Hepatic,Renal and Inflammatory Biomarkers are Positively Associated with Blood Pressure Changes in Healthy Pregnant Women: A Prospective Cohort

This article evaluates the association of hepatic, renal, and inflammatory biomarkers with changes in systolic (SBP) and diastolic (DBP) blood pressure (BP) during healthy pregnancies.A prospective cohort study with 225 healthy pregnant women was conducted in Rio de Janeiro, Brazil. SBP and DBP were evaluated throughout pregnancy (5th–13th, 20th–26th, and 30th–36th gestational weeks) and were the outcomes. The following biomarkers were measured at the first trimester and analyzed according to tertiles of the sample distribution and were considered the main independent predictors: alkaline phosphatase (ALP), alanine aminotransferase (ALT), aspartate aminotransferase (AST), uric acid (UA), creatinine (Cr), and C-reactive protein (CRP) concentrations. The statistical analysis included 3 stages of modeling with the longitudinal linear mixed-effects procedures: Model 1 was adjusted for gestational age and quadratic gestational age; Model 2 included interactions between the biomarkers and gestational age; and Model 3 was adjusted for self-reported skin color, education, parity, early-pregnancy body mass index (BMI) (under/normal <25; overweight/obese ≥25 kg/m²), smoking habit, and leisure-time physical activity. Additional models were performed for CRP and UA with the inclusion of interaction terms between the biomarkers and BMI.Women classified in the third tertile of the ALP (≥61.1 U/L; β_SBP = 3.474; 95% confidence interval [CI]: 0.955–5.992; β_DBP = 3.291; 95% CI: 1.098–5.485), ALT (≥14.3 U/L; β_SBP = 2.232; 95% CI: 0.221–4.242; β_DBP = 2.355; 95% CI: 0.721–3.989), and Cr values (≥48.6 μmol/L; β_DBP = 1.927; 95% CI: 0.347–3.508) presented higher BP levels during pregnancy compared to those in the first and second tertiles. Women in the highest tertile of the ALP concentration distribution presented a lower rate of change in SBP and DBP during pregnancy (interaction term with gestational age β_SBP = −0.004; 95% CI: −0.007 to −0.001; P = 0.02; β_DBP = −0.003; 95% CI: −0.006 to −0.001; P = 0.01). Higher UA concentrations were associated with higher SBP levels only in overweight/obese women (β = 3.878; 95% CI: 0.687–7.068), whereas higher CRP concentrations (≥2.6 mg/L) were associated with higher DBP in under/normal weight women (β =2.252; 95% CI: 0.267–4.236).ALP, ALT, and Cr concentrations were positively associated with BP levels, whereas ALP was associated with a lower rate of change in BP. The associations of UA and CRP with BP differ according to the early-pregnancy BMI.     

Chagasic meningoencephalitis: case report of a recently included AIDS-defining illness in Brazil

Recently, reactivation of Chagas disease (meningoencephalitis and/or myocarditis) was included in the list of AIDS-defining illnesses in Brazil. We report a case of a 52-year-old patient with no history of previous disease who presented acute meningoencephalitis. Direct examination of blood and cerebrospinal fluid (CSF) showed Trypanosoma cruzi. CSF culture confirmed the diagnosis. Serological assays for T. cruzi and human immunodeficiency virus (HIV) were positive. Despite treatment with benznidazol and supportive measures, the patient died 24 hours after hospital admission. In endemic areas, reactivation of Chagas disease should always be considered in the differential diagnosis of meningoencephalitis among HIV-infected patients, and its presence is indicative of AIDS.     

Dissemination of bla(IMP-1)-carrying integron In86 among Klebsiella pneumoniae isolates harboring a new trimethoprim resistance gene dfr23

The genetic context of the bla_IMP-1 gene was evaluated in 9 Klebsiella pneumoniae isolates recovered from 2 hospitals in São Paulo, Brazil. All isolates harbored a copy of In86 carrying bla_IMP-1, aac(6′)-31, and aadA1. Eight strains from the same hospital also carried another class 1 integron harboring a new trimethoprim resistance gene (dfr23) that was chromosomally embedded. In86 was likely to be in a 30-kb nontransferable plasmid and was flanked upstream by a sequence identical to one identified in an IMP-1–producing Pseudomonas putida isolate. The bla_IMP-1-carrying integron In86 was recently reported from nonfermentative bacilli isolated in São Paulo. These isolates appear to be the source of this integron now acquired by K. pneumoniae strains from different hospitals in the same city. Metallo-β-lactamase production is still rare among Enterobacteriaceae isolates in Brazil, but the acquisition of genetic structures carrying these mobile resistance determinants is worrisome and could lead to an increase in the prevalence of these phenotypes of resistance.     

