The major bactericidal activity of human seminal plasma is zinc-dependent and derived from fragmentation of the semenogelins.
One of the major roles of seminal plasma is to provide antimicrobial protection for the spermatozoa in the female reproductive tract. We found that the bactericidal activity of seminal plasma was highest after resolution of the seminal clot and that this antibacterial activity subsequently became greatly diminished. The antibacterial activity was derived from peptides generated by fragmentation of the semenogelins while the semenogelin holoproteins displayed no antibacterial activity. After ejaculation the semenogelin-derived peptides were fragmented to smaller and smaller fragments over time and thereby lost antibacterial activity. This paralleled the loss of antibacterial activity of whole seminal plasma both in vitro and after sexual intercourse. Moreover, the antibacterial activity of the semenogelin-derived peptides generated in seminal plasma was strictly zinc-dependent both at neutral and low pH. These data provide novel roles for the resolution of seminal clots and for the high zinc concentration in human seminal plasma.


Phylogeography, population history and conservation genetics of jaguars (Panthera onca, Mammalia, Felidae).
The jaguar (Panthera onca), the largest felid in the American Continent, is currently threatened by habitat loss, fragmentation and human persecution. We have investigated the genetic diversity, population structure and demographic history of jaguars across their geographical range by analysing 715 base pairs of the mitochondrial DNA (mtDNA) control region and 29 microsatellite loci in approximately 40 individuals sampled from Mexico to southern Brazil. Jaguars display low to moderate levels of mtDNA diversity and medium to high levels of microsatellite size variation, and show evidence of a recent demographic expansion. We estimate that extant jaguar mtDNA lineages arose 280 000-510 000 years ago (95% CI 137 000-830 000 years ago), a younger date than suggested by available fossil data. No strong geographical structure was observed, in contrast to previously proposed subspecific partitions. However, major geographical barriers such as the Amazon river and the Darien straits between northern South America and Central America appear to have restricted historical gene flow in this species, producing measurable genetic differentiation. Jaguars could be divided into four incompletely isolated phylogeographic groups, and further sampling may reveal a finer pattern of subdivision or isolation by distance on a regional level. Operational conservation units for this species can be defined on a biome or ecosystem scale, but should take into account the historical barriers to dispersal identified here. Conservation strategies for jaguars should aim to maintain high levels of gene flow over broad geographical areas, possibly through active management of disconnected populations on a regional scale.


Osteosarcoma tumor thrombus: a case report with a review of the literature.
Tumor thrombus arising from osteosarcoma is rare. We report the case of a 20-year-old man with proximal humerus osteosarcoma, accompanied by an extensive intravascular tumor thrombus extending into the heart. Our review of the literature found 14 previous reports on osteosarcoma with tumor thrombus. The combination of positron emission tomography and computed tomography is very useful in differentiating tumor thrombus from vascular thrombus, thereby avoiding unnecessary anticoagulation therapy. This same imaging combination can also be used to evaluate the response to treatment. Surgical resection of the tumor thrombus is highly recommended. The effect of tumor thrombus on survival is still unknown.


[Alcohol consumption and stress in second year nursing students].
The aim of this study was to identify the consumption of alcohol and academic stress in nursing students. This was a descriptive, cross-sectional study, performed in 2005. The questionnaires Academic Stress Inventory and AUDIT were applied to 82 students of a private University in Lima, Peru. The students had a mean age of 20.4 years, 92.7% were single, 69.5% did not work, 91.5% had no children and 86.6% lived with their parents. The academic overload represented the stressor of highest prevalence. Regarding the consumption of alcohol, 56.1% consumed alcohol once a month, 48.0% consumed 1-2 glasses a day, and 51.2% more than three glasses during a normal day; 11.0% failed to comply with their obligations. One third reported smoking, drinking or eating in excess. All situations, related to the factor activity/time, generated various levels of stress, with worry reported as the main response to stress.


Impact of early statin therapy in patients with ischemic stroke or transient ischemic attack.
Statin therapy has demonstrated benefits in ischemic stroke patients. However, little is known about whether the timing of statin initiation affects clinical outcomes. The possible association of statin use and cerebral hemorrhage is also a concern for early statin therapy after stroke. The objective of this study was to evaluate the efficacy and safety of the initiation timing of statins in acute ischemic stroke. A cohort study was performed using 5-year National Health Insurance Research Database in Taiwan. Patients without prior statin therapy admitted for their new ischemic stroke or transient ischemic attack (TIA) were enrolled. Patients were recognized as inhospital use group (2019 patients, statin initiation during hospitalization), intermediate use group (2266 patients, statin initiation within 1 year after discharge) or late use group (2958 patients, statin initiation 1 year later after discharge). The study endpoint was the composite outcome of ischemic stroke, TIA, hemorrhagic stroke, or acute coronary event. As compared with inhospital use, patients with late use had a 49% increased risk (adjusted HR: 1.49, 95% CI: 1.26-1.76) of composite endpoint. In contrast, patients with intermediate use had similar risk of endpoint as those with inhospital use. The risk of cerebral hemorrhage was similar in patients receiving inhospital, intermediate, or late statin treatment. In acute ischemic stroke, patients receiving late statin treatment carried a poorer clinical outcome than those with earlier statin initiation. Inhospital statin use after an acute ischemic stroke did not increase the risk of cerebral hemorrhage.


[Immunohistochemical expression of P53 suppressor genes and retinoblastoma in laryngeal carcinoma].
Carcinoma of the larynx is responsible for 1% of all tumors and for 25% of oncologic disease of the head and neck. Tumor suppressor genes control cell proliferation by suppressing specific mechanisms that stimulate the proliferative response. Rb and p53, both nuclear, are the most studied tumor suppressor genes. We evaluated the immunoexpression of these markers in 72 carcinomas of the larynx and correlated it with patients' clinical parameters: age, sex, occupation, tobacco and alcohol use, marital status, etc. Biological and anatomopathological parameters (tumor stage, histological type, degree of local invasion, and lymph node metastases) also were studied. Statistically significant differences were found in mean immunostaining for the Rb gene with respect to histological grade, lymph node enlargement, and smoking. We observed no positive correlation between p53 and the classic clinical-pathological parameters, although important trends were evident, as well as relatively frequent immunostaining (about 40%) of the total neoplastic population.


Short-Term Memory for Serial Order Moderates Aspects of Language Acquisition in Children With Developmental Language Disorder: Findings From the HelSLI Study.
Previous studies of verbal short-term memory (STM) indicate that STM for serial order may be linked to language development and developmental language disorder (DLD). To clarify whether a domain-general mechanism is impaired in DLD, we studied the relations between age, non-verbal serial STM, and language competence (expressive language, receptive language, and language reasoning). We hypothesized that non-verbal serial STM differences between groups of children with DLD and typically developing (TD) children are linked to their language acquisition differences. Fifty-one children with DLD and sixty-six TD children participated as part of the HelSLI project in this cross-sectional study. The children were 4-6-year-old monolingual native Finnish speakers. They completed several tests of language and cognitive functioning, as well as new game-like tests of visual and auditory non-verbal serial STM. We used regression analyses to examine how serial STM moderates the effect of age on language. A non-verbal composite measure of serial visual and auditory STM moderated cross-sectional development of receptive language in the children with DLD. This moderation was not observed in the TD children. However, we found more rapid cross-sectional development of non-verbal serial STM in the TD children than in the children with DLD. The results suggest that children with DLD may be more likely to have compromised general serial STM processing and that superior non-verbal serial STM may be associated with better language acquisition in children with DLD.


Nanopatterned Extracellular Matrices Enable Cell-Based Assays with a Mass Spectrometric Readout.
Cell-based assays are finding wider use in evaluating compounds in primary screens for drug development, yet it is still challenging to measure enzymatic activities as an end point in a cell-based assay. This paper reports a strategy that combines state-of-the-art cantilever free polymer pen lithography (PPL) with self-assembled monolayer laser desorption-ionization (SAMDI) mass spectrometry to guide cell localization and measure cellular enzymatic activities. Experiments are conducted with a 384 spot array, in which each spot is composed of ∼400 nanoarrays and each array has a 10 × 10 arrangement of 750 nm features that present extracellular matrix (ECM) proteins surrounded by an immobilized phosphopeptide. Cells attach to the individual nanoarrays, where they can be cultured and treated with small molecules, after which the media is removed and the cells are lysed. Phosphatase enzymes in the proximal lysate can then act on the immobilized phosphopeptide substrate to convert it to the dephosphorylated form. After the lysate is removed, the array is analyzed by SAMDI mass spectrometry to identify the extent of dephosphorylation and, therefore, the amount of enzyme activity in the cell. This novel approach of using nanopatterning to mediate cell adhesion and SAMDI to record enzyme activities in the proximal lysate will enable a broad range of cellular assays for applications in drug discovery and research not possible with conventional strategies.


Quantification of mitochondrial DNA copy number in suspected cancer patients by a well optimized ddPCR method.
Changes in mitochondrial DNA (mtDNA) content is a useful clinical biomarker for various diseases, however results are controversial as several analytical factors can affect measurement of mtDNA. MtDNA is often quantified by taking ratio between a target mitochondrial gene and a reference nuclear gene (mtDNA/nDNA) using quantitative real time PCR often on two separate experiments. It measures relative levels by using external calibrator which may not be comparable across laboratories. We have developed and optimized a droplet digital PCR (ddPCR) based method for quantification of absolute copy number of both mtDNA and nDNA gene in whole blood. Finally, the role of mtDNA in suspected cancer patients referred to a cancer diagnostic center was investigated. Analytical factors which can result in false quantification of mtDNA have been optimized and both target and reference have been quantified simultaneously with intra- and inter-assay coefficient variances as 3.1% and 4.2% respectively. Quantification of mtDNA show that compared to controls, solid tumors (but not hematologic malignancies) and other diseases had significantly lower copy number of mtDNA. Higher mtDNA (highest quartile) was associated with a significantly lower risk of both solid tumors and other diseases, independent of age and sex. Receiver operating curve demonstrated that mtDNA levels could differentiate controls from patients with solid tumors and other diseases. Quantification of mtDNA by a well optimized ddPCR method showed that its depletion may be a hallmark of general illness and can be used to stratify healthy individuals from patients diagnosed with cancer and other chronic diseases.


