Apoptosis and impairment of neurite network by short exposure of immature rat cortical neurons to unconjugated bilirubin increase with cell differentiation and are additionally enhanced by an inflammatory stimulus

Nerve cell injury induced by unconjugated bilirubin (UCB) has been implicated in brain damage during severe neonatal hyperbilirubinemia, although the molecular mechanisms underlying UCB neurotoxicity are still not clarified. It has been suggested recently that there is an association between hyperbilirubinemia and long-term neurologic dysfunctions. We incubated immature neurons with UCB to evaluate the short- and long-term effects of UCB on apoptotic death and on neuritic outgrowth and ramification. We also evaluated whether mature neurons, exposed previously to UCB in an early stage of differentiation, are more sensitive to apoptosis or to neuritic breakdown when treated with inflammatory agents, such as lipopolysaccharide and tumor necrosis factor-alpha. Results show that exposure of immature neurons to UCB increased apoptosis and provoked a reduction of both neurite extension and number of nodes. These injurious effects observed in immature cells treated with UCB were increasingly perpetuated along cell differentiation, as compared to neurons incubated in the absence of UCB. In addition, neurons that were exposed to UCB when immature showed an increased susceptibility to death by apoptosis, as well as an additional decrease in neurite outgrowth when incubated with an inflammatory agent afterward. This work shows, for the first time, that UCB induces neurite changes consistent with neurodevelopment abnormalities. Furthermore, pre-exposure to UCB followed by an inflammatory stimulus leads to an enhanced susceptibility to long-term apoptosis, as well as a greater neuritic breakdown. These data support the association between neonatal hyperbilirubinemia and the later development of mental illness, such as schizophrenia.     

Antiphospholipid antibodies in HIV-positive patients

Antiphospholipid (aPL) antibodies classically have been associated with thrombotic phenomena and abortion in patients with autoimmune diseases. The objective of the present work was to evaluate the frequency of such antibodies in patients infected with HIV and study its association with the presence of clinical manifestations of antiphospholipid syndrome (APS). Using a transversal study, a population of patients diagnosed with HIV, identified through an enzyme-linked immunosorbent assay (ELISA) test and confirmed by Western blotting, aged above 17 years old, was investigated. Through a standard questionnaire, the presence of APS manifestations was investigated, as well as the frequency of rheumatic manifestations. Antibodies against beta2 glycoprotein I (anti-beta2 GPI) and anticardiolipin (aCL) IgA, IgG, and IgM were investigated by the ELISA method using commercial kits (QUANTA Lite, INOVA Diagnostics). Ninety patients were studied, 47 (52.2%) male and 43 (47.8%) female. Clinical manifestations of APS were detected in 12 patients (13.3%) of the studied population, whereas arthralgia was the most common rheumatic manifestation (38.9%). Of the 90 patients, 40 (44.4%) were reactive for at least one type of aPL antibody (aCL and/or anti-beta2 GPI). The frequency of aCL was 17.8%, from which 15 (16.7%) had aCL IgG, 3 (3.3%) IgM, and 1 (1.1%) IgA. The frequency of the anti-beta2 GPI antibody was 33.3%, from which 29 (32.2%) were positive for isotype IgA, 4 (4.4%) isotype IgM, and 1 (1.1%) isotype IgG. No association was observed between immunoreactivity for aPL antibodies in general or each isotype in particular and the presence of APS manifestation. In the present study, it was possible to observe a relatively high frequency of aPL antibodies, particularly for isotype IgA anti-beta2 GPI in HIV. However, there was no association to APS manifestations, suggesting that such antibodies had no etiopathogenic role in these complications in patients with such retroviral infection.     

Opportunities for the replacement of animals in the study of nausea and vomiting

Nausea and vomiting are among the most common symptoms encountered in medicine as either symptoms of disease or side effects of treatments. Developing novel anti-emetics and identifying emetic liability in novel chemical entities rely on models that can recreate the complexity of these multi-system reflexes. Animal models (especially the ferret and dog) are the current gold standard; however, the selection of appropriate models is still a matter of debate, especially when studying the subjective human sensation of nausea. Furthermore, these studies are associated with animal suffering. Here, following a recent workshop held to review the utility of animal models in nausea and vomiting research, we discuss the limitations of some of the current models in the context of basic research, anti-emetic development and emetic liability detection. We provide suggestions for how these limitations may be overcome using non-animal alternatives, including greater use of human volunteers, in silico and in vitro techniques and lower organisms.     

