel is frequently difficult. Furthermore, there are several works of plaque growth modeling that ignore the reconstruction of the artery's outer layer in favor of a virtual one. In this paper, we investigate the importance of an accurate adventitia layer in plaque growth modeling. This is done as a comparative study by implementing a novel plaque growth model in two reconstructed carotid arterial segments using either their realistic or virtual adventitia layer as input. The results indicate that accurate adventitia reconstruction is of minor importance regarding species distributions and plaque growth in carotid segments, which initially did not contain any plaque regions.Clinical Relevance- The findings of this comparative study emphasize the importance of precise adventitia geometry in plaque growth modeling. As a result, this work sets a higher standard for publishing new plaque growth models.


Circadian Gene Selection for Time-to-event Phenotype by Integrating CNV and RNAseq Data.
The endogenous circadian clock, which controls daily rhythms in the expression of at least half of the mammalian genome, has a major influence on cell physiology. Consequently, disruption of the circadian system is associated with wide range of diseases including cancer. While several circadian clock genes have been associated with cancer progression, little is known about the survival when two or more platforms are considered together. Our goal was to determine if survival outcomes are associated with circadian clock function. To accomplish this goal, we developed a Bayesian hierarchical survival model coupled with the global local shrinkage prior and applied this model to available RNASeq and Copy Number Variation data to select significant circadian genes associates with cancer progression. Using a Bayesian shrinkage approach with the Bayesian accelerated failure time (AFT) model we showed the circadian clock associated gene DEC1 is positively correlated to survival outcome in breast cancer patients. The R package circgene implementing the methodology is available at https://github.com/MAITYA02/circgene. The proposed Bayesian hierarchical model is the first shrinkage prior based model in its kind which integrates two omics platforms to identify the significant circadian gene for cancer survival.


A 5-year retrospective study of canine and feline patients referred to an isolation unit for infectious diseases.
Referral of cases is becoming more and more frequent in companion animal practice. The Infectious Diseases Isolation Unit (IDIU) admits first opinion, second opinion and referred patients with a confirmed infectious disease (ID) or a clinically suspected ID that is awaiting laboratory diagnosis. The primary aims of this study were to describe the annual number and characteristics of patients referred to the IDIU and identify the most frequent IDs in referred dogs and cats. A secondary aim was to investigate possible differences in the length of the hospitalisation and the clinical outcome among referred cases and those admitted to the IDIU after first and second opinion appointments. A retrospective study was carried out on patients hospitalised at the unit over 5 years from 9th October 2013 to 31st December 2018. The study population consisted of 365 dogs and 515 cats to give a total of 880 patients hospitalised at the IDIU from October 2013 to December 2018. Among the 96 referred dogs, parvovirosis (37.7%) and leptospirosis (31.1%) were the most frequent IDs. Feline upper respiratory tract infection (38.2%) and feline leukaemia virus infections (36.4%) were the main causes in the 80 referred cats. Worrying noncompliance rates of dog (51.0%) and cat (52.5%) vaccination schedules were identified. The analysis of the length of hospitalisation in the three groups of patients was not statistically different. In both animal species there were statistically significant higher clinical discharge rates on the first opinion patients' group in comparison to referred patients and the second opinion group. Parvovirosis and leptospirosis in dogs and upper respiratory disease and feline leukaemia virus infection in cats were the most common diagnoses for patients admitted to the IDIU, reinforcing the need for accurate vaccination. Discharge rates results pinpoint the need for timely accurate reference.


Impact of GLP-1 receptor agonists on major gastrointestinal disorders for type 2 diabetes mellitus: a mixed treatment comparison meta-analysis.
We aimed to integrate evidence from all randomized controlled trials (RCTs) and assess the impact of different doses of exenatide or liraglutide on major gastrointestinal adverse events (GIAEs) in type 2 diabetes (T2DM). RCTs evaluating different doses of exenatide and liraglutide against placebo or an active comparator with treatment duration ≥4 weeks were searched and reviewed. A total of 35, 32 and 28 RCTs met the selection criteria evaluated for nausea, vomiting, and diarrhea, respectively. Pairwise random-effects meta-analyses and mixed treatment comparisons (MTC) of all RCTs were performed. All GLP-1 dose groups significantly increased the probability of nausea, vomiting and diarrhea relative to placebo and conventional treatment. MTC meta-analysis showed that there was 99.2% and 85.0% probability, respectively, that people with exenatide 10 μg twice daily (EX10BID) was more vulnerable to nausea and vomiting than those with other treatments. There was a 78.90% probability that liraglutide 1.2 mg once daily (LIR1.2) has a higher risk of diarrhea than other groups. A dose-dependent relationship of exenatide and liraglutide on GIAEs was observed. Our MTC meta-analysis suggests that patients should be warned about these GIAEs in early stage of treatment by GLP-1s, especially by EX10BID and LIR1.2, to promote treatment compliance.