Multi-way backpropagation for training compact deep neural networks.
Depth is one of the key factors behind the success of convolutional neural networks (CNNs). Since ResNet (He et al., 2016), we are able to train very deep CNNs as the gradient vanishing issue has been largely addressed by the introduction of skip connections. However, we observe that, when the depth is very large, the intermediate layers (especially shallow layers) may fail to receive sufficient supervision from the loss due to severe transformation through long backpropagation path. As a result, the representation power of intermediate layers can be very weak and the model becomes very redundant with limited performance. In this paper, we first investigate the supervision vanishing issue in existing backpropagation (BP) methods. And then, we propose to address it via an effective method, called Multi-way BP (MW-BP), which relies on multiple auxiliary losses added to the intermediate layers of the network. The proposed MW-BP method can be applied to most deep architectures with slight modifications, such as ResNet and MobileNet. Our method often gives rise to much more compact models (denoted by "Mw+Architecture") than existing methods. For example, MwResNet-44 with 44 layers performs better than ResNet-110 with 110 layers on CIFAR-10 and CIFAR-100. More critically, the resultant models even outperform the light models obtained by state-of-the-art model compression methods. Last, our method inherently produces multiple compact models with different depths at the same time, which is helpful for model selection. Extensive experiments on both image classification and face recognition demonstrate the superiority of the proposed method.


[Kidney involvement in infectious endocarditis (hematuria)].
As many as 113 patients suffering from infectious endocarditis (IE) were placed under observation. Renal damage was discovered in 28 patients (24.7%). Hematuria was the common laboratory sign of renal damage. 15% of patients showed microhematuria, 9.7 had macrohematuria. In 15% of patients with IE, hematuria was due to diffuse glomerulonephritis, in 5.3% to renal infarction, and in 4.4% to focal glomerulonephritis. In 3.5% of patients, the nephrotic syndrome developed at the disease onset, it was attended by hematuria and was thus a cause of erroneous diagnoses. The appearance of hematuria at the IE onset, attesting to involvement of the kidneys into the pathological process, complicates the diagnosis and early treatment institution. Detection of the hematuric syndrome in patients with a verified diagnosis of IE requires specification of the character of renal damage. The latter one contributes to a graver and prognostically unfavourable course of IE. In 2 out of 8 patients with associated IE and renal damage, the death was caused by progressive chronic renal failure. Postmortem examination confirmed mesangioproliferative glomerulonephritis in all the subjects; in 4, it was coupled with renal infarction. 14.1% of the patients manifested complete and 3.5% partial disappearance of hematuria under the influence of adequate antibacterial therapy of IE.


Lithium and neuroleptics in combination: the spectrum of neurotoxicity [corrected].
Classifying neurotoxicity in relation to neuroleptic use has been a longstanding concern with clinical, research, and epidemiologic import. This study examines the clinical manifestations of neurotoxicity and current concepts regarding its classification. The Food and Drug Administration (FDA) Spontaneous Reporting System data base and extant literature were reviewed for lithium/neuroleptic neurotoxicity spectrum cases. Lithium-alone (LI), lithium/haloperidol (LiHal), and lithium/non-haloperidol neuroleptics (Li-NonHal) groups, each paired for recovery and sequelae, were established for 237 cases. Data on demographic factors, psychiatric diagnosis, and symptoms/signs/findings were tabulated. Neuroleptic malignant syndrome (NMS) was used as a paradigm for severe neurotoxicity; the cases were evaluated by two strict, published sets of NMS diagnostic criteria and two "probable" classifications (one published and one established for study) based on these criteria. Altered consciousness was prominent in all groups. Hypertonia/rigidity was most pronounced in both LiHal groups, possibly reflecting higher relative neuroleptic dosing; Li and LINonHal recovery and sequelae pairs showed lower, similar percentages. Among other physical findings, tremor was either most common or prominent. Neither set of strict criteria diagnosed NMS in more than 30 percent of cases in any group. Expansion of classifications to include "probable" diagnoses resulted in appreciable global group percentage increases for only one set of criteria. The high percentage of study cases not meeting even "probable" NMS criteria, despite marked clinical morbidity that at times resulted in permanent sequelae, provides a cautionary note regarding the limitations of formulated diagnostic criteria. Data base caveats notwithstanding, study findings support the consideration of a spectrum approach to classifying and diagnosing psychotropic-related neurotoxicity.


Small-molecule CEM3 strengthens single-cell oscillators in the suprachiasmatic nucleus.
A robust endogenous clock is required for proper function of many physiological processes. The suprachiasmatic nucleus (SCN) constitutes our central circadian clock and allows us to adapt to daily changes in the environment. Aging can cause a decline in the amplitude of circadian rhythms in SCN and peripheral clocks, which contributes to increased risk of several chronic diseases. Strengthening clock function would therefore be an effective strategy to improve health. A high-throughput chemical screening has identified clock-enhancing molecule 3 (CEM3) as small molecule that increases circadian rhythm amplitude in cell lines and SCN explants. It is, however, currently not known whether CEM3 acts by enhancing the amplitude of individual single-cell oscillators or by enhancing synchrony among neurons. In view of CEM3's potential, it is of evident importance to clarify the mode of action of CEM3. Here, we investigated the effects of CEM3 on single-cell PERIOD2::LUCIFERASE rhythms in mouse SCN explants. CEM3 increased the amplitude in approximately 80%-90% of the individual cells in the SCN without disrupting the phase and/or period of their rhythms. Noticeably, CEM3's effect on amplitude is independent of the cell's initial amplitude. These findings make CEM3 a potential therapeutic candidate to restore compromised amplitude in circadian rhythms and will boost the development of other molecular approaches to improve health.


Differential regulation of cyclooxygenases 1 and 2 by interleukin-1 beta, tumor necrosis factor-alpha, and transforming growth factor-beta 1 in human lung fibroblasts.
In the present studies we found that incubation of human lung fibroblasts with transforming growth factor-beta 1 (TGF-beta 1) potentiated the interleukin-1 beta (IL-1 beta) and/or tumor necrosis factor-alpha (TNF-alpha)-stimulated production of prostaglandin E2 (PGE2). Analysis of fibroblast proteins showed the induction of cyclooxygenase-1 (Cox-1) by TGF-beta 1 and the induction of Cox-2 by IL-1 beta and TNF-alpha. The levels of transcripts for Cox-1 were minimally modified by IL-1 beta or TNF-alpha, however, they were increased by 12-fold by TGF-beta 1. Transcripts for Cox-2 were induced by IL-1 beta or TNF-alpha and their induction was potentiated by TGF-beta 1. TGF-beta 1 alone did not induce Cox-2 transcripts. In vitro transcription assays showed that IL-1 beta and TNF-alpha increased the transcription of the Cox-2 gene, whereas TGF-beta 1 had no effect. Addition of TGF-beta did not increase further the transcription of Cox-2 in IL-1 beta-treated cells, but increased the stability of the corresponding transcripts. The transcription rate of the Cox-1 gene was not increased by any of the cytokines studied. In summary, we demonstrate that the potentiation of PGE2 production by TGF-beta 1 in IL-1 beta and TNF-alpha-treated fibroblasts is the result of transcriptional stimulation of the Cox-2 gene by IL-1 beta and TNF-alpha and the stabilization of the resulting transcripts by TGF-beta 1.


Genomic signatures of the haarlem lineage of Mycobacterium tuberculosis: implications of strain genetic variation in drug and vaccine development.
Tuberculosis is the world's leading cause of death due to a single infectious agent, and efforts aimed at its control require a better understanding of host, environmental, and bacterial factors that govern disease outcome. Growing evidence indicates that certain Mycobacterium tuberculosis strains of distinct phylogeographic lineages elicit unique immunopathological events. However, identifying the genetic basis of these phenotypic peculiarities has proven difficult. Here we report the presence of six large sequence polymorphisms which, together with two single-nucleotide changes previously described by our group, consistently differentiate Haarlem strains from the remaining M. tuberculosis lineages. The six newly found Haarlem-specific genetic events are four deletions, which altogether involve more than 13 kb, and two intragenic insertions of the element IS6110. The absence of the genes involved in these polymorphisms could have an important physiological impact on Haarlem strains, i.e., by affecting key genes, such as Rv1354c and cyp121, which have been recently proposed as plausible drug targets. These lineage-specific polymorphisms can serve as genetic markers for the rapid PCR identification of Haarlem strains, providing a useful tool for strain surveillance and molecular epidemiology studies. Strain variability such as that described here underscores the need for the definition of a core set of essential genes in M. tuberculosis that are ubiquitously present in all circulating lineages, as a requirement in the development of effective antituberculosis drugs and vaccines.


Modulations of cognitive flexibility in obsessive compulsive disorder reflect dysfunctions of perceptual categorization.
Despite cognitive inflexibility is trait like in obsessive compulsive disorder (OCD) patients and underlies clinical symptomatology, it is elusive at what stage of information processing deficits, leading to cognitive inflexibility, emerges. We hypothesize that inhibitory control mechanisms during early stimulus categorization and integration into a knowledge system underlie these deficits. We examined N = 25 adolescent OCD patients and matched healthy controls (HC) in a paradigm manipulating the importance of the knowledge system to perform task switching. This was done using a paradigm in which task switches were signaled either by visual stimuli or by working memory processes. This was combined with event-related potential recordings and source localization. Obsessive compulsive disorder patients showed increased switch costs in the memory as compared with the cue-based block, while HC showed similar switch costs in both blocks. At the neurophysiological level, these changes in OCD were not reflected by the N2 and P3 reflecting response-associated processes but by the P1 reflecting inhibitory control during sensory categorization processes. Activation differences in the right inferior frontal gyrus and superior temporal gyrus are associated with the P1 effect. Cognitive flexibility in adolescent OCD patients is strongly modulated by working memory load. Contrary to common sense, not response-associated processes, but inhibitory control mechanisms during early stimulus categorization processes are likely to underlie cognitive inflexibility in OCD. These processes are associated with right inferior frontal and superior temporal gyrus mechanisms.


Feelings don't come easy: studies on the effortful nature of feelings.
We propose that experience of emotion is a mental phenomenon, which requires resources. This hypothesis implies that a concurrent cognitive load diminishes the intensity of feeling since the 2 activities are competing for the same resources. Two sets of experiments tested this hypothesis. The first line of experiments (Experiments 1-4) examined the intensity of participants' feelings as they performed a secondary (backward counting) task. The results showed that the intensity of both negative and positive feelings diminished under a cognitive load and that this attenuation of feeling was not mediated by either distraction from external stimuli or demand characteristics. In the second set of experiments (Experiments 5-6), load was created by asking the participants to focus on the feelings. Even in these circumstances, the participants who were under load reported a lower intensity of feeling than those who were not under load. We explain these findings in terms of a resource-dependent model of emotional experience. Possible implications of our findings for a broader class of phenomenological experiences are succinctly discussed.


