Transcriptome of iPSC-derived neuronal cells reveals a module of co-expressed genes consistently associated with autism spectrum disorder.

Evaluation of expression profile in autism spectrum disorder (ASD) patients is an important approach to understand possible similar functional consequences that may underlie disease pathophysiology regardless of its genetic heterogeneity. Induced pluripotent stem cell (iPSC)-derived neuronal models have been useful to explore this question, but larger cohorts and different ASD endophenotypes still need to be investigated. Moreover, whether changes seen in this in vitro model reflect previous findings in ASD postmortem brains and how consistent they are across the studies remain underexplored questions. We examined the transcriptome of iPSC-derived neuronal cells from a normocephalic ASD cohort composed mostly of high-functioning individuals and from non-ASD individuals. ASD patients presented expression dysregulation of a module of co-expressed genes involved in protein synthesis in neuronal progenitor cells (NPC), and a module of genes related to synapse/neurotransmission and a module related to translation in neurons. Proteomic analysis in NPC revealed potential molecular links between the modules dysregulated in NPC and in neurons. Remarkably, the comparison of our results to a series of transcriptome studies revealed that the module related to synapse has been consistently found as upregulated in iPSC-derived neurons-which has an expression profile more closely related to fetal brain-while downregulated in postmortem brain tissue, indicating a reliable association of this network to the disease and suggesting that its dysregulation might occur in different directions across development in ASD individuals. Therefore, the expression pattern of this network might be used as biomarker for ASD and should be experimentally explored as a therapeutic target.

The multinomial logistic regression model for predicting the discharge status after liver transplantation: estimation and diagnostics analysis.

The multinomial logistic regression model (MLRM) can be interpreted as a natural extension of the binomial model with logit link function to situations where the response variable can have three or more possible outcomes. In addition, when the categories of the response variable are nominal, the MLRM can be expressed in terms of two or more logistic models and analyzed in both frequentist and Bayesian approaches. However, few discussions about post modeling in categorical data models are found in the literature, and they mainly use Bayesian inference. The objective of this work is to present classic and Bayesian diagnostic measures for categorical data models. These measures are applied to a dataset (status) of patients undergoing kidney transplantation.

C3435T polymorphism of the MDR1 gene is not associated with blood levels of hypothalamus-pituitary-adrenal axis hormones in healthy male subjects.

In vitro studies have shown that multidrug resistance protein 1 (MDR1) has an affinity for cortisol; however, in vivo association studies on the relationship between MDR1 gene polymorphisms and blood cortisol levels have produced inconsistent results. Therefore, we examined the effects of the C3435T polymorphism of the MDR1 gene on blood levels of hypothalamus-pituitary-adrenal (HPA) axis hormones such as cortisol and adrenocorticotropic hormone (ACTH) in healthy subjects. The subjects comprised 30 healthy Japanese males. Ten subjects were recruited for each of the C3435T MDR1 genotypes: C/C, C/T, and T/T. Blood samples were taken at 6:00 pm on two occasions with an interval of 2 weeks. Blood levels of cortisol and ACTH were determined by an electrochemiluminescence immunoassay. There were no significant differences in the blood levels of the HPA axis hormones among the MDR1 genotypes. The present study suggests that the C3435T MDR1 polymorphism does not affect blood levels of HPA axis hormones in healthy Japanese males.

Pinhal virus, a new arenavirus isolated from calomys tener in Brazil

Arenavirus Sabiá was originally isolated from a fatal human infection in Brazil, and after the occurrence of the second fatal human case in São Paulo state, epidemiologic and virologic studies were performed in the area where the patient lived, aiming at the identification of the Sabiá natural rodent reservoir. A broadly cross-reactive enzyme-linked immunosorbent assay (ELISA) was used to screen for antibody-positive samples. Antibodies to arenavirus were detected in two of the 55 samples of Calomys tener, and from these results, samples of rodents were analyzed by a broad RT-PCR assay. RT-PCR amplification detected arenavirus sequences in five of the 55 C. tener samples, and sequencing showed that this virus is a distinct form of Sabiá virus. Thus, we describe here the evidence for the circulation of a new arenavirus in Brazil (proposed name Pinhal virus) and its genetic characterization compared to other arenaviruses. This study also suggests C. tener as a probable rodent reservoir for this virus and associates this new virus with the lineage C of New World arenaviruses. Although we have defined some characteristics of this virus, so far, there is no evidence of its involvement in human disease.

