Familial aggregation and linkage analysis of autoantibody traits in pedigrees multiplex for systemic lupus erythematosus.

Autoantibodies are clinically relevant biomarkers for numerous autoimmune disorders. The genetic basis of autoantibody production in systemic lupus erythematosus (SLE) and other autoimmune diseases is poorly understood. In this study, we characterized autoantibody profiles in 1,506 individuals from 229 multiplex SLE pedigrees. There was strong familial aggregation of antinuclear antibodies (ANAs), anti-double-stranded DNA (dsDNA), anti-La/SSB, anti-Ro/SSA, anti-Sm, anti-nRNP (nuclear ribonucleoprotein), IgM antiphospholipid (aPL) antibodies (Abs) and rheumatoid factor (RF) across these families enriched for lupus. We performed genome-wide linkage analyses in an effort to map genes that contribute to the production of the following autoantibodies: Ro/SSA, La/SSB, nRNP, Sm, dsDNA, RF, nuclear and phospholipids. Using an approach to minimize false positives and adjust for multiple comparisons, evidence for linkage was found to anti-La/SSB Abs on chromosome 3q21 (adjusted P=1.9 x 10(-6)), to anti-nRNP and/or anti-Sm Abs on chromosome 3q27 (adjusted P=3.5 x 10(-6)), to anti-Ro/SSA and/or anti-La/SSB Abs on chromosome 4q34-q35 (adjusted P=3.4 x 10(-4)) and to anti-IgM aPL Abs on chromosome 13q14 (adjusted P=2.3 x 10(-4)). These results support the hypothesis that autoantibody production is a genetically complex trait. Identification of the causative alleles will advance our understanding of critical molecular mechanisms that underlie SLE and perhaps other autoimmune diseases.

An international comparison of cancer survival: metropolitan Toronto, Ontario, and Honolulu, Hawaii.

OBJECTIVES: Comparisons of cancer survival in Canadian and US metropolitan areas have shown consistent Canadian advantages. This study tests a health insurance hypothesis by comparing cancer survival in Toronto, Ontario, and Honolulu, Hawaii. METHODS: Ontario and Hawaii registries provided a total of 9190 and 2895 cancer cases (breast and prostate, 1986-1990, followed until 1996). Socioeconomic data for each person's residence at the time of diagnosis were taken from population censuses. RESULTS: Socioeconomic status and cancer survival were directly associated in the US cohort, but not in the Canadian cohort. Compared with similar patients in Honolulu, residents of low-income areas in Toronto experienced 5-year survival advantages for breast and prostate cancer. In support of the health insurance hypothesis, between-country differences were smaller than those observed with other state samples and the Canadian advantage was larger among younger women. CONCLUSIONS: Hawaii seems to provide better cancer care than many other states, but patients in Toronto still enjoy a significant survival advantage. Although Hawaii's employer-mandated health insurance coverage seems an effective step toward providing equitable health care, even better care could be expected with a universally accessible, single-payer system.

An international comparison of cancer survival: relatively poor areas of Toronto, Ontario and three US metropolitan areas.

BACKGROUND: This study of cancer survival compared adults in Toronto, Ontario and three US metropolitan areas: Seattle, Washington; San Francisco, California; and Hartford, Connecticut. It examined whether socioeconomic status has a differential effect on cancer survival in Canada and the United States. METHODS: The Ontario Cancer Registry and the National Cancer Institute's Surveillance, Epidemiology and End RESULTS: (SEER) programme provided a total of 23,437 and 37,329 population-based primary malignant cancer cases for the Toronto and US samples, respectively (1986-1988, followed until 1994). Census-based measures of socioeconomic status were used to ecologically control absolute income status. RESULTS: Among residents of low-income areas, persons in Toronto experienced a 5 year survival advantage for 13 of 15 cancer sites [minimally one gender significant at 95 per cent confidence interval (CI)]. An aggregate 35 per cent survival advantage among the Canadian cohort was demonstrated (survival rate ratio (SRR) = 1.35, 95 per cent CI= 1.30-1.40), and this effect was even larger among younger patients not yet eligible for Medicare coverage in the United States (SRR = 1.46, 95 per cent CI = 1.40-1.52). CONCLUSION: Systematically replicating a previous Toronto-Detroit comparison, this study's observed consistent pattern of Canadian survival advantage across various cancer sites suggests that their more equitable access to preventive and therapeutic health care services may be responsible for the difference.