Identity of the amino acid residues involved in C3bi binding to the I-domain supports a mosaic model to explain the broad ligand repertoire of integrin alpha M beta 2.
Interactions between the complement degradation product C3bi and leukocyte integrin alpha(M)beta(2) are critical for host defense against foreign pathogens and in tumor cell surveillance. To gain insight into the mechanism by which the alpha(M)I-domain of the integrin interacts with C3bi, detailed mapping of the C3bi binding site was undertaken. Previous mutagenesis studies had implicated five small structural segments within the alpha(M)I-domain in recognition of this ligand. Sets of three amino acids within the five implicated segments were mutated to the corresponding alpha(L)I-domain residues. Then, within the affected mutants, single point mutations were introduced to precisely define the requisite residues. Ultimately, H148, F150, Q204, L205, R208, T211, T213, I256, P257 were identified as being critical for C3bi binding. A synthetic peptide approach confirmed the involvement of the specified residues with the complex midsegment, Q204-I215, in C3bi recognition. Furthermore, the alpha(D)I-domain, which has a low intrinsic affinity for C3bi, acquired high affinity for the ligand when the implicated residues were inserted. The residues necessary to engage C3bi reside on or adjacent to the cation binding MIDAS site of the alpha(M)I-domain. The amino acids involved in C3bi binding are distinct from those involved in interaction of previously mapped ligands with the alpha(M)I-domain. This divergence supports a mosaic model, in which different ligands engage different amino acids to bind to alpha(M)I-domain, accounting for the broad recognition capacity of integrin alpha(M)beta(2).


N (6)-substituted AMPs inhibit mammalian deoxynucleotide N-hydrolase DNPH1.
The gene dnph1 (or rcl) encodes a hydrolase that cleaves the 2'-deoxyribonucleoside 5'-monophosphate (dNMP) N-glycosidic bond to yield a free nucleobase and 2-deoxyribose 5-phosphate. Recently, the crystal structure of rat DNPH1, a potential target for anti-cancer therapies, suggested that various analogs of AMP may inhibit this enzyme. From this result, we asked whether N (6)-substituted AMPs, and among them, cytotoxic cytokinin riboside 5'-monophosphates, may inhibit DNPH1. Here, we characterized the structural and thermodynamic aspects of the interactions of these various analogs with DNPH1. Our results indicate that DNPH1 is inhibited by cytotoxic cytokinins at concentrations that inhibit cell growth.


Multimodal In Vivo Skin Imaging with Integrated Optical Coherence and Multiphoton Microscopy.
In this paper, we demonstrate high-resolution, multimodal in vivo imaging of human skin using optical coherence (OCM) and multiphoton microscopy (MPM). These two modalities are integrated into a single instrument to enable simultaneous acquisition and coregistration. The system design and the OCM image processing architecture enable sufficient performance of both modalities for in vivo imaging of human skin. Examples of multimodal in vivo imaging are presented as well as time lapse imaging of blood flow in single capillary loops. By making use of multiple intrinsic contrast mechanisms this integrated technique improves the ability to noninvasively visualize living tissue. Integrated OCM and MPM has potential applications for in vivo diagnosis of various pathological skin conditions, such as skin cancer, as well as potential pharmaceutical and cosmetic research applications.


A possible essential role for dietary linolenic acid in the development of the young rat.
Female rats were fed semi-purified diets containing 10% safflower oil or 10% soybean oil for six weeks prior to mating and through-out pregnancy and lactation. The progeny were weaned to the diet of the dam. Physical, neuromotor and reflex development was monitored in the progeny prior to weaning and learning ability of the mature progeny was assessed in a simple Y-maze test. Brain lipid analyses were conducted in the progeny at birth, 21 and 210 days of age. Inclusion of soybean oil in the diet resulted in higher levels of 22:6omega3 and lower levels of 22:5omega6 in the brain ethanolamine glycerophosphatides. The nature of the dietary fat exerted no effect on the physical development, onset of reflexologic responses or onset of neuromotor co-ordination in the pups. The soybean oil-fed animals spent more time in certain neuromotor activities possibly associated with explorative drive than did their safflower oil-fed counterparts. The performance of the mature soybean oil-fed progeny in the discrimination-learning test was superior to that of progeny fed safflower oil. The association of superior learning capacity with dietary soybean oil-induced incorporation of omega3 fatty acids into the brain glycerophosphatides is offered as support for an essential role for dietary linolenic acid for the young rat.