[Ilheus arbovirus in wild birds (Sporophila caerulescens and Molothrus bonariensis)]. / Arbovírus Ilheus em aves silvestres (Sporophila caerulescens e Molothrus bonariensis).

OBJECTIVE: To report the first Ilheus arboviruses isolated from wild birds and analyze its public health impact. METHODS: Wild birds and mammals were captured using mist nets and Tomahawk traps, respectively. Blood samples were drawn from these animals and inoculated intracerebrally in Swiss suckling mice found in the Parque Ecológico do Tietê, Brazil. The isolates were identified by serological tests, such as hemagglutination, hemagglutination inhibition, complement fixation and neutralization. Besides virus isolation, serum samples were also tested for the presence of hemagglutination inhibition antibodies. RESULTS: Two strains of Ilheus virus were isolated from the bird species Sporophila caerulescens and Molothrus bonariensis. Specific antibodies to Ilheus virus were detected in serum samples of some birds (Columbina talpacoti, Geopelia cuneata, Sicalis flaveola and Molothrus bonariensis), marmosets (Callithrix jacchus and Callithrix penicillata) and coati (Nasua nasua). CONCLUSIONS: Virus isolation and detection of specific antibodies in serum samples of local, migratory and captive birds, captive marmosets and wild coati corroborate the circulation of Ilheus virus in the Parque Ecológico do Tietê. The migrating behavior of some species of wild birds, like Sporophila caerulescens, enables the virus spread to other regions. Taking into consideration its human pathogenicity and the presence of the virus in this area, local authorities should be aware of the risk of infecting the local community.

Hantavirus pulmonary syndrome in the State of São Paulo, Brazil, 1993-1998.

Between 1993 and 1998, 10 cases of clinical hantavirus infection were diagnosed in Brazil. Hantavirus-specific IgM, or positive immunohistochemical analysis for hantavirus antigen, or positive reverse transcription-polymerase chain reaction results for hantavirus RNA were used to confirm nine of these cases; eight were hantavirus pulmonary syndrome (HPS), and one was mild hantavirus disease. The remaining clinical case of hantavirus infection was fatal, and no tissue was available to confirm the diagnosis. During the first 7 months of 1998, five fatal HPS cases caused by a Sin Nombre-like virus were reported from three different regions in the State of São Paulo, Brazil: two in March (Presidente Prudente Region), two in May (Ribeirão Preto Region), and one in July (Itapecerica da Serra Region). Epidemiologic, ecologic, and serologic surveys were conducted among case contacts, area residents, and captured rodents in five locations within the State of São Paulo in June of 1998. Six (4.8%) of 125 case contacts and six (5.2%) of 116 area residents had IgG antibody to Sin Nombre virus (SNV) antigen. No case contacts had a history of HPS-compatible illness, and only one area resident reported a previous acute respiratory illness. A total of 403 rodents were captured during 9 nights of trapping (1969 trap nights). All 27 rodents that were found to be positive for IgG antibody to SNV antigen were captured in crop border and extensively deforested agricultural areas where four of the 1998 HPS case-patients had recently worked. The IgG antibody prevalence data for rodents suggest that Bolomys lasiurus and perhaps Akodon sp. are potential hantavirus reservoirs in this state of Brazil.

Jungle yellow fever: clinical and laboratorial studies emphasizing viremia on a human case.