Evaluation of common problems in primary care: effects of physician, practice, and financial characteristics.

OBJECTIVES: To identify the resource use and costs associated with the diagnosis of common problems in primary care practice and to investigate the influence of physician characteristics, practice organization, and financial incentives on physician behavior. STUDY DESIGN: Cross-sectional survey. PATIENTS AND METHODS: A national sample of 1721 primary care physicians from 53 managed care organizations were surveyed about their use of diagnostic laboratory, imaging, and invasive procedures; ambulatory visits; empiric drug therapies; and specialty consultations for a hypothetical middle-aged female patient presenting with 1 of 6 common clinical problems: depression, fatigue, impaired memory, anxiety, low back pain, or high cholesterol. Information regarding the physician's arrangement with managed care organizations was also collected. Cost estimates were made from Maryland Medicare Fee Schedule and Red Book data. RESULTS: Total costs (mean +/- standard deviation) were estimated for management of depression ($520 +/- $235), fatigue ($389 +/- $201), impaired memory ($569 +/- $243), high cholesterol ($367 +/- $191), low back pain ($726 +/- $369), and anxiety ($438 +/- $207). Younger physicians (less than 50 years old) generated higher costs in the treatment of depression but used fewer resources in the evaluation of high cholesterol. Physicians paid by salary had significantly lower costs compared with physicians in fee-for-service arrangements for depression and high cholesterol (P < .05). Physicians in multispecialty groups were more likely to have lower costs for depression and low back pain in multivariate analyses. More stringent financial incentives such as capitation, withholds, and bonuses were not associated with lower costs. CONCLUSIONS: Multispecialty group practice and compensation by salary consistently predict lower costs for evaluation of common problems in primary care practice. Financial incentives such as capitation, withholds, and bonuses were not associated with an effect on costs of diagnostic evaluation.

The Asian Pacific Economic Cooperation Emerging Infections Network.

ISSUE: The Asia Pacific Economic Cooperation (APEC) has undertaken an initiative in emerging infections. PROJECT: The APEC Emerging Infections Network project uses collaborative telecommunications tools such as e-mail and a World Wide Web site to bridge the broad geographic expanse and diversity of APEC. Scientists and policymakers share information to effectively combat emerging infectious disease (EID) through surveillance, prevention, research, and control measures. RESULTS: In the project's first year, site visits compiled information on Internet access in selected economies. Information sharing via electronic lists has been successful; feedback suggests that these strategies will become increasingly useful. The Emerging Infections Network (EINet) Web site includes project information, library access, surveillance data, prevention guidelines, and distance learning resources. A pilot effort to promote the secure electronic exchange of surveillance data demonstrated that informal communications may be both preferable and more feasible during the early stages of this project. LESSONS LEARNED: Human networking is as important as technology-based networking in addressing emerging infections. Internet technology in some APEC economies is barely adequate, but is becoming more reliable and accessible. Numerous member economies are eager to be included in project activities.

Transvaginal chorionic villus sampling using transabdominal ultrasound guidance.

Transvaginal chorionic villus sampling (CVS) using concurrent transabdominal ultrasound guidance was performed in six women who desired CVS but could not be offered transcervical or transabdominal approaches because of uterine position and placental location. Satisfactory amounts of chorionic villi were obtained in all six cases with no maternal discomfort, an occurrence that contrasts with our experience in transvaginal CVS using endovaginal ultrasound guidance. We believe that transvaginal CVS using concurrent transabdominal ultrasound guidance warrants consideration as an alternative technique for first-trimester CVS in selected patients.

