Role for interleukin-1 (IL-1) in benzene-induced hematotoxicity: inhibition of conversion of pre-IL-1 alpha to mature cytokine in murine macrophages by hydroquinone and prevention of benzene-induced hematotoxicity in mice by IL-1 alpha

Chronic exposure of humans to benzene (BZ), a myelotoxin, causes aplastic anemia and acute leukemia. The stromal macrophage that produces interleukin-1 (IL-1), a cytokine essential for hematopoiesis, is a target of BZ's toxicity. Monocyte dysfunction and decreased IL-1 production have been shown to be involved in aplastic anemia in humans. Hydroquinone (HQ), a toxic bone marrow (BM) metabolite of BZ, causes time- and concentration-dependent inhibition of processing of the 34-Kd pre-interleukin-1 alpha (IL-1 alpha) to the 17-Kd mature cytokine in murine P388D1 macrophages and BM stromal macrophages, as measured by Western immunoblots of cell lysate proteins using a polyclonal rabbit antimurine IL-1 alpha antibody. HQ over a 10-fold concentration range had no effect on the lipopolysaccharide (LPS)-induced production of pre- IL-1 alpha precursor or on cell viability or DNA and protein synthesis. Stromal macrophages obtained from the femoral BM of C57Bl/6 mice exposed to BZ (600 or 800 mg/kg body weight) for 2 days were incapable of processing the 34-Kd pre-IL-1 alpha to the mature 17-Kd cytokine when stimulated in culture with LPS. Stromal macrophages from mice coadministered BZ and indomethacin, a prostaglandin H synthase (PHS) inhibitor that has been shown to prevent BZ-induced myelotoxic and genotoxic effects in mice when coadministered with benzene were able to convert the pre-IL-1 alpha to mature cytokine. Administration of recombinant murine IL-1 alpha (rMuIL-1 alpha) to mice before a dose of BZ that causes severe depression of BM cellularity completely prevents BM depression, most probably by bypassing the inability of the stromal macrophage in BZ-treated animals to process pre-IL-1 alpha to the mature cytokine.     

<Emphasis Type="Italic">TCF7L2</Emphasis>variant genotypes and type 2 diabetes risk in Brazil: significant association,but not a significant tool for risk stratification in the general population

Background  

Genetic polymorphisms of the TCF7L2 gene are strongly associated with large increments in type 2 diabetes risk in different populations worldwide. In this study, we aimed to confirm the effect of the TCF7L2 polymorphism rs7903146 on diabetes risk in a Brazilian population and to assess the use of this genetic marker in improving diabetes risk prediction in the general population.     

Direct evidence for the involvement of carbohydrate sequences in human sperm-zona pellucida binding

Several lines of evidence indicate that mammalian fertilization is initiated via a binding process that is dependent upon the recognition of oligosaccharide sequences associated with zona pellucida (ZP) glycoproteins. Here, specific chemical and enzymatic methods were employed to modify human ZP and to test their effects on sperm binding in the hemizona assay system (HZA). Periodate oxidation of human ZP under very mild conditions (10 min, 0 degrees C, 1 mM sodium m- periodate) that attacks only terminal sialic acid resulted in a 30% loss of human sperm binding in the HZA [hemizona index (HZI) = 70.2 +/- 10.9, n = 22; P < 0.05]. Periodate oxidation under mild conditions (1 h, 23 degrees C, 10 mM sodium m-periodate) caused a 40% decrease in binding (HZI = 60.8 +/- 10.3; n = 24; P< 0.01). Treatment of human ZP with neuraminidase caused a substantial increase in sperm binding to human ZP (HZI = 297 +/- 45, n = 22; P < 0.01). These findings indicate that there are sialic acid dependent binding sites coexisting with binding sites that are obscured by sialic acid. To determine the periodate sensitivity of these obscured sites, hemizona were first digested with neuraminidase and subsequently subjected to mild periodate oxidation. The combined enzymatic and chemical treatments caused a 79% decrease in sperm binding compared to control hemizona (HZI = 20.7 +/- 4.4, n = 16; P < 0.001). Human sperm-ZP interaction was also increased by digestion of human ZP with endo-beta-galactosidase (HZI = 710 +/- 232, n = 14; P < 0.01), indicating that potential binding sites for spermatozoa are also obscured by lactosaminoglycan sequences. These studies support a definitive role for the involvement of ZP-associated glycans in the binding of human spermatozoa to oocytes.      

'Psychiatric nursing was great, but I want to be a "real" nurse': is psychiatric nursing a realistic choice for nursing students?

The present paper reports the results of a quasi-experimental study that examined the relationship between exposure to the theory and practice of psychiatric nursing and the desirability of psychiatric nursing as a future career choice. A time series design was utilized to enable a comparison between pre- and post-test scores. A significant increase in the popularity of psychiatric nursing was evident in the experimental group in the post-test phase, while no significant change was detected in the control group. Despite this increase, a large number of students from the experimental group indicated their reluctance to undertake a career in psychiatric nursing without first consolidating their skills in the medical-surgical area. This situation reflects an image of nursing that is contrary to the caring philosophy it purports to embrace, but which appears to favour certain areas of nursing practice at the expense of others.     