Dermatomyositis and acquired ichthyosis as paraneoplastic manifestations of ovarian tumor

Case 1 A 37-year-old white woman was seen at the Dermatology Clinic presenting muscle weakness of the pelvic and scapular girdles, as well as a violaceous erythema and periorbital infiltration (heliotropium) and erythematous-violaceous lesions on the dorsum of the finger joints, with periungual telangiectasia. A diagnosis of dermatomyositis was confirmed and treatment with prednisone, 1 mg/kg per day, was started, with improvement.
One year and two months later she presented ascites, bilateral pleural effusion, and a 7-kg weight loss. Cytology of the ascitic fluid revealed cells compatible with adenocarclnoma. Exploratory laparotomy demonstrated peritoneal carcinomatosis, and an implant biopsy confirmed a moderately differentiated adenocarcinoma of the ovary of the endometriold type. The patient died 1 year and 4 months after the diagnosis of dermatomyositis (Fig. 1 and Table 1).
Case 2 An 8-year-old white girl was seen at the Dermatology Clinic presenting generalized ichthyotic skin of a brovi/nish color, perilabial and palmo-plantar fissures of 5 months duration, and hair fall. For the last 2 months, she had been presenting daily fever (38°C) and lack of appetite, and had lost 7 kg.
Abdominal ultrasound revealed a large pelvic mass (9 × 8 × 7 cm) located in a small basin, with possible right renal invasion, as well as periaortic and pericaval adenomegaly, findings that were later confirmed by computerized tomography. Radiologic examinations of the thorax, skull, spine, and long bones were normal. Exploratory laparotomy confirmed the presence of a dysgerminoma of the right ovary as determined by biopsy (Fig. 2).
Chemotherapy was started (carboplatin, bleomycin, and vinblastine) and an abdominal ultrasound taken 1 5 days later showed a 67.5% reduction of the pelvic mass, as well as reduction of rectoperitoneal adenomegaly.     

Long-term modulation of Na+ and K+ channels by TGF-��1 in neonatal rat cardiac myocytes

Previous work shows that transforming growth factor-β1 (TGF-β1) promotes several heart alterations, including atrial fibrillation (AF). In this work, we hypothesized that these effects might be associated with a potential modulation of Na(+) and K(+) channels. Atrial myocytes were cultured 1-2?days under either control conditions, or the presence of TGF-β1. Subsequently, Na(+) (I(Na)) and K(+) (I(K)) currents were investigated under whole-cell patch-clamp conditions. Three K(+) currents were isolated: inward rectifier (I(Kin)), outward transitory (I(to)), and outward sustained (I(Ksus)). Interestingly, TGF-β1 decreased (50%) the densities of I(Kin) and I(Ksus) but not of I(to). In addition, the growth factor reduced by 80% the amount of I(Na) available at -80?mV. This effect was due to a significant reduction (30%) in the maximum I(Na) recruited at very negative potentials or I(max), as well as to an increased fraction of inactivated Na(+) channels. The latter effect was, in turn, associated to a -7?mV shift in V(1/2) of inactivation. TGF-β1 also reduced by 60% the maximum amount of intramembrane charge movement of Na(+) channels or Q(max), but did not affect the corresponding voltage dependence of activation. This suggests that TGF-β1 promotes loss of Na(+) channels from the plasma membrane. Moreover, TGF-β1 also reduced (50%) the expression of the principal subunit of Na(+) channels, as indicated by western blot analysis. Thus, TGF-β1 inhibits the expression of Na(+) channels, as well as the activity of K(+) channels that give rise to I(Ksus) and I(Kin). These results may contribute to explaining the previously observed proarrhythmic effects of TGF-β1.     

Investigation of Genetic Polymorphisms Related to the Outcome of Radiotherapy for Prostate Cancer Patients

The purpose of this study was to evaluate the association between ATM, TP53 and MDM2 polymorphisms in prostate cancer patients and morbidity after radiotherapy. The presence of ATM (rs1801516), TP53 (rs1042522, rs1800371, rs17878362, rs17883323, and rs35117667), and MDM2 (rs2279744) polymorphisms was assessed by direct sequencing of PCR fragments from 48 patients with histologically proven prostate adenocarcinoma and treated with external beam radiation. The side effects were classified according to the Radiation Therapy Oncology Group (RTOG) score. The results showed no association between clinical characteristics and the development of radiation toxicities (P > 0.05). The C>T transition in the position 16273 (intron 3) of TP53 (rs35117667) was significantly associated with the risk of acute skin toxicity (OR: 0.0072, 95% CI 0.0002–0.227, P = 0.003). The intronic TP53 polymorphism at position 16250 (rs17883323) was associated with chronic urinary toxicity (OR: 0.071, 95%CI 0.006–0.784, P = 0.032). No significant associations were found for the remaining polymorphisms (P > 0.05). The results show that clinical characteristics were not determinant on the developing of radiation sensitivity in prostate cancer patients, and intronic TP53 polymorphisms would be associated with increased acute and chronic radiation toxicities. These observations corroborate the importance of investigating the genetic profile to predict adverse side effects in patients undergoing radiotherapy.     