Subglottic cysts in the premature infant.

Supraglottic cysts in the newborn are a well-recognized entity, but subglottic cysts have been rarely reported. Over the past 6 years we have observed subglottic cysts in nine patients with relatively long intubations from the neonatal intensive care unit of two university hospitals. Most frequently the patients were extubated and did well for weeks or months, but then they had progressive biphasic stridor. On endoscopy the patients had a subglottic stenosis that was irregular but with a smooth mucosal lining. Usually the cysts were apparent, but in two patients the mucosa was thickened and the patients were treated as a subglottic stenosis with tracheostomy. These subglottic cysts were recognized at the time of laryngotracheoplasty. In six patients the cysts were managed either by marsupialization with cup forceps, endoscopic diathermy, or carbon dioxide laser without recurrence. It is our belief that this condition is most likely due to scarring and obstruction of mucus glands of the subglottic area from prolonged intubation. This entity should be recognized and looked for in the neonate who has an acquired subglottic stenosis and should first be treated conservatively with endoscopic marsupialization.

Presynaptic alpha 2-adrenoreceptors affecting terminal synaptic transmission by the nervi cardiaci accelerantes in the rat.

1. Changes in heart rate were monitored in response to supramaximal electrical stimulation of the spinal sympathetic cardiac nerves in the pithed rat. 2. Submaximal positive chronotropic responses of the heart to stimulation (0.1-1.0 Hz) were inhibited after intravenous injection of the alpha 2-adrenoreceptor agonists B-HT 920 and xylazine, but not after the alpha 1-adrenoreceptor agonist methoxamine. 3. The alpha 2-adrenoreceptor antagonist yohimbine or idazoxan but not the alpha 1-adrenoreceptor antagonist prazosin, given intravenously, reduced the inhibitory effect of B-HT 920 on positive chronotropic responses to cardiac sympathetic nerve stimulation. Neither yohimbine, idazoxan nor prazosin had any effect on positive chronotropic responses to nerve stimulation. 4. Desmethylimipramine (DMI) potentiated the increased heart rate during continuous stimulation of the cardiac nerves at 0.2 Hz. Responses to stimulation, at this frequency, were unaffected by yohimbine, either in the absence or presence of the neuronal uptake inhibitor, DMI. 5. Intravenous infusion of the angiotensin antagonist saralasin or injection of the angiotensin converting enzyme inhibitor captopril had no significant effect, either on positive chronotropic responses to stimulation or on the inhibitory effects of B-HT 920. Positive chronotropic responses to stimulation were also unaffected by yohimbine in the presence of captopril, indomethacin, or indomethacin plus captopril. 6. Although presynaptic effects of alpha 2-agonists and their antagonists on cardiac nerve function were demonstrated, no evidence was obtained that prejunctional alpha 2-adrenoreceptors modulate transmission during continuous supramaximal firing at constant frequency.(ABSTRACT TRUNCATED AT 250 WORDS)

Sequence conservation in potential regulatory regions of the mouse and human leukocyte common antigen gene.

