Dengue and dengue hemorrhagic fever among adults: clinical outcomes related to viremia, serotypes, and antibody response

BACKGROUND: Clinical manifestations of dengue vary in different areas of endemicity and between specific age groups, whereas predictors of outcome have remained controversial. In Brazil, the disease burden predominantly affects adults, with an increasing trend toward progression to dengue hemorrhagic fever (DHF) noted. METHODS: A cohort of adults with confirmed cases of dengue was recruited in central Brazil in 2005. Patients were classified according to the severity of their disease. Associations of antibody responses, viremia levels (as determined by real-time polymerase chain reaction [PCR]), and serotypes (as determined by multiplex PCR) with disease severity were evaluated. RESULTS: Of the 185 symptomatic patients >14 years of age who had a confirmed case of dengue, 26.5% and 23.2% were classified as having intermediate dengue fever (DF)/DHF (defined as internal hemorrhage, plasma leakage, manifested signs of shock, and/or thrombocytopenia [platelet count, < or =50,000 platelets/mm3]) and DHF, respectively. The onset of intermediate DF/DHF and DHF occurred at a late stage of disease, around the period of defervescence. Patients with DHF had abnormal liver enzyme levels, with a >3-fold increase in aspartate aminotransferase level, compared with the range of values considered to be normal. Overall, 65% of patients presented with secondary infections with dengue virus, with such infection occurring in similar proportions of patients in each of the 3 disease category groups. Dengue virus serotype 3 (DV3) was the predominant serotype, and viremia was detected during and after defervescence among patients with DHF or intermediate DF/DHF. CONCLUSIONS: Viremia was detected after defervescence in adult patients classified as having DHF or intermediate DF/DHF. Secondary infection was not a predictor of severe clinical manifestation in adults with infected with the DV3 serotype.     

Two novel mutations in the gonadotropin-releasing hormone receptor gene in Brazilian patients with hypogonadotropic hypogonadism and normal olfaction

Several point mutations in the GnRH receptor gene have been described in an autosomal recessive form of congenital isolated hypogonadotropic hypogonadism (HH). We investigated 17 Brazilian patients (10 males and 7 females) from 14 different families, with HH and normal olfaction. The diagnosis of HH was based on absent or incomplete sexual development after 17 yr of age associated with low or normal levels of LH in both sexes and low levels of testosterone in males and of estradiol in females. All patients presented with a normal sense of smell in an olfactory specific test. The coding region of the GnRH receptor gene was amplified by PCR and directly sequenced. A novel missense mutation, Arg(139)His, located in the conserved DRS motif at the junction of the third transmembrane and the second intracellular loop of the GnRH receptor was identified in the homozygous state in one female with complete HH. The Arg(139)His mutation completely eliminated detectable GnRH-binding activity and prevented GnRH-induced stimulation of inositol phosphate accumulation in vitro. In another family, a new compound heterozygous mutation (Asn(10)Lys and Gln(106)Arg) was identified in four siblings (two males and two females) with partial HH. The Gln(106)Arg mutation, located in the first extracellular loop, has been previously described, and in vitro analysis indicated that the mutant receptor was able to bind GnRH, but with a reduced affinity. The Asn(10)Lys mutation in the extracellular amino-terminal domain of the receptor also reduced the affinity for GnRH in vitro. In this family we also identified a previously described silent polymorphism at amino acid residue 151 in the second intracellular loop that segregated with the two inactivating mutations of the GnRH receptor. This polymorphism was also found in two unrelated patients with sporadic HH without GnRH receptor loss of function mutations. No mutations were identified in the remaining cases. A good correlation between genotype and phenotype was found in our patients. The woman, who is homozygous for the completely inactivating Arg(139)His mutation, has complete HH with undetectable serum basal LH and FSH levels that failed to respond to GnRH stimulation. In addition, the affected patients who are compound heterozygotes for the Asn(10)Lys/Gln(106)Arg mutations, have partial HH with low serum basal LH levels that were responsive to GnRH stimulation. No clinical or hormonal differences were found between HH patients with and without mutations in the GnRH receptor gene, indicating that these data do not contribute to the identification of HH patients with GnRH receptor mutations. In conclusion, we report the first naturally occurring mutation within the conserved DRS motif of the GnRH receptor in a female with complete HH and a novel compound heterozygous mutation (Asn(10)Lys and Gln(106)Arg) in a family with partial HH, increasing the repertoire of the inactivating mutations of the GnRH receptor.     