The authors report the clinical, laboratorial and epidemiological aspects of a human case of jungle yellow fever. The patient suffered from fever, chills, sweating, headaches, backaches, myalgia, epigastric pains, nausea, vomiting, diarrhea and prostration. He was unvaccinated and had been working in areas where cases of jungle yellow fever had been confirmed. Investigations concerning the yellow fever virus were performed. Blood samples were collected on several days in the course of the illness. Three of these samples (those obtained on days 5, 7 and 10) were inoculated into suckling mice in attempt to isolate virus and to titrate the viremia level. Serological surveys were carried out by using the IgM Antibodies Capture Enzyme Linked Immunosorbent Assay (MAC-ELISA), Complement Fixation (CF), Hemagglutination Inhibition (HI) and Neutralization (N) tests. The yellow fever virus, recovered from the two first samples and the virus titration, showed high level of viremia. After that, specific antibodies appeared in all samples. The interval between the end of the viremia and the appearance of the antibodies was associated with the worsening of clinical symptoms, including bleeding of the mucous membrane. One must be aware of the risk of having a urban epidemics in areas where Aedes aegypti is found in high infestation indexes.

Aortocoronary bypass surgery for coronary arterial lesions resulting from Kawasaki disease.

To establish the indications for aortocoronary bypass surgery on coronary artery lesions caused by Kawasaki disease, we analyzed surgical outcome in 26 patients. Ages at operation ranged from 1 to 17 years. All patients were followed up with selective coronary arteriography, thallium myocardial imaging, electrocardiography at rest, and the Master "two-step" and treadmill exercise tests for coronary insufficiency. Surgical outcome was analyzed by comparing results of patient examinations made preoperatively with those both at 1 month and 1 year postoperatively. One month after the operation, 25 (93%) of 27 internal mammary artery grafts and 6 (86%) of 7 saphenous vein grafts were patent; 1 year after the operation, 19 (86%) of 22 internal mammary artery grafts and 6 (67%) of 9 saphenous vein grafts were patent. By comparing the preoperative findings of myocardial imaging with those obtained 1 month after surgery, we found that 17 (68%) of 25 showed improvement and 3 (12%) of 25 were worse. At 1 year, 6 (29%) of 21 showed further improvement than at 1 month, suggesting increased development of the coronary bed after internal mammary artery graft anastomosis. Thus an internal mammary artery graft has proved to be satisfactory in the management of children with coronary artery obstruction caused by Kawasaki disease; it appears that both the quality of life and the life expectancy of those patients can be improved by the surgery.

Characterization of a class of nonformylated Enterococcus faecalis-derived neutrophil chemotactic peptides: the sex pheromones.

Bacteria produce a heterogeneous mixture of neutrophil chemotactic agents in culture filtrates. Formylmethionyl peptides have been shown to comprise a significant portion of the chemotactic activity in bacterial culture filtrates; however, not all of the chemotactic agents in bacterial culture filtrates are formylated peptides. To examine whether nonformylated peptides derived from bacteria could act as chemotactic agents, we studied several nonformylated hepta- and octapeptide Enterococcus faecalis-derived sex pheromones, their modified derivatives, and their competitive inhibitors for activation of rat peritoneal neutrophils. Several of these peptides, in particular cAM373 and cPD1, proved to be potent chemotactic agents in submicromolar concentrations as well as inducers of lysosomal granule enzyme secretion. Moreover, the more biologically active peptides were able to compete with fMet-Leu-[3H]Phe for binding to the formyl peptide receptor. These studies demonstrate that the formylmethionyl moiety may be an absolute requirement only for the binding of di- and tripeptides to the formyl peptide receptor. Larger peptides that may have or that may allow for additional contact points between the peptide and receptor may require N-formylation only relatively. Indeed, by removing this structural restraint, the formyl peptide receptor may interact with an unlimited number of peptide fragments of both infectious and host origins to then modulate neutrophil responses to infection and inflammation.

Isolation of tremerogens A-9291-I and A-9291-II, novel sex hormones of tremella brasiliensis.

Two hormones, tremerogens A-9291-I and A-9291-II, that induce conjugation tube formation in a-type cells of Tremella brasiliensis were isolated from the culture filtrate of A-type cells. Both hormones are peptides and they have similar amino acid compositions. The N-terminal amino acids of these peptides are aspartic acid or asparagine.