Causal effect of disconnection lesions on interhemispheric functional connectivity in rhesus monkeys

In the absence of external stimuli or task demands, correlations in spontaneous brain activity (functional connectivity) reflect patterns of anatomical connectivity. Hence, resting-state functional connectivity has been used as a proxy measure for structural connectivity and as a biomarker for brain changes in disease. To relate changes in functional connectivity to physiological changes in the brain, it is important to understand how correlations in functional connectivity depend on the physical integrity of brain tissue. The causal nature of this relationship has been called into question by patient data suggesting that decreased structural connectivity does not necessarily lead to decreased functional connectivity. Here we provide evidence for a causal but complex relationship between structural connectivity and functional connectivity: we tested interhemispheric functional connectivity before and after corpus callosum section in rhesus monkeys. We found that forebrain commissurotomy severely reduced interhemispheric functional connectivity, but surprisingly, this effect was greatly mitigated if the anterior commissure was left intact. Furthermore, intact structural connections increased their functional connectivity in line with the hypothesis that the inputs to each node are normalized. We conclude that functional connectivity is likely driven by corticocortical white matter connections but with complex network interactions such that a near-normal pattern of functional connectivity can be maintained by just a few indirect structural connections. These surprising results highlight the importance of network-level interactions in functional connectivity and may cast light on various paradoxical findings concerning changes in functional connectivity in disease states.     

Colonic motility diagnosis based on colonic pressure

Manometry of the alimentary tract is a valuable and widely used means to evaluate and diagnose the function of the alimentary tract. However, the measurement can be inconvenient due to the invasive method used, and the many factors affecting results. Research on colonic pressure data is even more insufficient. This paper deals with colonic pressure data via an improved method ensuring that pressure data of the whole colon is available. The data is analysed based on the learning vector quantization (LVQ) method. Testing results show that this method distinguishes the normal data and the abnormal data, consistently with the original diagnoses. This method can serve as an assistant diagnosis of colonic motility and contributes to further research on colonic motility based on pressure data.     

Immunologic status of hemophilia patients treated with cryoprecipitate or lyophilized concentrate

We evaluated 37 patients with moderate or severe hemophilia A and six patients with severe factor IX deficiency for clinical or laboratory evidence of immune abnormalities. Patients were assigned to one of four groups according to the type of clotting factor replacement. Twenty patients had received only cryoprecipitate during the two years preceding the evaluation (group I); 11 additional patients were treated predominantly with cryoprecipitate but had also received up to nine bottles of factor VIII concentrate (group II); six patients received factor VIII concentrate (group III); six patients received factor IX concentrate (group IV). There was no clinical or laboratory evidence of immunodeficiency among the 43 patients. The mean absolute number of Th cells was normal in all patient groups, but the mean absolute number of Ts cells was increased compared with controls, both in patients treated with cryoprecipitate and in patients treated with factor VIII or factor IX concentrate. There was no correlation between the Th/Ts ratio and patient age, alanine aminotransferase level, hepatitis serology, in vitro lymphocyte function, or amount of clotting factor administered. Our observations demonstrate that the volunteer or commercial origin of clotting factor replacement cannot fully explain the alterations in lymphocyte subset distribution previously described in patients with hemophilia A.     

Development and course of heart failure after a myocardial infarction in younger and older people

Background Acute myocardial infarction （AMI） is a common cause of heart failure （HF）, which can develop soon after AMI and may persist or resolve or develop late. HF after an MI is a major source of mortality. The cumulative incidence, prevalence and resolution of HF after MI in different age groups are poorly described. This study describes the natural history of HF after AMI according to age. Methods Patients with AMI during 1998 were identified from hospital records. HF was defined as treatment of symptoms and signs of HF with loop diuretics and was considered to have resolved if loop diuretic therapy could be stopped without recurrence of symptoms. Patients were cate- gorised into those aged 〈 65 years, 65-75 years, and 〉 75 years. Results Of 896 patients, 311,297 and 288 were aged 〈 65, 65-75 and 〉75 years and of whom 24%, 57% and 82% had died respectively by December 2005. Of these deaths, 24 （8%）, 68 （23%） and 107 （37%） oc- curred during the index admission, many associated with acute HF. A further 37 （12%）, 63 （21%） and 82 （29%） developed HF that persisted until discharge, of whom 15, 44 and 62 subsequently died. After discharge, 53 （24%）, 55 （40%） and 37 （47%） patients developed I-IF for the first time, of whom 26%, 62% and 76% subsequently died. Death was preceded by the development of HF in 35 （70%）, 93 （91%） and 107 （85%） in aged 〈 65 years, 65-75 years and 〉75 years, respectively. Conclusions The risk of developing HF and of dying after an MI in- creases progressively with age. Regardless of age, most deaths after a MI are preceded by the development of HF.