Cavity-QED Quantum Simulator of Dynamical Phases of a Bardeen-Cooper-Schrieffer Superconductor.
We propose to simulate dynamical phases of a BCS superconductor using an ensemble of cold atoms trapped in an optical cavity. Effective Cooper pairs are encoded via the internal states of the atoms, and attractive interactions are realized via the exchange of virtual photons between atoms coupled to a common cavity mode. Control of the interaction strength combined with a tunable dispersion relation of the effective Cooper pairs allows exploration of the full dynamical phase diagram of the BCS model as a function of system parameters and the prepared initial state. Our proposal paves the way for the study of the nonequilibrium features of quantum magnetism and superconductivity by harnessing atom-light interactions in cold atomic gases.


Addressing older people's mental health needs in the community setting.
It is estimated that more than one third of older people may experience problems with their mental health. While, in some of these cases, people will be able to self-manage with little or no support, individuals who are socially isolated or physically unwell may experience significant mental distress. Community nurses are ideally placed to identify mental health problems in patients who are housebound, and to make appropriate referrals. Yet many nurses report apprehension regarding a perceived lack of knowledge and skills in which to undertake an initial assessment. This article outlines the most common mental illnesses experienced by older people living in the community and provides guidance for community nurses on conducting an initial assessment to ensure that patients' holistic needs are met.


Sensitivity of cloned high- and low-metastatic murine Lewis lung tumor cells to lysis by cytotoxic autoreactive cells.
Cloned malignant cell lines from primary tumor sites (two lines) and from a lung metastatic focus (one line) were established 14 and 28 days after s.c. inoculation of Lewis lung tumor cells into C57BL/6 mice. Cloning was done in semisolid agarose culture medium and individual clones expanded in liquid medium. In vivo malignancy of the three lines was assured by graft experiments to healthy C57BL/6 recipients. Morphology, cloning efficiency in agarose, and growth rate were the same for all three lines. However, the cloned line from a metastatic focus had a higher metastatic rate (number of lung metastases per 10(5) injected tumor cells) compared to the two other cell lines. T-lymphocyte-depleted mononuclear spleen cells from mice grafted with tumor cells 2 to 4 weeks previously were found to be cytotoxic to cells from all three lines, whereas unfractionated mononuclear spleen cells from the same animals had weak or no cytotoxic activity. The cytotoxicity of T-lymphocyte-depleted spleen cells was found to include other malignant and nonmalignant target cells of C57BL/6 origin, but not allogeneic cells. In mixing experiments, splenic T-lymphocytes inhibited the cytotoxic activity of non-T-lymphocytes. The high- and low-metastatic tumor cell lines were found to be equally sensitive to lysis by T-cell-depleted spleen cells, suggesting that the effector cells (cytotoxic autoreactive cells) may have a significant antineoplastic potential.


Evaluation of CD4+ cells infiltration as a prognostic factor in cervical intraepithelial neoplasia 2.
To identify candidate predictors for the prognosis of cervical intraepithelial neoplasia 2 (CIN2) lesions and evaluate the prognostic value of the local immune response. One hundred fifteen CIN2 patients were enrolled. The percentage of p16-, minichromosome maintenance complex component 2- or apolipoprotein B mRNA editing enzyme catalytic subunit 3G (APOBEC3G)-positive cells was determined immunohistochemically. Tumor-infiltrating lymphocytes (TILs) in intertumoral lesions were scored using an automated system. CIN3 disease progression and regression rates were estimated by the Kaplan-Meier method. A case-control study was conducted to screen CIN2 prognostic factors in 10 regression and 10 progression patients. Selected factors were examined in a cohort study to determine their prognostic value for CIN2. Among all participants, the cumulative progression and regression rates at 60 months were 0.477 and 0.510, respectively. In the case-control study, p16- and APOBEC3G-positive cells were higher in the progression group (p=0.043, p=0.023). Additionally, CD4+ cell infiltration was enhanced in the regression group (p=0.023). The cohort study revealed a significantly increased progression rate in patients with elevated p16-positive cells (p<0.001), and increased CD4+ TIL infiltration was associated with better regression (p=0.011). Kaplan-Meier analysis according to human papillomavirus (HPV) positivity revealed a greater CIN3 development risk in HPV16-positive patients than in HPV16-negative cases. Finally, multivariate analysis identified HPV16 infection and CD4+ TIL infiltration as independent prognostic factors in CIN2 regression. CD4+ TIL infiltration in intertumoral lesions was related with CIN2 regression. Our findings suggest CD4+ TIL infiltration may be useful for the triage of CIN2 patients.


Associations between feeding practices and growth and neurodevelopmental outcomes at 36 months among children living in low- and low-middle income countries who participated in the BRAIN-HIT trial.
Feeding practices over the first several years of a child's life can critically influence development. The purpose of this study was to examine associations between feeding practices and growth and neurodevelopmental outcomes at 36 months of age among children from low- and low-middle-income countries (LMIC). We conducted a secondary analysis using data collected from children in India, Pakistan, and Zambia who were enrolled in a randomized controlled trial of a home-based early development intervention program called Brain Research to Ameliorate Impaired Neurodevelopment Home-based Intervention Trial. Qualitative dietary data collected at 36 months was used to assess the modified Minimum Acceptable Diet (mMAD), a measure based on a core indicator developed by the World Health Organization to measure whether young children receive the minimum number of meals recommended and adequate diversity of major food groups in their diet. Regression models were used to assess cross-sectional associations between diet and growth indices, including Z-scores for height-for-age (HAZ), weight-for-age (WAZ), weight-for-height (WHZ), head circumference (HCZ), and Bayley Scales of Infant Development II mental and psychomotor developmental measures at 36 months of age. Of 371 children, 174 (47%) consumed the mMAD, with significantly higher mean adjusted WHZ than those who did not meet mMAD (0.20 vs - 0.08, p = 0.05). Egg consumption was found to be significantly associated with a decreased risk of wasting [adjusted RR (95% CI): 0.37 (0.15, 0.89), p = 0.03]. HCZ at 36 months did not differ significantly for children who did and did not receive the mMAD. Meeting the mMAD was associated with better weight-for-height outcomes at 36 months in children in these three LMIC, highlighting the importance of adequate food quantity and quality. registered on March 20, 2008.


Metformin Use Is Associated with Decreased Mortality in COVID-19 Patients with Diabetes: Evidence from Retrospective Studies and Biological Mechanism.
The coronavirus disease 2019 (COVID-19) increases hyperinflammatory state, leading to acute lung damage, hyperglycemia, vascular endothelial damage, and a higher mortality rate. Metformin is a first-line treatment for type 2 diabetes and is known to have anti-inflammatory and immunosuppressive effects. Previous studies have shown that metformin use is associated with decreased risk of mortality among patients with COVID-19; however, the results are still inconclusive. This study investigated the association between metformin and the risk of mortality among diabetes patients with COVID-19. Data were collected from online databases such as PubMed, EMBASE, Scopus, and Web of Science, and reference from the most relevant articles. The search and collection of relevant articles was carried out between 1 February 2020, and 20 June 2021. Two independent reviewers extracted information from selected studies. The random-effects model was used to estimate risk ratios (RRs), with a 95% confidence interval. A total of 16 studies met all inclusion criteria. Diabetes patients given metformin had a significantly reduced risk of mortality (RR, 0.65; 95% CI: 0.54-0.80, p < 0.001, heterogeneity I2 = 75.88, Q = 62.20, and τ2 = 0.06, p < 0.001) compared with those who were not given metformin. Subgroup analyses showed that the beneficial effect of metformin was higher in the patients from North America (RR, 0.43; 95% CI: 0.26-0.72, p = 0.001, heterogeneity I2 = 85.57, Q = 34.65, τ2 = 0.31) than in patients from Europe (RR, 0.67; 95% CI: 0.47-0.94, p = 0.02, heterogeneity I2 = 82.69, Q = 23.11, τ2 = 0.10) and Asia (RR, 0.90; 95% CI: 0.43-1.86, p = 0.78, heterogeneity I2 = 64.12, Q = 11.15, τ2 = 0.40). This meta-analysis shows evidence that supports the theory that the use of metformin is associated with a decreased risk of mortality among diabetes patients with COVID-19. Randomized control trials with a higher number of participants are warranted to assess the effectiveness of metformin for reducing the mortality of COVID-19 patients.


Intussusception and rotavirus associated hospitalisation in New Zealand.
To describe the epidemiology of intussusception and its relation to rotavirus associated hospitalisation in New Zealand. National hospital discharge data between January 1998 and June 2003 for all children younger than 3 years of age with intussusception were reviewed. Independently, children from the same age group, admitted to eight paediatric units with rotavirus gastroenteritis between May 1998 and May 2000, were identified prospectively. Epidemiological characteristics of cases with intussusception were compared with those of hospitalised rotavirus disease. During the 5.5 year study period, there were 277 cases of intussusception and no deaths. Most (72%) occurred in the first year of life (age adjusted incident rate 65 per 100,000 child-years, 95% CI 56 to 74). Risk of intussusception was less in females (risk ratio 0.58; 95% CI 0.43 to 0.78) and for Maori (risk ratio 0.52; 95% CI 0.35 to 0.77) when compared with European infants. In contrast to hospitalised rotavirus cases, intussusception peaked at a younger age and lacked seasonality. This study provides national baseline data on intussusception for future rotavirus vaccine programmes in New Zealand. Wild-type rotaviruses do not appear to have a major role in triggering intussusception. Prospective surveillance systems, using standardised case definitions and nested case-control methodology, are needed to further our understanding of the aetiology and epidemiology of intussusception.


Average quantitative concentration of cotinine within the system pregnant woman-baby.
The findings presented by the authors of this report contribute to the diagnosis of pathology of pregnancy i.e. they assess the influence of nicotine on the organisms of a mother and a new-born child, estimated by concentration of cotinine, the most important metabolite of nicotine. The mean proportional share of cotinine in the fluids and organs in the pregnant women smoking actively was as follows: urine 72.1%, amniotic fluids 14.3%, colostrum 8.9% and placenta 4.7%. The authors pay a particular attention to the "colostrum-milk way" in the mother-child relationship what is emphasized in this report.