Global DNA hypomethylation occurs in the early stages of intestinal type gastric carcinoma.

BACKGROUND: Global DNA hypomethylation has been found in the premalignant stages of some neoplasms and has been implicated as an important factor for tumour progression. AIMS: The aim of this study was to evaluate whether DNA hypomethylation occurs during the process of gastric carcinogenesis. METHODS: Gastric specimens were obtained from 49 patients and histologically classified as: normal 10, superficial gastritis 14, chronic atrophic gastritis with intestinal metaplasia 15, and intestinal type of gastric carcinoma 10. Global DNA methylation was assessed by incubating DNA with (3H)-S-adenosylmethionine and Sss1 methylase. A higher incorporation of (3H) methyl groups reflects a lower degree of intrinsic methylation. RESULTS: A graduated increase in (3H) methyl group incorporation into DNA was found over the range extending from normal gastric mucosa, to superficial gastritis and to chronic atrophic gastritis (136,556 (24,085) v 235,725 (38,636) v 400,998 (26,747 dpm/micrograms/DNA respectively; p = 0.0002). No further increase was found in specimens from patients with carcinoma. No differences were found between extent of DNA methylation in neoplastic or non-neoplastic mucosa from patients with gastric carcinoma. Hypomethylation of DNA increased substantially with severe atrophy (p = 0.01) or with type III intestinal metaplasia (p = 0.15). CONCLUSIONS: Global DNA hypomethylation occurs in the early stages of gastric carcinogenesis, and it may be a novel biomarker of gastric neoplasia, useful in monitoring the response to chemopreventive agents.     

Pulmonary function and exercise-associated changes with chronic low-level paraquat exposure

The present study was undertaken to test the hypothesis that chronic, low-level paraquat exposure causes restrictive lung function with gas transfer impairment. Three hundred thirty-eight Costa Rican farm workers from banana, coffee, and palm oil farms completed a questionnaire, spirometry, and a test of single-breath carbon monoxide diffusing capacity. Subjects 40 years of age or older, without other medical risk factors, completed maximal cardiopulmonary exercise tests. Most (66.6%) were paraquat handlers; 24.8% of handlers and 27.3% of nonhandlers reported current cigarette smoking. In linear regression models, cumulative paraquat exposure was not an independent predictor of VA, carbon monoxide diffusing capacity, peak oxygen uptake, FVC, or oxygen pulse peak. However, the ventilatory equivalent for CO(2), although within normal range, was significantly higher with increased cumulative paraquat exposure. Oxygen desaturation greater than 5% from rest to peak exercise had an odds ratio of 1.7 (95% confidence interval = 0.9-3.0) with the cumulative paraquat exposure index in models adjusted for age, weight, and smoking status. The association of paraquat exposure with ventilatory equivalent and oxygen desaturation suggests that paraquat may be associated with subclinical gas exchange abnormalities, but overall these findings are consistent with no clinically significant increases in interstitial thickening or restrictive lung disease among this population.     

Clinical outcomes of dexamethasone-eluting stent implantation in ST-elevation acute myocardial infarction.

OBJECTIVES: The aim of our study was to evaluate the safety and midterm clinical results of dexamethasone-eluting stent (DexES) implantation in ST-segment elevation acute myocardial infarction (STEMI). BACKGROUND: Inflammation plays a pivotal role in both inestabilization of coronary atherosclerotic plaques and development of restenosis after stent placement. Antiinflammatory agents may attenuate those mechanisms and improve clinical outcomes. There is little information about clinical results of DexES and no data are available about their utilization during percutaneous coronary intervention (PCI) in STEMI. METHODS: Consecutive patients with STEMI that underwent primary or rescue PCI in our institution were treated with DexES. Clinical follow-up with routine realization of noninvasive test for detection of myocardial ischemia and coronariography if necessary, were performed. The objective of the study was to evaluate the rate of MACE (death, reinfarction, or target lesion revascularization) during midterm follow-up. RESULTS: The procedure was successful in 96.7% of cases. There were no in-hospital deaths or reinfarctions. One acute stent thrombosis occurred and no subacute thrombosis were observed. During a mean follow-up period of 384 days, cardiac-related death was 1.1%, there were no reinfarctions or late stent thrombosis and target lesion revascularization rate was 4.2%. CONCLUSION: We conclude that utilization of DexES for PCI in STEMI is safe and provides good midterm clinical outcomes.