The leukocyte common antigen is a family of glycoproteins uniquely expressed by cells of hemopoietic origin. The family is generated by alternative splicing of 3 exons, and individual members are expressed in a cell type-specific fashion. The glycoprotein consists of a heavily glycosylated exterior domain of approximately 100 kDa, a single membrane spanning region, and a cytoplasmic domain that has homology to a protein tyrosine phosphatase of 83 kDa. To further understand the regulation and structure of this family of molecules, genomic clones were isolated from mouse lambda and cosmid libraries. The genomic organization was determined from 20 genomic clones. Eighteen of the clones clustered within a 75-kilobase region, whereas the promoter region, the exons for the 5'-untranslated region, and the leader domain are located an unknown distance further 5' within in an unlinked clone. The gene is composed of 34 exons: two 5'-untranslated exons, 1a and 1b, and 32 exons that encode protein sequence. Exon 2 contains part of the 5'-untranslated region and encodes the 23 amino acids of the leader sequence. Exons 3-15 encode amino acid residues 1-538 of the external domain, exon 16 encodes residues 539-574, encompassing the membrane-spanning domain, and exons 17-33 encode residues 575-1268 of the cytoplasmic domain. Exon 33, the largest exon, contains the 1.1-kilobase 3'-untranslated region. A comparison between mouse and human (Hall, L.R., Streuli, M., Schlossman, S.F., and Saito, H. (1988) J. Immunol. 141, 2781-2787) promoter regions reveals significant homologies 5' to the transcription start site. The relationship between exon structure and glycoprotein structure is discussed.

Differences in the chromatographic and mass spectral properties of 3,3',5,5'-tetrachlorodiphenoquinone and 2,3,7,8-tetrachlorodibenzo-p-dioxin.

Tetrachlorodiphenoquinones have the same exact mass and elemental composition as the toxic environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin. However, analysis of 3,3'-5,5'-tetrachlorodiphenoquinone showed a pronounced tendency toward chemical reduction in the mass spectrometer to the quinol compound, producing a molecular ion two mass units higher than 2,3,7,8-tetrachlorodibenzo-p-dioxin. Distinct differences were also apparent between the mass spectral fragmentation patterns of 3,3',5,5'-tetrachlorodiphenoquinone and 2,3,7,8-tetrachloridibenzo-p-dioxin. The 3,3',5,5'-tetrachlorodiphenoquinone spectrum shows a successive loss of carbon monoxide, with the most prominent fragment corresponding to loss of two molecules of carbon monoxide plus chlorine. In the mass fragmentation of 2,3,7,8-tetrachlorodibenzo-p-dioxin carbon monoxide loss is suppressed, but loss of one molecule of carbon monoxide plus chlorine is a major fragment ion. During an alumina column clean-up procedure 3,3',5,5'-tetrachlorodiphenoquinone did not coelute with the fraction containing 2,3,7,8-tetrachlorodibenzo-p-dioxin. This evidence indicates that tetrachlorodiphenoquinones are unlikely to interfere with mass spectrometric determination of 2,3,7,8-tetrachlorodibenzo-p-dioxin in environmental samples.

Regulation of nitrogenase in the photosynthetic bacterium Rhodopseudomonas capsulata as studied by two-dimensional gel electrophoresis.

By using two-dimensional electrophoresis, five putative soluble nif gene products were identified, and the regulation of nif gene expression in Rhodopseudomonas capsulata was investigated. Expression of nif was repressed by ammonia and atmospheric concentrations of oxygen. Deprivation of molybdenum caused an interesting pattern of partial repression of nif gene expression that was not relieved by tungsten. These results are discussed in relation to the better understood system of nif regulation in Klebsiella pneumoniae.

Isolation and characterization of a protein with cyanide-sensitive superoxide dismutase activity from the prokaryote, Paracoccus denitrificans.

1. A protein with cyanide-sensitive superoxide dismutase activity was isolated from the prokaryote Paracoccus denitrificans. 2. This enzyme, present in low amount in the cell, represented not more than 10% of the total cellular superoxide dismutase activity. It was obtained in a form which was 20-40-times less active than the main superoxide dismutase of P. denitrificans which is a manganese-containing enzyme. 3. It was a soluble monomeric enzyme, highly negatively charged (pI = 4.8), with an apparent molecular weight of 33,000. 4. Cyanide sensitivity was observed by NMR assay, enzyme assay and by staining the protein for superoxide dismutase activity on polyacrylamide electrophoretogram. KCN was shown to be a competitive inhibitor of this dismutase, with an inhibitor constant of 0.15 mM. 5. From the amino acid analysis, S delta Q values lower than 100 were obtained with copper-containing proteins such as the subunit II of cytochrome oxidase from P. denitrificans (69), the azurin from P. denitrificans (77), the bacteriocuprein from Photobacter leiognathi (71); with iron and manganese superoxide dismutases (40-88), and with some eukaryotic copper/zinc dismutases of fish origin (55-82).