Analysis of transcriptional factors and regulation networks in laryngeal squamous cell carcinoma patients with lymph node metastasis.
The present study was to identify and quantitate differentially expressed proteins in laryngeal squamous cell carcinoma (LSCC) tissues with or without lymph node metastasis and to explore transcriptional factors and regulation networks associated with the process. Tissue specimens were taken from 20 patients with LSCC, including 10 cases of LSCC without metastasis LSCC (N0) and 10 cases of LSCC with metastasis LSCC (Nx). Among the 643 unique proteins identified by using iTRAQ labeling and quantitative proteomic technology, 389 proteins showed an abundance change in LSCC (Nx) as compared to LSCC (N0). Cytoskeleton remodeling, cell adhesion, and immune response activation were found to be the main processes in LSCC metastasis. The construction of transcription regulation networks identified key transcription regulators for lymph node metastasis of LSCC, including Sp1, c-myc, and p53, which may affect LSCC metastasis through the epithelial-mesenchymal transition. Furthermore, our results suggest that ubiquitination may be a critical factor in the networks. The present study provides insights into transcriptional factors and regulation networks involved in LSCC metastasis, which may lead to new strategies for treatment of LSCC metastasis.


Adaptation of a cyanobacterium to a biochemically rich environment in experimental evolution as an initial step toward a chloroplast-like state.
Chloroplasts originated from cyanobacteria through endosymbiosis. The original cyanobacterial endosymbiont evolved to adapt to the biochemically rich intracellular environment of the host cell while maintaining its photosynthetic function; however, no such process has been experimentally demonstrated. Here, we show the adaptation of a model cyanobacterium, Synechocystis sp. PCC 6803, to a biochemically rich environment by experimental evolution. Synechocystis sp. PCC 6803 does not grow in a biochemically rich, chemically defined medium because several amino acids are toxic to the cells at approximately 1 mM. We cultured the cyanobacteria in media with the toxic amino acids at 0.1 mM, then serially transferred the culture, gradually increasing the concentration of the toxic amino acids. The cells evolved to show approximately the same specific growth rate in media with 0 and 1 mM of the toxic amino acid in approximately 84 generations and evolved to grow faster in the media with 1 mM than in the media with 0 mM in approximately 181 generations. We did not detect a statistically significant decrease in the autotrophic growth of the evolved strain in an inorganic medium, indicating the maintenance of the photosynthetic function. Whole-genome resequencing revealed changes in the genes related to the cell membrane and the carboxysome. Moreover, we quantitatively analyzed the evolutionary changes by using simple mathematical models, which evaluated the evolution as an increase in the half-maximal inhibitory concentration (IC50) and estimated quantitative characteristics of the evolutionary process. Our results clearly demonstrate not only the potential of a model cyanobacterium to adapt to a biochemically rich environment without a significant decrease in photosynthetic function but also the properties of its evolutionary process, which sheds light of the evolution of chloroplasts at the initial stage.


Evaluation of quality-control materials for high-density-lipoprotein cholesterol quantitation.
Commercial quality-control materials and frozen plasma and serum pools were evaluated for high-density lipoprotein (HDL) cholesterol quantitation by the heparin-Mn2+ and phosphotungstate-Mg2+ precipitation methods and by ultracentrifugal and electrophoretic methods. We evaluated among-day precision; inter-method differences in HDL cholesterol quantitation; lipid composition and electrophoretic mobility of th lipoprotein density fractions; and the effects of modifications in reagent concentration and temperature. Frozen plasma pools (in-house) and frozen serum pools (prepared by the Center for Disease Control) were determined to be suitable HDL controls. Also, a commercial lyophilized serum free of very-low-density lipoprotein (VLDL) to which VLDL is added in a diluent solution (Analytical Control) also appeared suitable as an HDL control material. Conventional lyophilized pools (Lyphochek Elevated, Monitrol I, Ortho Normal, Precilip) were less suitable as control materials because of poor between-day precision for one or both of the precipitation methods and, in some cases, because of large absolute differences observed between the HDL methods. A serum pool stabilized with ethylene glycol (Beckman Level I) was the least as appropriate as an HDL control material. Other lyophilized pools--Lipid Fraction Control (Hyland) prepared by a modified lyophilization process and Lipidophor (Immuno Diagnostika) prepared by lyophilization with a stabilizing agent--appear promising.


Preventing unintentional scald burns: moving beyond tap water.
The goal was to examine in detail the mechanisms of significant scald burns among children <5 years of age, to discover insights into prevention. Medical records for children <5 years of age who were admitted with scald burns between January 1, 2002, and December 31, 2004, were identified through the University of Chicago Burn Center database. Demographic data and details of the circumstances and mechanisms of injury were extracted from the medical records. Of 640 admissions to the University of Chicago Burn Center during the 3-year study period, 140 (22%) involved children <5 years of age with scald burns. Of the 137 available charts reviewed, 118 involved unintentional injuries. Of those unintentional injuries, 14 were tap water scalds and 104 were non-tap water scalds. Of the non-tap water scalds, 94 scalds (90.4%) were related to hot cooking or drinking liquids. Two unexpected patterns of injury were discovered. Nine children (8.7%) between the ages of 18 months and 4 years were scalded after opening a microwave oven and removing the hot substance themselves. Seventeen children (16.3%) were scalded while an older child, 7 to 14 years of age, was cooking or carrying the scalding substance or supervising the younger child. Current prevention strategies and messages do not adequately address the most common mechanisms of scald injury requiring hospitalization. Easy access to a microwave oven poses a significant scald risk to children as young as 18 months of age, who can open the door and remove the hot contents. An engineering fix for microwave ovens could help protect young children from this mechanism of scalding. Involvement of older children in a subset of scald injuries is a new finding that may have prevention implications.


Path analysis of familial resemblance of pulmonary function and cigarette smoking.
The techniques of path analysis were utilized to assess the relative importance of genetic factors, personal smoking behavior, and shared environment in the resemblance of pulmonary function among relatives using both cross-sectional and longitudinal data from nuclear families. Data on 1-s forced expiratory volume, FEV1 (adjusted for age, sex, race, height, and ascertainment group) and the number of cigarettes smoked per day were available on 978 individuals in 384 nuclear families residing in the Baltimore metropolitan area. All these individuals were seen twice between 1971 and 1981, with an average of 5 yr between visits. The direct effect of an individual's own smoking explained 10 and 3% of variation in adjusted FEV1 among parents and offspring, respectively. Shared environmental factors influencing personal smoking behavior accounted for 5% of the parent-offspring correlation in adjusted FEV1 and 3% of the sibling correlation in adjusted FEV1 in this sample. Undefined environmental factors that influenced an individual's smoking habits and could be shared among relatives were found to explain 19% of the familial correlations in smoking. Genetic heritability estimates ranged between 36 and 40%, with no evidence of intergenerational differences in the expression of apparent genetic control of pulmonary function.


[Bone disorder after gastrectomy--clinical & experimental studies].
To study the pathophysiology of bone disorder after gastrectomy, 320 patients and 40 Wistar male rats were used. Clinically, patients who had received gastrectomy 1-15 years previously, were examined for skeletal symptoms, serum biochemistry, microdensitometry of second metacarpal bone, and 20 of them were then studied in a calcium infusion test. Using microdensitometry, abnormality of bone metabolism was observed in 38% of the patients. In severe cases, a significant decrease of serum Ca. and increase of alkaline phosphatase were observed (p less than 0.05), 65% complained of joint pain. In the calcium infusion test, severe cases showed a low urinary excretion of Ca, like osteomalacia, and unlike osteoporosis. Experimentally, body weight & amount of food intake decreased and fatty diarrhea was observed in rats after total gastrectomy. Skeletal changes including thinning of the cortex, loss of medullary trabeculation & decrease of bone ash and biochemical changes such as low serum Ca. 25(OH)D3, 24, 25(OH)2D3 and high iPTH levels were observed. Also the bone formation rate was lower than control as detected by tetracycline double labelling method. As low food intake & fatty diarrhea after gastrectomy which result in Ca. & vit. D insufficiency may be the major etiology of bone disorder.


Synovial fibroblasts: key players in rheumatoid arthritis.
Rheumatoid arthritis (RA) is a chronic autoimmune-disease of unknown origin that primarily affects the joints and ultimately leads to their destruction. The involvement of immune cells is a general hallmark of autoimmune-related disorders. In this regard, macrophages, T cells and their respective cytokines play a pivotal role in RA. However, the notion that RA is a primarily T-cell-dependent disease has been strongly challenged during recent years. Rather, it has been understood that resident, fibroblast-like cells contribute significantly to the perpetuation of disease, and that they may even play a role in its initiation. These rheumatoid arthritis synovial fibroblasts (RASFs) constitute a quite unique cell type that distinguishes RA from other inflammatory conditions of the joints. A number of studies have demonstrated that RASFs show alterations in morphology and behaviour, including molecular changes in signalling cascades, apoptosis responses and in the expression of adhesion molecules as well as matrix-degrading enzymes. These changes appear to reflect a stable activation of RASFs, which occurs independently of continuous exogenous stimulation. As a consequence, RASFs are no longer considered passive bystanders but active players in the complex intercellular network of RA.


MAPK11 in breast cancer cells enhances osteoclastogenesis and bone resorption.
Breast cancer cells frequently metastasize to bone and induce osteolytic bone destruction in patients. These metastases cause severe bone pain, high risk of fractures and hypercalcemia, and are essentially incurable and fatal. Recent studies show that breast cancer cells in bone activate osteoclastogenesis and bone resorption. However the underlying mechanism is poorly understood. This study shows that the p38 MAPK (p38) isoform MAPK11 (p38β) is expressed in breast cancer cells. By using specific small hairpin RNAs for MAPK11, we demonstrated that p38β-mediated p38 activity in breast cancer cells is responsible for breast cancer-induced osteolytic bone destruction. The addition of conditioned media from breast cancer cell lines MDA-MB-231 and MDA-MB-468, which have high expression of p38β, induced osteoclast differentiation and bone resorption. In contrast, knockdown of p38β in breast cancer cells reduced osteoclast differentiation in vitro and reduced bone destruction in severe combined immunodeficiency (SCID) mouse models. The knockdown of p38β did not affect tumor growth or survival or the ability of cancer cells to home to bone. Furthermore, our results showed that p38β upregulated the expression and secretion of monocyte chemotactic protein-1 (MCP-1) in breast cancer cells, and upregulated MCP-1 activates osteoclast differentiation and activity. This study elucidates a novel molecular mechanism of breast cancer cell-induced osteolytic bone destruction. This study also indicates that targeting breast cancer cell p38β and its product MCP-1 may be a viable approach to treat or prevent bone destruction in patients with bone-metastatic breast cancer.