Haemorrhagic reactions elicited at sites of passive cutaneous anaphylaxis by the intravenous injection of aggregated γ-globulin

In guinea-pigs injected intradermally with a small amount of antibody and challenged 2 hours later, by the intravenous route, with a mixture of homologous antigen and aggregated γ-globulin, haemorrhagic reactions of the Arthus type develop at the sites of intradermal sensitization. This effect was obtained with γ-globulins of different species (human, rabbit and horse) by using different techniques for aggregation (heat, mercaptoethanol—urea and bis-diazobenzidine) and was always correlated with the ability of the aggregated globulin to fix complement.

Fluorescein labelled aggregates of γ-globulin were detectable in the wall of vessels at sensitized sites.

In experiments performed with guinea-pig antibodies, the localizing effect was observed only with γ₁, whereas the γ₂, Arthus-producing fraction proved completely ineffective.

Histamine and histamine liberators are not sufficient for eliciting the effect obtained with sensitizing antibody plus homologous antigen. It is postulated, therefore, that other effects occurring at the site of specific sensitization may also be responsible for the phenomenon.

     

Flow cytometric analysis of intestinal intraepithelial lymphocytes in the diagnosis of refractory celiac sprue

The etiology of refractory celiac sprue (RCS) is unclear. In a high proportion of cases, the clonal nature of intestinal intraepithelial lymphocytes (IEL) can be demonstrated and a pathogenetic implication of intestinal IEL has been postulated. The prognosis of this subgroup of RCS is poor, with a high risk to develop an overt lymphoma and uncontrolled malabsorption despite steroid/immunosuppressive therapy. Cases with a relatively indolent clinical course, however, exist and their early diagnosis may be difficult. To gain insight into the pathogenic implication of intestinal IEL in refractory celiac sprue, we have performed an extensive phenotypic and functional characterization of clonal intestinal IEL in a patient with an indolent form of refractory celiac sprue, using multiparametric flow cytometry. The abnormal lymphocyte infiltrate lacked surface membrane expression of CD3/T-cell receptor (TCR) complexes (TCR(-), CD4(-), CD8(-), sCD3(-)), but contained intracellular CD3(epsilon) (CyCD3(+)) and surface CD103(+) and CD7(+). In particular, these cells showed a unique spontaneous ex-vivo cytokine secretion profile with an increased percentage of CD3(-) IEL containing TNF-alpha and IL-10, in the absence of IL-2, IL-4 and IFN-gamma. Altogether our results suggest that flow cytometry immunophenotyping of intestinal IEL, in cases suspected of celiac disease and their complicated forms, could be of great help in the correct diagnosis of RCS and the understanding of the immunopathogenic mechanisms of the disease and their clinical and/or therapeutical implications.     

Modulation of cardiac mitochondrial permeability transition and apoptotic signaling by endurance training and intermittent hypobaric hypoxia

Background

Modulation of the mitochondrial permeability transition pore (MPTP) and inhibition of the apoptotic signaling are critically associated with the cardioprotective phenotypes afforded by both intermittent hypobaric-hypoxia (IHH) and endurance-training (ET). We recently proposed that IHH and ET improve cardiac function and basic mitochondrial capacity, although without showing addictive effects. Here we investigate whether a combination of IHH and ET alters cardiac mitochondrial vulnerability to MPTP and related apoptotic signaling.

Methods

Male Wistar rats were divided into normoxic-sedentary (NS), normoxic-exercised (NE, 1 h/day/5 week treadmill-running), hypoxic-sedentary (HS, 6000 m, 5 h/day/5 weeks) and hypoxic-exercised (HE) to study susceptibility to calcium-induced cardiac MPTP opening. Mitochondrial cyclophilin D (CypD), adenine nucleotide translocator (ANT), Bax and Bcl-2 protein contents were semi-quantified by Western blotting. Cardiac caspase 3-, 8- and 9-like activities were measured. Mitochondrial aconitase and superoxide dismutase (MnSOD) activity and malondialdehyde (MDA) and sulphydryl group (–SH) content were determined.

Results

Susceptibility to MPTP decreased in NE and HS vs. NS and even further in HE. The ANT content increased in HE vs. NS. Bcl-2/Bax ratio increased in NE and HS compared to NS. Decreased activities in tissue caspase 3-like (HE vs. NS) and caspase 9-like (HS and HE vs. NS) were observed. Mitochondrial aconitase increased in NE and HS vs. NS. No alterations between groups were observed for caspase 8-like activity, MnSOD, CypD, MDA and –SH.

Conclusions

Data confirm that IHH and ET modulate cardiac mitochondria to a protective phenotype characterized by decreased MPTP induction and apoptotic signaling, although without visible addictive effects as initially hypothesized.