Nitrogenase from the photosynthetic bacterium Rhodopseudomonas capsulata: purification and molecular properties.

Nitrogenase proteins were isolated from cultures of the photosynthetic bacterium Rhodopseudomonas capsulata grown on a limiting amount of ammonia. Under these conditions, the nitrogenase N2ase A was active in vivo, and nitrogenase activity in vitro was not dependent upon manganese and the activating factor. The nitrogenase proteins were also isolated from nitrogen-limited cultures in which the in vivo nitrogenase activity had been stopped by an ammonia shock. This nitrogenase activity, N2ase R, showed an in vitro requirement for manganese and the activating factor for maximal activity. The Mo-Fe protein (dinitrogenase) was composed of two dissimilar subunits with molecular weights of 55,000 and 59,500; the Fe protein (dinitrogenase reductase), from either type of culture, was composed of a single subunit (molecular weight), 33,500). The metal and acid labile sulfur contents of both nitrogenase proteins were similar to those found for previously isolated nitrogenases. The Fe proteins from both N2ase A and N2ase R contained phosphate and ribose, 2 mol of each per mol of N2ase R Fe protein and about 1 mol of each per mol of N2ase A Fe protein. The greatest difference between the two types of Fe protein was that the N2ase R Fe protein contained about 1 mol per mol of an adenine-like molecule, whereas the N2ase A Fe protein content of this compound was insignificant. These results are compared with various models previously presented for the short-term regulation of nitrogenase activity in the photosynthetic bacteria.

Ostemielitis por Salmonella (sindrome mano-pie). / Osteomyelitis by Salmonella (hand-food syndrome)

Nos alento para la presentacion de este trabajo, la rara incidencia de osteomielitis com las caracteristicas del sindrome mano-pie, sin estar asociado a la drepanocitosis. Presentamos a una nina de 3 anos de edad que, luego de un episodio de deshidratacion aguda, manifiesta un cuadro septico con hemocultivos y coprovultivos positivos para Salmonella paratyphi A. Se observa tumefaccion dolorosa en ambas manos y en ambos pies que, posteriormente, tiene manifestacion radiologica compatible con osteomielitis (imagenes en sacabocado en todos los metacarpianos y metatarsianos Se le instituyo tratamiento segun antibiograma, obteniendose una mejoria clinica y radiologica ostensible

Ostemielitis por Salmonella (sindrome mano-pie). / Osteomyelitis by Salmonella (hand-food syndrome)

Nos alento para la presentacion de este trabajo, la rara incidencia de osteomielitis com las caracteristicas del sindrome mano-pie, sin estar asociado a la drepanocitosis. Presentamos a una nina de 3 anos de edad que, luego de un episodio de deshidratacion aguda, manifiesta un cuadro septico con hemocultivos y coprovultivos positivos para Salmonella paratyphi A. Se observa tumefaccion dolorosa en ambas manos y en ambos pies que, posteriormente, tiene manifestacion radiologica compatible con osteomielitis (imagenes en sacabocado en todos los metacarpianos y metatarsianos Se le instituyo tratamiento segun antibiograma, obteniendose una mejoria clinica y radiologica ostensible

Sport and recreation for the severely disabled.

A classification of sport and recreation and an explanation of the term "severely" disabled are given, as well as the physical, psychological, social and work attributes of sport and the problems experienced by the disabled in these areas. The relevance and importance of occupational therapy in this field are briefly discussed and the article concludes with an introduction to the SA Sports Association for the physically disabled. A list of recognized competitive sports for the various groups and an address list for the use of medical practitioners and allied professions is given.