Usefulness of red cell distribution width in association with biological parameters in an epidemiological survey of iron deficiency in children.
The diagnostic usefulness of red cell distribution width (RDW) in association with usual biochemical and haematological parameters in detection of iron deficiency has been studied in a representative sample population of 384 children aged six months to six years in Reunion. Traditional parameters measured included serum ferritin (Fri), total iron binding capacity (TIBC), serum iron (SI), transferrin saturation (TSat), free erythrocyte protoporphyrin (FEP), mean corpuscular haemoglobin concentration (MCHC), mean corpuscular haemoglobin (MCH), mean corpuscular volume (MCV) and haemoglobin concentration (Hb). RDW is an index of the variation in red cell size (anisocytosis). This recently derived parameter is measured by some models of electronic cell counter. It is not usually used in epidemiological investigations. Of the children studied, 13.6% had Hb less than 11 g/dl. The Pearson correlation coefficients between circulating iron parameters (SI, TSat, TIBC) or iron storage parameters (Fri) and RDW, MCV, MCH and FEP were greater than with Hb. The best correlations were observed for RDW, MCV and MCH with all other parameters. In this study, the upper limit value of RDW was defined as 18% using a Technicon model H-6000 counter. Other iron deficiency criteria were also defined and found to be in agreement with the international reference values for children aged six months to six years; MCV less than 70 fl, MCH less than 22 pg, MCHC less than 32%, FEP greater than 35 micrograms/dl whole blood, SI less than 6 mumols/l, TIBC greater than 85 mumols/l, TSat less than 10% and Fri less than 12 micrograms/l. The combination of sensitivity and specificity was best for RDW and worst for MCHC.(ABSTRACT TRUNCATED AT 250 WORDS)


[The species composition of mosquitoes and ticks in Armenia].
Comprehensive epidemiological, entomological, virological, and parasitological studies were conducted to examine the species composition and size of bloodsucking arthropoda (mosquitoes and ticks). A total of 64,567 mosquitoes and 45,180 Ixodes ticks were collected. Among the mosquitoes, Anopheles maculipennis was a prevalent species (81.6%). In all climatic zones, Dermacentor marginatus was the largest in number and most abundant during flag collections from cattle and plants (62.5% and 95.5%, respectively). Virological studies of the collected field material identified 125 strains of arboviruses belonging to 10 viruses: Tyaginya, Sindbis, Batai, Dkhori, tick-borne encephalitis, West Nile fever, Tamdy, KGL, Geta, and Bkhandzha. The identified arboviruses are environmentally associated with both mosquitoes and ticks. The larger number and diversity of bloodsucking artropoda present a potential risk of outbursts of arbovirus infections on the territory of the republic.


G 1359A polymorphism of the cannabinoid receptor gene (CNR1) and clinical results of biliopancreatic diversion.
Bariatric surgery is the most effective long-term treatment for morbid obesity, reducing obesity-associated co-morbidities. We decide to investigate the role of the polymorphism (G1359A) of the cannabinoid (CB)1 receptor gene on clinical outcomes 1 year after biliopancreatic diversion in morbidly obese patients. A sample of 66 morbidly obese patients (BMI >40 kg/m2) were operated. Weight, fat mass, blood pressure, basal glucose, triacylglycerols, total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol were measured at basal visit and at each visit. The frequency of metabolic comorbidities was recorded at each visit. Thirty-nine patients (59.1%) had genotype G1359G (wild type group) and 27 (40.9%) patients had genotype G1359A (mutant type group). In wild and mutant type groups, body mass index, weight, waist circumference, systolic blood pressure, glucose, total cholesterol, low-density lipoprotein cholesterol and triacylglycerols concentrations decreased, without statistical between genotype groups. Initial weight percent loss at 1 year of follow up was similar in both genotypes (33.1% vs 33.6%; ns). The present study demonstrates that polymorphism G1359A in the CB1 receptor did not have a significant effect on biochemical and anthropometric improvements after biliopancreatic diversion surgery.


Pseudogenization of sopA and sopE2 is functionally linked and contributes to virulence of Salmonella enterica serovar Typhi.
The difference in host range between Salmonella enterica serovar Typhimurium (S. Typhimurium) and S. enterica serovar Typhi (S. Typhi) can be partially attributed to pseudogenes. Pseudogenes are genomic segments homologous to functional genes that do not encode functional products due to the presence of genetic defects. S. Typhi lacks several protein effectors implicated in invasion or other important processes necessary for full virulence of S. Typhimurium. SopA and SopE2, effectors that have been lost by pseudogenization in S. Typhi, correspond to an ubiquitin ligase involved in cytokine production by infected cells, and to a guanine exchange factor necessary for invasion of epithelial cells, respectively. We hypothesized that sopA and/or sopE pseudogenization contributed to the virulence of S. Typhi. In this work, we found that S. Typhi expressing S. Typhimurium sopE2 exhibited a decreased invasion in different epithelial cell lines compared with S. Typhi WT. S. Typhimurium sopA completely abolished the hypo-invasive phenotype observed in S. Typhi expressing S. Typhimurium sopE2, suggesting that functional SopA and SopE2 participate concertedly in the invasion process. Finally, the expression of S. Typhimurium sopA and/or sopE2 in S. Typhi, determined changes in the secretion of IL-8 and IL-18 in infected epithelial cells.


Effects of antineoplastic agents on the cell cycle progression.
Almost all antineoplastic drugs are able to delay--or block--cells in a particular phase of the cell cycle. Few clinically active drugs seem to interact with the G1-states where cell growth can be arrested, although new compounds could be of interest with this respect. In contrast, most antineoplastic agents interact with DNA and/or DNA metabolism and have been shown to provoke a delay in G2. This could be the consequence of the DNA damage or of interference with controls which take place within the G2 phase.


Scientists' and science writers' experiences reporting genetic discoveries: toward an ethic of trust in science journalism.
To describe the relationship between scientists and science writers and their experiences with media reporting of genetic discoveries. This study included individual interviews with 15 scientists who specialize in genetics and 22 science writers who have covered their stories and a qualitative analysis of the data. Scientists and science writers place an equally high priority on accuracy of media reports. They agree on what makes genetics stories newsworthy and the particular challenges in reporting genetic discoveries (i.e., poor public understanding of genetics, the association of genetics with eugenics, and the lack of immediately apparent applications of genetic discoveries to human health). The relationship between scientists and bona fide science writers is largely positive. Scientists tend to trust, respect, and be receptive to science writers. Both scientists and science writers acknowledge that trust is an essential component of a good interview. Science writers report a fair degree of autonomy with respect to the relationship they have with their editors. To the degree that trust facilitates the access that science writers have to scientists, as well as higher quality interviews between scientists and science writers, trust might also contribute to higher quality media reporting. Therefore, scientists and science writers have an ethical obligation to foster trusting relationships with each other. Future research should systematically explore ways to cultivate such relationships and assess their impact on the quality of science journalism.


GaN-based light-emitting diodes on graphene-coated flexible substrates.
We demonstrate GaN-based thin light-emitting diodes (LEDs) on flexible polymer and paper substrates covered with chemical vapor deposited graphene as a transparent-conductive layer. Thin LEDs were fabricated by lifting the sapphire substrate off by Excimer laser heating, followed by transfer of the LEDs to the flexible substrates. These substrates were coated with tri-layer graphene by a wet transfer method. Optical and electrical properties of thin laser lift-offed LEDs on the flexible substrates were characterized under both relaxed and strained conditions. The graphene on paper substrates remained conducting when the graphene/paper structure was folded. The high transmittance, low sheet resistance and high failure strain of the graphene make it an ideal candidate as the transparent and conductive layer in flexible optoelectronics.


[Vascular tumors of the jaw. Analysis].
The vascular tumors of the jaw bones are rare. Misdiagnosed, these tumors represent a vital danger for the patient submitted to a surgical work in this area. The treatment of these vascular tumors is oft difficult and leads yet too much to maxillofacial mutilations. The superselective embolisation has permit a more conservative therapeutic approach to these lesions.


Tobacco addiction augments obesity and carcinogenesis: Matter of concern for Indian patients.
Life-style and tobacco addiction is the major risk factors for cancer progression in all over the world. Knowledge gaps between tobacco addiction, obesity and cancer in Indian patients brought an interdisciplinary group of investigators together to discuss the present study. We calculated the body mass index (BMI) of all the patients (N = 927) who were diagnosed with cancer for its treatment. National Institutes of Health (NIH) criteria were used to categorize the patients. All the patients of this disease could be contacted in person to find out the history of the disease. The frequency of addiction in urban cancer patient was found to be about 53.3% and in a rural area it was only 33.7%. Tobacco addiction was independently associated with younger age of cancer patient (odds ratio [OR] 2.242; 95% Confidence interval (CI) 1.653-3.042), obese (OR 7.433; 95% CI 3.746-14.750), overweight (OR 4.676; 95% CI 3.381-6.468) and advanced stage of cancer (OR 11.950; 95% CI 5.283-27.030). Tobacco consumption appears to be a major contributor to cancer in younger age with elevated BMI in India. Rapid changes in diet and life-style, increase in tobacco consumption appear to be strongly associated with the carcinoma in this middle-income country.


Ligation of the Maxillary Artery Prior to Caudal Maxillectomy in the Dog-A Description of the Technique, Retrospective Evaluation of Blood Loss, and Cadaveric Evaluation of Maxillary Artery Anatomy.
Two different surgical techniques have been described for performing caudal maxillectomies in dogs including the intraoral (IO) and combined dorsolateral and intraoral (DL-IO) approach. Hemorrhage is the most common intraoperative complication reported during these procedures as maxillary arterial ligation is not performed until after all osteotomies and mobilization of tumor-bearing bone. The objectives of this study were to describe a modified approach for caudal maxillectomy in the dog involving preligation of the maxillary artery, to retrospectively evaluate the ability of this modified approach to limit hemorrhage in a cohort of 22 dogs, and to clarify the vascular anatomy of the maxillary artery and its branches in relation to associated nerves. Medical records were retrospectively reviewed for cases that had caudal maxillectomy via a combined approach (with or without preligation of the maxillary artery) from January 1, 2004 to December 31, 2019. Twenty-two cases were identified, six without, and 16 with arterial preligation, respectively. Osteotomies were completed with a high-speed handpiece and rotary bur (n = 18), or oscillating bone saw (n = 4). All six (100%) dogs in the traditional DL-IO group developed hypotension under general anesthesia. Four (67%) of these required intraoperative blood transfusions, one of which required an additional postoperative blood transfusion. In contrast, only one of 16 (6%) dogs in the modified DL-IO group required an intraoperative blood transfusion, and only three (19%) developed hypotension. Moreover, a significant association was detected between postoperative PCV and the two different surgical approaches (P = 0.021). These results demonstrate the effectiveness of preligation of the maxillary artery in preventing hemorrhage in caudal maxillectomies in dogs and this represents an improvement in outcome over previously reported studies. Decreased intraoperative hemorrhage may improve surgical exposure and decrease overall patient morbidity.


