Towards a vaccine against rheumatic fever.

Rheumatic fever (RF) is an autoimmune disease which affects more than 20 million children in developing countries. It is triggered by Streptococcus pyogenes throat infection in untreated susceptible individuals. Carditis, the most serious manifestation of the disease, leads to severe and permanent valvular lesions, causing chronic rheumatic heart disease (RHD). We have been studying the mechanisms leading to pathological autoimmunity in RF/RHD for the last 15 years. Our studies allowed us a better understanding of the cellular and molecular pathogenesis of RHD, paving the way for the development of a safe vaccine for a post-infection autoimmune disease. We have focused on the search for protective T and B cell epitopes by testing 620 human blood samples against overlapping peptides spanning 99 residues of the C-terminal portion of the M protein, differing by one amino acid residue. We identified T and B cell epitopes with 22 and 25 amino acid residues, respectively. Although these epitopes were from different regions of the C-terminal portion of the M protein, they showed an identical core of 16 amino acid residues. Antibodies against the B cell epitope inhibited bacterial invasion/adhesion in vitro. Our results strongly indicated that the selected T and B cell epitopes could potentially be protective against S. pyogenes.

Rheumatic fever: how S. pyogenes-primed peripheral T cells trigger heart valve lesions.

The pathogenesis of rheumatic fever (RF) is related to autoimmune humoral and cellular responses against human tissues triggered by Streptococcus pyogenes. CD4(+) T cells are the ultimate effectors of chronic heart lesions in rheumatic heart disease (RHD). Heart-infiltrating CD4(+) T cell clones are able to recognize heart tissue and streptococcal antigens by molecular mimicry. The streptococcal M5(81-103) region, an immunodominant region, was recognized by both intralesional and peripheral T cell clones (62% and 38%, respectively). Peripheral T lymphocytes from Brazilian patients with severe RHD preferentially recognized the M5(81-96) peptide, in the context of HLA-DR7(+) and DR53(+) molecules. HLA-DR7 seems to be related to the development of multiple valvular lesions in RHD patients from different countries. In addition, the fact that peripheral and intralesional T cells recognized the M5(81-103) region points to this region as one of the streptococcal triggers of autoimmune reactions in RHD. T cell repertoire analysis from peripheral and intralesional T cell lines derived from RHD patients showed several oligoclonal expansions of BV families. Major expansions were found in the heart lesions, suggesting that such T cell populations preferentially migrate from the periphery to the heart. Some cross-reactive intralesional T cell clones displayed the same T cell receptor (TCR) BVBJ and CDR3 sequences, showing a degenerate pattern of antigen recognition. Heart tissue-infiltrating cells from myocardium and valvular tissue produced TNF-alpha, IFN-gamma, IL-10, and IL-4, whereas few cells from valvular tissue produced IL-4, showing that the lack of regulation in the valves could be responsible for the permanent and progressive valvular lesions.

T-cell reactivity against streptococcal antigens in the periphery mirrors reactivity of heart-infiltrating T lymphocytes in rheumatic heart disease patients.

T-cell molecular mimicry between streptococcal and heart proteins has been proposed as the triggering factor leading to autoimmunity in rheumatic heart disease (RHD). We searched for immunodominant T-cell M5 epitopes among RHD patients with defined clinical outcomes and compared the T-cell reactivities of peripheral blood and intralesional T cells from patients with severe RHD. The role of HLA class II molecules in the presentation of M5 peptides was also evaluated. We studied the T-cell reactivity against M5 peptides and heart proteins on peripheral blood mononuclear cells (PBMC) from 74 RHD patients grouped according to the severity of disease, along with intralesional and peripheral T-cell clones from RHD patients. Peptides encompassing residues 1 to 25, 81 to 103, 125 to 139, and 163 to 177 were more frequently recognized by PBMC from RHD patients than by those from controls. The M5 peptide encompassing residues 81 to 96 [M5(81-96) peptide] was most frequently recognized by PBMC from HLA-DR7+ DR53+ patients with severe RHD, and 46.9% (15 of 32) and 43% (3 of 7) of heart-infiltrating and PBMC-derived peptide-reactive T-cell clones, respectively, recognized the M5(81-103) region. Heart proteins were recognized more frequently by PBMC from patients with severe RHD than by those from patients with mild RHD. The similar pattern of T-cell reactivity found with both peripheral blood and heart-infiltrating T cells is consistent with the migration of M-protein-sensitized T cells to the heart tissue. Conversely, the presence of heart-reactive T cells in the PBMC of patients with severe RHD also suggests a spillover of sensitized T cells from the heart lesion.