AIDS related malignancies in Brazil

PURPOSE OF REVIEW: There have been relatively few studies of HIV-related malignancies in Brazil. Universal access to antiretroviral drugs in Brazil has changed both the mortality and morbidity rates of AIDS. Nevertheless, there is also extreme poverty in both urban and rural areas and complications of prolonged immune suppression such as mycobacterial and malignant diseases have put a significant strain on the country's healthcare system. This brief review outlines the existing data regarding AIDS related malignancies in the largest Latin American country. RECENT FINDINGS: Currently, there are almost 600 000 people infected with HIV in Brazil and 170,000 patients are receiving highly active antiretroviral therapy. In the studies done of HIV malignancies in Brazil, it appears that these tumors are histologically similar to those that occur in other equatorial countries and differ somewhat from those seen in Europe and the US. Another unique distinction is the high association with oncogenic herpes viruses. SUMMARY: The existence of federally sponsored highly active antiretroviral therapy, clinicians and healthcare providers experienced in the care of HIV patients and high incidence of malignancies associated with oncogenic viruses make Brazil an important site for clinical and basic research in AIDS and immunodeficiency related malignancies.     

Prevalence of sexually transmitted infections among HIV-infected women in Brazil

This study aimed to evaluate the prevalence of sexually transmitted infections (STIs) and associated risk factors in HIV-infected pregnant women followed for prenatal care in Salvador, Bahia. This was a cross-sectional study of 63 women seeking prenatal care at a reference center. Participants were interviewed regarding socio-epidemiological and clinical history, and were tested for HBsAg, anti-HCV, anti HTLV I/II, VDRL, Chlamydia trachomatis, Neisseria gonorrhoeae, Mycoplasma hominis, Ureaplasma urealyticum, CD4 count, and HIV plasma viral load. The main outcome variable was the presence of any STI. The mean age of patients was 28.2 years (16-40 years). 23 (36.5%) were diagnosed with at least one STI. The frequency of diagnoses was: HBV, 3.2%; HCV, 8.1%; HTLV I/II, 3.4%; syphilis, 9.5%; Chlamydia trachomatis, 11.1%; HPV, 15.0%; Mycoplasma hominis, 2.1%, and Ureaplasma urealyticum, 2.1%. No case of Neisseria gonorrhoeae was identified. No association was found between socio-epidemiological variables and the presence of an STI. CD4 T lymphocyte < 500 cells/μL (p = 0.047) and plasma viral load >1,000 copies (p = 0.027) were associated with the presence of STI. STIs are frequent in pregnant women infected with HIV, and all HIV-infected pregnant women should be screened to decrease transmission of these pathogens and to protect their own health.     

一叶萩碱全合成的研究

以1,4-环己二酮为原料经与哌啶缩合、还原、乙酸汞环合、碱催化分子内缩合等11步反应完成了一叶萩碱的全合成。合成品的熔点及光谱数据与天然一叶萩碱的熔点及光谱数据一致。     

Ataxia with loss of Purkinje cells in a mouse model for Refsum disease

Refsum disease is caused by a deficiency of phytanoyl-CoA hydroxylase (PHYH), the first enzyme of the peroxisomal α-oxidation system, resulting in the accumulation of the branched-chain fatty acid phytanic acid. The main clinical symptoms are polyneuropathy, cerebellar ataxia, and retinitis pigmentosa. To study the pathogenesis of Refsum disease, we generated and characterized a Phyh knockout mouse. We studied the pathological effects of phytanic acid accumulation in Phyh^−/− mice fed a diet supplemented with phytol, the precursor of phytanic acid. Phytanic acid accumulation caused a reduction in body weight, hepatic steatosis, and testicular atrophy with loss of spermatogonia. Phenotype assessment using the SHIRPA protocol and subsequent automated gait analysis using the CatWalk system revealed unsteady gait with strongly reduced paw print area for both fore- and hindpaws and reduced base of support for the hindpaws. Histochemical analyses in the CNS showed astrocytosis and up-regulation of calcium-binding proteins. In addition, a loss of Purkinje cells in the cerebellum was observed. No demyelination was present in the CNS. Motor nerve conduction velocity measurements revealed a peripheral neuropathy. Our results show that, in the mouse, high phytanic acid levels cause a peripheral neuropathy and ataxia with loss of Purkinje cells. These findings provide important insights in the pathophysiology of Refsum disease.