The Impact of Obesity and Metabolic Syndrome on Vaccination Success.
The increase in the prevalence of obesity represents a worldwide phenomenon which is associated with several chronic diseases. In this review, we summarize published data showing how obesity, alone or together with the metabolic syndrome, induces defects in B cells similar to those induced by aging, contributes to systemic and B cell intrinsic inflammation and increases the secretion of autoimmune antibodies. We show that obese individuals contract more bacterial, viral, and fungal infections as compared to lean controls. These include periodontal, cutaneous, gastric, and respiratory tract infections, as well as postsurgical infections occurring after solid organ transplantation and surgeries for weight loss. Moreover, because obese individuals have a compromised immune system, they respond poorly to vaccination against influenza, hepatitis B, tetanus, and rabies. The results in this review highlight the importance to vaccinate individuals with obesity and/or with metabolic syndrome to prevent morbidity from vaccine-preventable diseases.


Ponatinib in Japanese patients with Philadelphia chromosome-positive leukemia, a phase 1/2 study.
In this ongoing Phase 1/2 study (NCT01667133), we evaluated ponatinib and assessed its recommended dose in Japanese patients with chronic myeloid leukemia (CML) resistant/intolerant to dasatinib or nilotinib, or with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL) resistant/intolerant to ≥1 tyrosine kinase inhibitor (TKI). The primary endpoints were safety of the recommended dose (Phase 1) and major cytogenetic response (MCyR) by 12 months in chronic-phase CML (CP-CML) patients or major hematologic response (MaHR) by 6 months in patients with advanced phase disease (Phase 2). MCyR was achieved/maintained by 12 months in 65% of CP-CML patients; MaHR was achieved by 6 months in 61% of patients with advanced phase disease. The most common nonhematologic grade 3/4 treatment-emergent adverse event (AE) was hypertension (37%); common hematologic grade 3/4 AEs were thrombocytopenia (57%), neutropenia (34%), and leukopenia (26%). Overall, five (14%) patients experienced arterial occlusive events (AOEs); no grade 5 AOEs were reported. The steady-state accumulation ratio of ponatinib (based on area under the curve) ranged from 2.6 (15 mg/day) to 1.3 (45 mg/day). In summary, ponatinib demonstrated efficacy in Japanese patients with CML and Ph+ALL resistant/intolerant to prior TKI treatment; safety data support a recommended starting dose of 45 mg/day in these patients.


The frontal longitudinal system as revealed through the fiber microdissection technique: structural evidence underpinning the direct connectivity of the prefrontal-premotor circuitry.
The purpose of this study was to investigate the morphology, connectivity, and correlative anatomy of the longitudinal group of fibers residing in the frontal area, which resemble the anterior extension of the superior longitudinal fasciculus (SLF) and were previously described as the frontal longitudinal system (FLS). Fifteen normal adult formalin-fixed cerebral hemispheres collected from cadavers were studied using the Klingler microdissection technique. Lateral to medial dissections were performed in a stepwise fashion starting from the frontal area and extending to the temporoparietal regions. The FLS was consistently identified as a fiber pathway residing just under the superficial U-fibers of the middle frontal gyrus or middle frontal sulcus (when present) and extending as far as the frontal pole. The authors were able to record two different configurations: one consisting of two distinct, parallel, longitudinal fiber chains (13% of cases), and the other consisting of a single stem of fibers (87% of cases). The fiber chains' cortical terminations in the frontal and prefrontal area were also traced. More specifically, the FLS was always recorded to terminate in Brodmann areas 6, 46, 45, and 10 (premotor cortex, dorsolateral prefrontal cortex, pars triangularis, and frontal pole, respectively), whereas terminations in Brodmann areas 4 (primary motor cortex), 47 (pars orbitalis), and 9 were also encountered in some specimens. In relation to the SLF system, the FLS represented its anterior continuation in the majority of the hemispheres, whereas in a few cases it was recorded as a completely distinct tract. Interestingly, the FLS comprised shorter fibers that were recorded to interconnect exclusively frontal areas, thus exhibiting different fiber architecture when compared to the long fibers forming the SLF. The current study provides consistent, focused, and robust evidence on the morphology, architecture, and correlative anatomy of the FLS. This fiber system participates in the axonal connectivity of the prefrontal-premotor cortices and allegedly subserves cognitive-motor functions. Based in the SLF hypersegmentation concept that has been advocated by previous authors, the FLS should be approached as a distinct frontal segment within the superior longitudinal system.


Differential responses of plasma atrial and brain natriuretic peptides to acute alteration in atrial pressure in pigs.
To describe the differential dynamic responses of atrial natriuretic peptide (ANP), N-terminal proatrial natriuretic peptide (Nt-proANP) and brain natriuretic peptide (BNP) to acute changes in atrial pressure, 6 pigs were studied during and after a 24-h period of rapid atrial pacing (225 bpm). During pacing, left atrial pressure increased acutely. ANP plasma concentrations showed a sharp initial peak followed by a decline, but remained significantly increased throughout the 24-h period. Nt-proANP followed a smoother pattern, increasing significantly only after 24 h. BNP increased significantly after 8 h after pacing and even more after 24 h. An opposite but similarly differential pattern of peptide responses was found in the post-pacing period. The different responses in ANP, Nt-proANP and BNP plasma concentrations may reflect the different mechanisms of regulation of secretion as well as plasma clearance. If the present findings reflect the acute clinical situation in humans, they may be of diagnostic relevance. An isolated ANP elevation would indicate a recent acute pressure increase, while elevation of two or more natriuretic peptides would point to a pressure increase of longer duration.


Immunostaining for the tumour suppressor gene p16 product is a useful marker to differentiate melanoma metastasis from lymph-node nevus.
Upon the introduction of extensive sampling protocols of sentinel node biopsies, pathologists are increasingly confronted with small melanoma metastases. Using conventional histology, it proves sometimes difficult or impossible to differentiate small melanoma metastases from lymph-node nevi. Loss of the tumour suppressor gene p16 has been shown to be associated with tumour progression of melanoma. We investigated nevus and melanoma cells for the presence of the product of the gene p16, using immunohistochemistry. All nevus cells, independent of their location (nodal or skin) displayed an extensive nuclear and cytoplasmic staining for p16. In contrast, all cells of melanoma metastases, except one skin metastasis, lacked nuclear staining for p16. These findings indicate that p16 is a reliable marker to distinguish lymph-node nevi from melanoma metastasis.


Lactoferrin Alleviates Ethanol-Induced Injury via Promoting Nrf2 Nuclear Translocation in BRL-3A Rat Liver Cells.
Our previous animal studies found that the preventive effects of lactoferrin (Lf) on alcoholic liver injury (ALI) are associated with nuclear factor E2-related factor 2 (Nrf2). To further explore the causality, experiments were performed using rat normal liver BRL-3A cells. Lf treatment reduced ethanol-induced death and apoptosis; meanwhile, Lf treatment alleviated excessive LDH release. These findings confirmed the protection of Lf against ethanol-induced injury in BRL-3A cells. Mechanistically, Lf treatment reversed the reduction in nuclear Nrf2 induced by ethanol without affecting the cytoplasmic Nrf2 level, which led to antioxidant enzyme activity restoration. However, the blocking of Nrf2 nuclear translocation by ML385 eliminated the protective effects of Lf. In a conclusion, Lf protects BRL-3A cells from ethanol-induced injury via promoting Nrf2 nuclear translocation.


De novo large cell neuroendocrine carcinoma of the prostate gland with pelvic lymph node metastasis: a case report with review of literature.
Neuroendocrine (NE) differentiation in prostate carcinomas can be seen in two settings: as a focal finding in conventional acinar adenocarcinoma, identifiable by immunohistochemical staining, or as a primary NE tumor of the prostate gland, such as carcinoid, small cell carcinoma, or large cell NE carcinoma. Of particular interest is the large cell NE carcinoma, which had been previously reported in isolated cases or in limited case series. In this report, we describe a case of a large cell NE carcinoma diagnosed in a 48-year-old man who presented with difficulty in voiding and urine retention. A cystoscopy revealed an enlarged, elongated prostate with an intra-urethral obstructing mass in the prostatic urethra. Subsequently, a transurethral resection of prostate (TURP) was performed at an outside hospital under the clinical diagnosis of benign prostatic hyperplasia (BPH). Microscopic examination of the TURP specimen revealed several foci of low-grade transitional-zone-type adenocarcinoma corresponding to Gleason score 5 (3 + 2), and a focus of high-grade large cell NE carcinoma. Concurrent x-ray computed tomography scans of the chest, abdomen, and pelvis demonstrated an enlarged left pelvic lymph node, which was biopsied and the patient was diagnosed with metastatic large cell NE carcinoma. He subsequently underwent 8 cycles of neoadjuvant chemotherapy with Lupron, a laparoscopic robotic-assisted radical retropubic prostatectomy, and pelvic lymphadenectomy. He died of widely metastatic prostatic carcinoma with leptomeningeal metastases 13 months after radical prostatectomy. Here, we present a rare case of large cell NE carcinoma with a review of the published literature.


[The clinical value of Doppler ultrasound in obstetrics].
Doppler sonography now has many indications in obstetrical diagnosis. Its wide and often uncritical application was the reason for our study group to confirm its importance. Moreover, we wanted to prove our own procedure. We made 950 Doppler examinations in a group of 449 pregnant women and correlated the results to the fetal outcome. Children with pathological Doppler findings showed a significantly lower birth weight of 599 g, a significantly lower duration of pregnancy of 6 days, a significantly higher rate of Caesarean sections and a significantly higher death rate compared to children with normal Doppler findings. Concerning Apgar- and pH-values there was not any significant difference between the two collectives. These results show that fetuses with pathological Doppler values or growth retardation can have the same prognosis as fetuses with normal Doppler findings if they are recognized and monitored at an early stage. The morbidity by acidosis can thus be reduced.