Heart-directed autoimmunity: the case of rheumatic fever.

Molecular mimicry was proposed as a potential mechanism for streptococcal sequelae leading to rheumatic fever (RF) and rheumatic heart disease (RHD). CD4(+)infiltrating T cells are able to recognize streptococcal M peptides and heart tissue proteins. We analyzed the M5 peptide- and heart-specific responses, cytokine profile and T cell receptor (TCR) BV usage from peripheral and heart-infiltrating T cell lines and clones from patients across the clinical spectrum of ARF/RHD. The patient with ARF displayed a higher frequency of mitral valve infiltrating T cell clones reactive against M5: 1-25, 81-103 and 163-177 regions and several valve-derived proteins than the post-RF and chronic RHD patient (67%; 20% and 27%, respectively). The presence of oligoclonal BV families indicative of oligoclonal T cell expansion among mitral valve-derived T cell lines was increased in the chronic RHD patient. Furthermore, mitral valve T cell lines from all patients produced significant amounts of inflammatory cytokines interferon-gamma (IFN-gamma) and tumour necrosis factor-alpha (TNFalpha) in response to M5(81-96) peptide, with the highest production attained by the chronic RHD patient. These data are consistent with an important role for M5 peptide and host antigen-driven, T1-type CD4(+)T cells in the pathogenesis of RHD and heart lesion progression after recurrence of the streptococcal infection.

[Stillbirth as a perinatal health indicator]. / A natimortalidade como indicador de saúde perinatal.

The authors carried out a literature review of the subject "stillbirth", with special emphasis on its conceptual and epidemiological features, aimed at highlighting its importance as a perinatal health indicator.

Molecular evidence for antigen-driven immune responses in cardiac lesions of rheumatic heart disease patients.

Rheumatic heart disease (RHD) is a sequel of post-streptococcal throat infection. Molecular mimicry between streptococcal and heart components has been proposed as the triggering factor of the disease, and CD4(+) T cells have been found predominantly at pathological sites in the heart of RHD patients. These infiltrating T cells are able to recognize streptococcal M protein peptides, involving mainly 1-25, 81-103 and 163-177 N-terminal amino acids residues. In the present work we focused on the TCR beta chain family (TCR BV) usage and the degree of clonality assessed by beta chain complementarity-determining region (CDR)-3 length analysis. We have shown that in chronic RHD patients, TCR BV usage in peripheral blood mononuclear cells (PBMC) paired with heart-infiltrating T cell lines (HIL) is not suggestive of a superantigen effect. Oligoclonal T cell expansions were more frequently observed in HIL than in PBMC. Some major BV expansions were shared between the mitral valve (Miv) and left atrium (LA) T cell lines, but an in-depth analysis of BJ segments usage in these shared expansions as well as nucleotide sequencing of the CDR3 regions suggested that different antigenic peptides could be predominantly recognized in the Miv and the myocardium. Since different antigenic proteins probably are constitutively represented in myocardium and valvular tissue, these findings could suggest a differential epitope recognition at the two lesional heart sites after a common initial bacterial challenge.

[Early neonatal mortality in Caxias do Sul: a cohort study] / Mortalidade neonatal precoce no município de Caxias do Sul: um estudo de coorte.

OBJECTIVES: To establish the profile of neonates in Caxias do Sul city, and to study early neonatal mortality, its causes and related variables.METHODS: This cohort study enrolled 5,545 newborns, which were followed up to 7 days after birth. The probability of early neonatal mortality was calculated and multiple logistic regression was performed to relate all studied variables to the outcome of early neonatal death.RESULTS: The observed probability of early neonatal mortality was 7.44 per thousand live births. The incidence of premature births and low birth weight was 9.4% and 8.1%, respectively. Fifty five percent of the neonates were born through cesarean section, which were related to socioeconomic and educational level. Previous history of neonatal mortality, maternal age > 35 years, gestational age, Apgar score < 7, male sex and low birth weight were related to early neonatal death. The main cause of death was hyaline membrane disease, followed by congenital cardiopaties, extreme preterm and abruptio placentae.CONCLUSION: Even though the observed probability of early neonatal mortality was low, some deaths may have been avoided if better prenatal and delivery care, as well as newborn assistance had been offered.

[Health and nutritional status of infants in a population of the Center-Western region of Brazil]. / Saúde e estado nutricional infantil de uma população da região Centro-Oeste do Brasil.

OBJECTIVE: To evaluate the nutritional status of infants who reside in the city of Campo Grande, State of Mato Grosso do Sul, Brazil. METHODS: The method used was that of a cross sectional household study by means of an anthropometric social survey, sampling 652 children from 0 to 59 months of age. RESULTS: A low prevalence of nutritional deficit, excepting that of height-for-age, starting in the first year of life, was found. The nutritional status proved to be influenced by the socioeconomic conditions, especially concerning per capita family income. Nearly all children started breast-feeding but were weaned during the first month. Exclusive breast-feeding is of short duration and soon replaced by infant formula. The survey of mother-child assistance demonstrated an excellent coverage of prenatal care, but inadequacy in the follow-up of the child's health at all income levels. CONCLUSIONS: The need to carry out changes in the approach to preventive actions and in the monitoring of the nutritional situation of the children, concerning the problems identified in this study in order to allow for the development of differential actions in the nutritional field has been identified.

[Female mortality in the Municipality of São Paulo: quality of medical death certificates]. / Mortalidade feminina na região Sul do Município de São Paulo: qualidade da certificação médica dos óbitos.

OBJECTIVE: To evaluate the quality of the medical certification of deaths of 10-49 year-old women, resident in the Southern region of the city of S. Paulo METHODS: The Puffer methodology was utilized to investigate the causes of death of all 10-49 year-old women, resident in the region, and deceased in the year 1989 (664 deaths in the total). The main causes of death in the original death certificates and the "new" causes of death arisen from the research were compared. The sensitivity and the kappa index were calculated. RESULTS: In some chapters of the International Classification of Diseases and Causes of Death, 9th Revision (CID-9), a high sensitivity was found: "Diseases of the Circulatory System" (91.9%), "Neoplasms" (89.7%) and "External Causes" (84.1 %). In some others, a very low sensitivity was found. The chapter "Mental Illnesses", with a 34.3 percent sensitivity only, must be mentioned. From 11 deaths originally classified in this chapter, 32 cases were found. In most of these "new" cases, the main cause of death was found to be alcoholism. The chapter "Complications of Pregnancy, Delivery and the Puerperium", also showed a low sensitivity (44.9%). The kappa index was found to be 0.63, which indicated a regular concordance. DISCUSSION: The quality of the medical certification of causes of death is still unsatisfactory in the studied area. This poor quality may affect negatively the interventions in the area of women's health, masking the severity of important problems

Mid-upper arm circumference in pregnant women and its relation to birth weight.

OBJECTIVE: In order to determine the relationship between some maternal anthropometric indicators and birth weight, crown-heel length and newborn's head circumference, 92 pregnant women were followed through at the prenatal service of hospital in S. Paulo, Brazil. MATERIAL AND METHOD: The following variables were established for the mother: weight, height, mid-upper arm circumference, pre-pregnancy weight, gestational weight gain and Quetelet's index. For the newborn the following variables were recorded: birth weight, crown-heel length, head circumference and gestational age by Dubowitz's method. RESULTS: Significant associations were noted between gestational age and newborn variables. In addition, maternal mid-arm circumference (MUAC) and pre-pregnancy weight were found to be positively correlated to birth weight (r = 0.399; r = 0.378, respectively). The multivariate linear regression shows that gestational age, mother's arm circumference and pre-pregnancy weight continue to be significant predictors of birth weight. On the other hand, only gestational age and mother's age was associated with crown-heel length. Similarly MUAC was significantly associated with crown-heel length (r = 0.306; P = 0.0030). CONCLUSION: Maternal mid-upper arm circumference is a potential indicator of maternal nutritional status. It could be used in association with other anthropometric measurements, instead of pre-pregnancy weight, as an alternative indicator to assess women at risk of poor pregnancy outcome.

[Paradigms in obstetric nursing]. / Os paradigmas da enfermagem obstétrica.