Neuroprotective effect of curcumin on transient focal cerebral ischemia in rats.
Curcumin, a member of the curcuminoid family of compounds, is a yellow colored phenolic pigment obtained from the powdered rhizome of C. longa Linn. Recent studies have demonstrated that curcumin has protective effects against cerebral ischemia/reperfusion injury. However, little is known about its mechanism. Hence, in the present study the neuroprotective potential of curcumin was investigated in middle cerebral artery occlusion (MCAO) induced focal cerebral IR injury. Administration of curcumin 100 and 300 mg/kg i.p. 60 min after MCAO significantly diminished infarct volume, and improved neurological deficit in a dose-dependent manner. Nissl staining showed that the neuronal injury was significantly improved after being treated with curcumin. Curcumin significantly decreased the expression of caspase-3 protein. A higher number of TUNEL-positive cells were found in the vehicle group, but they were significantly decreased in the treated group. Taken together, these results suggest that the neuroprotective potentials of curcumin against focal cerebral ischemic injury are, at least in part, ascribed to its anti-apoptotic effects.


Using thoracic ultrasound to detect interstitial lung disease in patients with rheumatoid arthritis: a protocol for the diagnostic test accuracy AURORA study.
Pulmonary diseases are significant contributors to morbidity and mortality in patients with rheumatoid arthritis (RA). RA-associated interstitial lung disease (RA-ILD) may be prevalent in up to 30% and clinically evident in 10% of patients with RA. Feasible methods to detect concomitant ILD in RA are warranted. Our objective is to determine the diagnostic accuracy of thoracic ultrasound (TUS) for ILD in patients with RA with respiratory symptoms, by using chest high-resolution CT (HRCT) as the reference standard. Further, we aim to evaluate the diagnostic accuracy for the promising blood biomarkers surfactant protein-D and microfibrillar-associated protein 4 in the detection of ILD in this group of patients. By use of a standardised 14 zone protocol patients suspected of having RA-ILD will undergo TUS as index test performed by a junior resident in rheumatology (BKS), who is certified by the European Respiratory Society in performing TUS assessments. Participants form a consecutive series of up to 80 individuals in total. The anonymised TUS images will be stored and scored by the junior resident as well as two senior rheumatologists, who have received training in TUS, and a TUS-experienced pulmonologist. HRCT will be used as the gold standard for ILD diagnosis (reference standard). The two basic measures for quantifying the diagnostic test accuracy of the TUS test are the sensitivity and specificity in comparison to the HRCT. Data will be collected and stored in the Research Electronic Data Capture database. The study is approved by the Committees on Health Research Ethics and the Danish Data Protection Agency. The project is registered at clinicaltrials.gov (NCT05396469, pre-results) and data will be published in peer-reviewed journals.


Loss of MAP3K1 enhances proliferation and apoptosis during retinal development.
Precise coordination of progenitor cell proliferation and differentiation is essential for proper organ morphogenesis and function during mammalian development. The mitogen-activated protein kinase kinase kinase 1 (MAP3K1) has a well-established role in anterior eyelid development, as Map3k1-knockout mice have defective embryonic eyelid closure and an `eye-open at birth' (EOB) phenotype. Here, we show that MAP3K1 is highly expressed in the posterior of the developing eye and is required for retina development. The MAP3K1-deficient mice exhibit increased proliferation and apoptosis, and Müller glial cell overproduction in the developing retinas. Consequently, the retinas of these mice show localized rosette-like arrangements in the outer nuclear layer, and develop abnormal vascularization, broken down retinal pigment epithelium, photoreceptor loss and early onset of retinal degeneration. Although the retinal defect is associated with increased cyclin D1 and CDK4/6 expression, and RB phosphorylation and E2F-target gene upregulation, it is independent of the EOB phenotype and of JNK. The retinal developmental defect still occurs in knockout mice that have undergone tarsorrhaphy, but is absent in compound mutant Map3k1(+/ΔKD)Jnk1(-/-) and Map3k1(+/ΔKD)Jnk(+/-)Jnk2(+/-) mice that have EOB and reduced JNK signaling. Our results unveil a novel role for MAP3K1 in which it crosstalks with the cell cycle regulatory pathways in the prevention of retina malformation and degeneration.


Hypothesis: proteasomal dysfunction: a primary event in neurogeneration that leads to nitrative and oxidative stress and subsequent cell death.
It is proposed that a primary mechanism leading to neuronal cell death in common neurodegenerative diseases is interference with proteasome function. This can involve genetic defects, direct inactivation of the proteasome (e.g., by reactive oxygen species), or overloading with proteins. The latter can be caused by excessive production of normal proteins or by the formation of poorly degradable proteins as a result of genetic mutations, faulty posttranslational modification, or protein modification by reactive oxygen or nitrogen species. Blockage of the proteasome leads to increased oxidative and nitrative stress, the latter apparently due to upregulation of nitric oxide synthase. Thus, agents that increase proteasome function may be generally neuroprotective, as may be NOS inhibitors. Proteasome inhibitors should be used with caution as therapeutic agents.


Ethics of rationing of nursing care.
Rationing of various needed services, for example, nursing care, is inevitable due to unlimited needs and limited resources. Rationing of nursing care is considered an ethical issue since it requires judgment about potential conflicts between personal and professional values. The present research sought to explore aspects of rationing nursing care in Iran. This study applied qualitative content analysis, a method to explore people's perceptions of everyday life phenomena and interpret the subjective content of text data. Data collection was performed through in-depth, unstructured, face-to-face interviews with open-ended questions. Participants and research context: The study population included Iranian nurses of all nursing positions, from clinical nurses to nurse managers. Purposive sampling was employed to select 15 female and 3 male nurses (11 clinical nurses, 3 supervisors, 1 matron, 1 nurse, and 2 members of the Nursing Council) working in hospitals of three cities in Iran. Ethical considerations: The study protocol was approved by Tehran University of Medical Sciences (91D1302870). Written informed consent was also obtained from all participants. According to the participants, rationing of nursing care consisted of two categories, that is, causes of rationing and consequences of rationing. The first category comprised three subcategories, namely, patient needs and demands, routinism, and VIP patients. The three subcategories forming the second category were missed nursing care, patient dissatisfaction, and nurses' feeling of guilt. Levels at which healthcare practices are rationed and clarity of the rationing are important structural considerations in the development of an equal, appropriate, and ethical healthcare system. Moreover, the procedure of rationing is critical as it not only influences people's lives but also reflects the values that dominate in the society. Therefore, in order to minimize the negative consequences of rationing of nursing care, further studies on the ethical dimensions of this phenomenon are warranted.


Views of managed care--a survey of students, residents, faculty, and deans at medical schools in the United States.
Views of managed care among academic physicians and medical students in the United States are not well known. In 1997, we conducted a telephone survey of a national sample of medical students (506 respondents), residents (494), faculty members (728), department chairs (186), directors of residency training in internal medicine and pediatrics (143), and deans (105) at U.S. medical schools to determine their experiences in and perspectives on managed care. The overall rate of response was 80.1 percent. Respondents rated their attitudes toward managed care on a 0-to-10 scale, with 0 defined as "as negative as possible" and 10 as "as positive as possible." The expressed attitudes toward managed care were negative, ranging from a low mean (+/-SD) score of 3.9+/-1.7 for residents to a high of 5.0+/-1.3 for deans. When asked about specific aspects of care, fee-for-service medicine was rated better than managed care in terms of access (by 80.2 percent of respondents), minimizing ethical conflicts (74.8 percent), and the quality of the doctor-patient relationship (70.6 percent). With respect to the continuity of care, 52.0 percent of respondents preferred fee-for-service medicine, and 29.3 percent preferred managed care. For care at the end of life, 49.1 percent preferred fee-for-service medicine, and 20.5 percent preferred managed care. With respect to care for patients with chronic illness, 41.8 percent preferred fee-for-service care, and 30.8 percent preferred managed care. Faculty members, residency-training directors, and department chairs responded that managed care had reduced the time they had available for research (63.1 percent agreed) and teaching (58.9 percent) and had reduced their income (55.8 percent). Overall, 46.6 percent of faculty members, 26.7 percent of residency-training directors, and 42.7 percent of department chairs reported that the message they delivered to students about managed care was negative. Negative views of managed care are widespread among medical students, residents, faculty members, and medical school deans.


Examining the Relationship Between the Use of a Mobile Peer-Support App and Self-Injury Outcomes: Longitudinal Mixed Methods Study.
Many individuals who self-injure seek support and information through online communities and mobile peer-support apps. Although researchers have identified risks and benefits of participation, empirical work linking participation in these web-based spaces to self-injury behaviors and thoughts is limited. This study aims to investigate the relationship between behavioral and linguistic traces on a mobile peer support app and self-injury outcomes. Natural use data and web-based surveys (N=697) assessing self-injury outcomes were collected from 268 users (aged 13-38 years; median 19; 149/268, 55.6% female) of a mobile peer-support app for 4 months. Participants were identified as having posted self-injury content using an internal classifier. Natural log data was used to predict self-injury outcomes in a series of multilevel logistic and linear regressions. Greater engagement on a mobile peer-support app was associated with a decreased likelihood of self-injury thoughts (odds ratio [OR] 0.25, 95% CI 0.09-0.73) and fewer intentions to self-injure (b=-0.37, SE 0.09), whereas posting triggering content was associated with an increased likelihood of engaging in behaviors (OR 5.37, 95% CI 1.25-23.05) and having self-injury thoughts (OR 17.87, 95% CI 1.64-194.15). Moreover, viewing triggering content was related to both a greater ability to resist (b=1.39, SE 0.66) and a greater intention to self-injure (b=1.50, SE 0.06). To our knowledge, this is the first study to connect naturally occurring log data to survey data assessing self-injury outcomes over time. This work provides empirical support for the relationship between participation in online forums and self-injury outcomes, and it articulates mechanisms contributing to this relationship.