The course of childbirth care practice in England and in the United States of America can be described by focusing on the relationship between the incipient nursing profession and the traditional profession of midwife, throughout the XVIIIth and the XIXth centuries. This paper proposes the study of such a relationship by adopting the Greek mythology goddesses as archetypical figures of female behavior. It relates the nurse to the goddess Athena, protector of the arts, the cities, the patriarchal values, the status quo-the personification of the father's daughter archetype-and the traditional midwife to Artemis, goddess of the hunt and the moon, protector of the wilderness, the weak, and the young-the personification of the great sister archetype. Under such a perspective, it deals with the decline of the traditional midwife practice in those countries. Finally, it poses the question of the obstetrics nursing pattern as something to be constituted in conformity and in complicity with the women's organized movement and their claims in the field of health.

[Aortic arch interruption with restrictive ductus arteriosus]. / Interrupção do arco aórtico com canal arterial restritivo.

Interruption of the aortic arch is an uncommon cardiovascular anomaly. It is usually associated with a large ductus arteriosus (DA) and interventricular septal defects. Two cases of one and two month old girls with restrictive DA are reported. The clinical, anatomical and surgical findings are discussed.

[Transposition of the great arteries with posterior aorta]. / Transposição das grandes artérias com aorta posterior.

Two cases of transposition of the great arteries (TGA) with posterior aorta are reported. The first was submitted to the Senning procedure with good outcome; the other had the diagnosis of double outlet right ventricle with severe pulmonary stenosis, and a Blalock-Taussig shunt was accomplished for hypoxic crisis. The patient died 11 days after surgery and the necropsy demonstrated TGA with posterior aorta. In both cases there was a sub-pulmonary infundibulum. The presence of ventricular septal defects allowed aortic-mitral fibrous continuity, a finding previously described in anatomical reports. Clinical and angiographic aspects are discussed.

[Maternal and perinatal health status in the State of São Paulo, Brazil]. / Situação de saúde materna e perinatal no Estado de São Paulo, Brasil.

The assistance offered during pregnancy and labour as also to the newborn child, and its relationship to maternal and perinatal mortality in the State of S. Paulo in 1984, is analysed on the basis of official available data. With respect to prenatal care the number of visits per woman was considered to be "sufficient" though of doubtful quality. The proportion of cesarean sections was very high (46.2%). Maternal mortality was found to be 4.86 deaths per 10,000 live births, but despite its being high, this figure is certainly too low and the correct figure is probably twice as high. The principal cause of maternal deaths is toxemia in pregnancy, followed by hemorrhage and abortion. Most of these deaths could have been avoided with care during pregnancy and labour. The rate of perinatal mortality was found to be 29.2 deaths per thousand births in 1984. This figure is also very high. The analysis of the causes of death for this period showed that the disorders which arose during the perinatal period were responsible for 90 per cent of the total number of deaths. The main causes of death in this group were the intra-uterine hypoxias and anoxias, asphyxia, respiratory distress syndrome and massive aspiration syndrome. These data bring to light the poor quality of the care offered to this group. The authors trust that the new policy of the Decentralized and Unified System of Health will take the quality of care as much as the integration of services into consideration with a view to overcoming the precarious maternal and perinatal health situation in S. Paulo.

[Maternal mortality in Brazil, 1980]. / Mortalidade materna no Brasil, 1980.

PIP: The authors studied Brazilian maternal mortality by examining official statistics from the country's various geographical regions, including the state of Sao Paulo, Brazil. 1980 was selected because of the possibility of working with data from the Population Census of that year. The principal causes of death in Brazil were hypertension, hemorrhage, puerperal infection, and abortion. In Sao Paulo, where the 4th digit of the IDC is used, the main cause of death was eclampsia. The 2nd was hemorrhage, and the 3rd was infection, whether due to or associated with pregnancy. As for age, the lowest maternal mortality rate occurred in the 20-29 year old age group, the rate was slightly higher for those ages 15-19, and increasing gradually in those ages 30-39 and 40-49. It was not possible to analyze the rates for those ages 10-14 and over age 50 because of lack of data on livebirths. However, there were 18 deaths and 4 deaths respectively in those groups which shows that at opposite poles of the reproductive span, there exists a considerably high mortality rate. In comparing these data with those of other countries, it was found that the majority of deaths are avoidable and that it should be possible to reduce the number considerably by means of better health care for women and by using techniques and resources which are already available. (author's modified)^ieng