Syncope management unit: evolution of the concept and practice implementation.
Syncope, a clinical syndrome, has many potential causes. The prognosis of a patient experiencing syncope varies from benign outcome to increased risk of mortality or sudden death, determined by the etiology of syncope and the presence of underlying disease. Because a definitive diagnosis often cannot be established immediately, hospital admission is frequently recommended as the "default" approach to ensure patient's safety and an expedited evaluation. Hospital care is costly while no studies have shown that clinical outcomes are improved by the in-patient practice approach. The syncope unit is an evolving practice model based on the hypothesis that a multidisciplinary team of physicians and allied staff with expertise in syncope management, working together and equipped with standard clinical tools could improve clinical outcomes. Preliminary data have demonstrated that a specialized syncope unit can improve diagnosis in a timely manner, reduce hospital admission and decrease the use of unnecessary diagnostic tests. In this review, models of syncope units in the emergency department, hospital and outpatient clinics from different practices in different countries are discussed. Similarities and differences of these syncope units are compared. Outcomes and endpoints from these studies are summarized. Developing a syncope unit with a standardized protocol applicable to most practice settings would be an ultimate goal for clinicians and investigators who have interest, expertise, and commitment to improve care for this large patient population.


COVID-19 in India: Are Biological and Environmental Factors Helping to Stem the Incidence and Severity?
The ongoing Corona virus (COVID-19) pandemic has witnessed global political responses of unimaginable proportions. Many nations have implemented lockdowns that involve mandating citizens not to leave their residences for non-essential work. The Indian government has taken appropriate and commendable steps to curtail the community spread of COVID-19. While this may be extremely beneficial, this perspective discusses the other reasons why COVID-19 may have a lesser impact on India. We analyze the current pattern of SARS-CoV-2 transmission, testing, and mortality in India with an emphasis on the importance of mortality as a marker of the clinical relevance of COVID-19 disease. We also analyze the environmental and biological factors which may lessen the impact of COVID-19 in India. The importance of cross-immunity, innate immune responses, ACE polymorphism, and viral genetic mutations are discussed.


Graphene oxide prevents lateral amygdala dysfunctional synaptic plasticity and reverts long lasting anxiety behavior in rats.
Engineered small graphene oxide (s-GO) sheets were previously shown to reversibly down-regulate glutamatergic synapses in the hippocampus of juvenile rats, disclosing an unexpected translational potential of these nanomaterials to target selective synapses in vivo. Synapses are anatomical specializations acting in the Central Nervous System (CNS) as functional interfaces among neurons. Dynamic changes in synaptic function, named synaptic plasticity, are crucial to learning and memory. More recently, pathological mechanisms involving dysfunctional synaptic plasticity were implicated in several brain diseases, from dementia to anxiety disorders. Hyper-excitability of glutamatergic neurons in the lateral nucleus of the amygdala complex (LA) is substantially involved in the storage of aversive memory induced by stressful events enabling post-traumatic stress disorder (PTSD). Here we translated in PTSD animal model the ability of s-GO, when stereotaxically administered to hamper LA glutamatergic transmission and to prevent the behavioral response featured in long-term aversive memory. We propose that s-GO, by interference with glutamatergic plasticity, impair LA-dependent memory retrieval related to PTSD.


Improving Prognostic Web Calculators: Violation of Preferential Risk Independence.
Web-based applications are available for prognostication of individual patients. These prognostic models were developed for groups of patients. No one is the average patient, and using these calculators to inform individual patients could provide misleading results. This article gives an example of paradoxical results that may emerge when indices used for prognosis of the average person are used for care of an individual patient. We calculated the expected mortality risks of stomach cancer and its associated comorbidities. Mortality risks were calculated using data from 140,699 Veterans Administration nursing home residents. On average, a patient with hypertension has a higher risk of mortality than one without hypertension. Surprisingly, among patients with lung cancer, hypertension is protective and reduces risk of mortality. This paradoxical result is explained by how group-level, average prognosis could mislead individual patients. In particular, average prognosis of lung cancer patients reflects the impact of various comorbidities that co-occur in lung cancer patients. The presence of hypertension, a relatively mild comorbidity of lung cancer, indicates that more serious comorbidities have not occurred. It is not that hypertension is protective; it is the absence of more serious comorbidities that is protective. The article shows how the presence of these anomalies can be checked through the mathematical concept of preferential risk independence. Instead of reporting average risk scores, web-based calculators may improve accuracy of predictions by reporting the unconfounded risks.


Development and Validation of an Instrument for Assessing Patient Experience of Chronic Illness Care.
The experience of chronic patients with the care they receive, fuelled by the focus on patient-centeredness and the increasing evidence on its positive relation with other dimensions of quality, is being acknowledged as a key element in improving the quality of care. There are a dearth of accepted tools and metrics to assess patient experience from the patient's perspective that have been adapted to the new chronic care context: continued, systemic, with multidisciplinary teams and new technologies. Development and validation of a scale conducting a literature review, expert panel, pilot and field studies with 356 chronic primary care patients, to assess content and face validities and reliability. IEXPAC is an 11+1 item scale with adequate metric properties measured by Alpha Chronbach, Goodness of fit index, and satisfactory convergence validity around three factors named: productive interactions, new relational model and person's self-management. IEXPAC allows measurement of the patient experience of chronic illness care. Together with other indicators, IEXPAC can determine the quality of care provided according to the Triple Aim framework, facilitating health systems reorientation towards integrated patient-centred care.


In vitro pituitary prolactin, growth hormone and follicle stimulating hormone secretion during sexual maturation of female rats primed with melatonin.
The influence of in vivo melatonin administration on in vitro pituitary follicle stimulating hormone (FSH), growth hormone (GH) and prolactin secretion, as well as the possible influence of dopamine (DA) were evaluated in prepubertal (31-day-old), pubertal (33-day-old) and adult female rats at diestrus phase of the sexual cycle. The in vitro pituitary hormone secretions were evaluated at basal rate for the first hour of incubation only, in Krebs Ringer phosphate (KRP) (I1) and after a second hour of incubation with KRP (I2) or with KRP+DA (I2 plus DA). I1PRL secretion was significantly higher in 33-day-old control and melatonin treated (MEL) rats as compared to I2 periods. However, in 31-day-old rats I1 secretion was higher than in the I2 or I2+DA periods, in MEL rats. In vitro GH secretion was significantly higher at I1 than during I2 periods in the control 31- and 33-day-old groups, but not in MEL rats. The only significant effect of DA was the elevation of GH in prepubertal MEL rats. In vitro FSH release was increased by melatonin in 31- and 33-day-old female rats. No differences in PRL, GH and FSH secretion were found in adult rats. In conclusion, the results show that melatonin effects upon in vitro pituitary gland activity are reproductive-stage-dependent modifying the secretory capacity of the lactotrop, gonadotrop and somatotrop during prepubertal and pubertal ages but not in adult rats studied at a quiescent phase of the sexual cycle.


Epidemiology of hookworm infection in Itagua, Paraguay: a cross sectional study.
A cross-sectional study in Itagua, Paraguay tested 192 people for the presence, intensity and species of hookworm infection. Fifty-nine percent of these individuals were found to be infected. Intensity of infection was determined on 92% of infected individuals by quantitative egg counts. The high intensity hookworm infections, which cause the greatest morbidity, were clustered between the ages of five and 14 years. No differences were seen between genders. The species of hookworm was determined for parasites reared from 72% of infected individuals. Both Necator americanus and Ancylostoma duodenale were identified, although the former species predominated. We conclude that hookworm infection continues to be a public health problem in Paraguay, particularly among children and adolescents who suffer from high intensity infections. A. duodenale continues to persist in the Western Hemisphere and has not been completely displaced by N. americanus.


Functional effects of activation of alpha-1 adrenoceptors by dexmedetomidine: in vivo and in vitro studies.
Dexmedetomidine, an alpha-2 adrenoceptor (AR) agonist, produces a biphasic hypnotic response in rats. Since central alpha-1 AR stimulation may reverse the hypnotic response produced by central alpha-2 AR stimulation, we have investigated, in both in vivo and in vitro models, the functional effects of dexmedetomidine on alpha-1 AR. For in vivo studies, stainless steel cannulas were inserted stereotaxically into the lateral ventricle of halothane-anesthetized rats to facilitate i.c.v. drug administration. Four to 7 days later, the alpha-1 AR antagonist prazosin (1 mg/kg-1) or saline was administered i.p. 15 min before i.c.v. injections of dexmedetomidine (10-333 micrograms) and the sleep-time (duration of loss of righting reflex) was assessed. The sleep-time increased, in a linear fashion, up to 33 micrograms; above this dose, there was a decrease in sleep-time. Pretreatment with prazosin prevented the decrease in sleep-time which was seen at higher doses. For in vitro studies, binding parameters of dexmedetomidine and its anesthetically inert L-isomer were determined from competition binding curves using [125I]2-[beta-(4-hydroxy-3-[125I]iodo- phenyl)ethylaminomethyl]-tetralone as the radiolabeled ligand and membranes prepared from HeLa cell lines stably expressing either alpha-1B or alpha-1C AR subtypes. Dexmedetomidine bound with equal affinity to both the alpha-1B (1178 +/- 63 nM) and the alpha-1C (1344 +/- 230 nM) isoreceptors.(ABSTRACT TRUNCATED AT 250 WORDS)


Uropathogens antibiotic resistance patterns among type 2 diabetic patients in Kisii Teaching and Referral Hospital, Kenya.
Non-insulin dependent diabetes mellitus is a major risk factor for urinary tract infections. Irrational use of antibiotics has led to the emergency of uropathogens resistant to available antibiotics. The main objective was to determine the bacterial causative agents of urinary tract infections and their antibiotic resistance patterns. One hundred and eighty (180) type 2 diabetic patients were recruited to take part in the study. Urine samples were collected and cultured for urinary tract infections diagnosis and antibiotic sensitivity. A total of 35 isolates were obtained from the study. All the isolates were sensitive to gentamicin. All 21 (100%) isolates of E. coli were sensitive to gentamicin and cephalexin. All 10 (100%) K. pneumoniaeisolates were sensitive to gentamicin and nitrofurantoin. Out of the 21 E. coli isolates, five of them showed resistance to ampicillin, three E. coli isolates showed resistance to nitrofurantoin and another three E. coliisolates showed resistance to co-trimoxazole. Out of 10 K. pneumoniae isolates, two of them were found to be resistant to ampicillin, one K. pneumoniae isolate was resistant to cephalexin and two K. pneumoniaeisolates were resistant to co-trimoxazole. Out of the four P. mirabilis isolates, there were three cases where one isolate was each resistant to ampicillin, nitrofurantoin and co-trimoxazole. There is a need to have a regular screening of bacterial isolates causing urinary tract infection in diabetic patients and their antibiotic sensitivity in order to have effective therapy. Present findings show that there is increased resistance to the commonly prescribed antibiotics.