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1.
J Exp Med ; 144(3): 754-67, 1976 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-182898

RESUMO

Lipids extracted from rabbit skin block the hemolytic capacity of SO and also suppress the neutralizing antibody response to this streptococcal extracellular antigen in rabbith immunized intravenosly. The modification in antibody response is specific for SO; the antibody responses to streptococcal DNase B and to streptococcal NADase are not affected. Cholesterol, a lipid present in abundance in skin, has a similar specific effect on the antigenicity of SO and may be the component responsible for the demonstrated effects of these lipid extracts of skin. In vitro experiments indicate that lipid extracts of rabbit skin have a greater capacity to block the hemolytic capacity of SO than do lipid extracts of rabbit heart, kidney, lung, liver, or spleen. These data support the view that the feeble ASO response observed in patients with streptococcal pyoderma is a result of the abundance of a local lipid inhibitor, such as cholesterol, in the skin. They may also bear on the pathogenesis of rheumatic fever, a complication which apparently does not occur following group A streptococcal pyoderma. Two possible explanations for this remarkable epidemiologic observation, both related to the presence of a local inhibitor, are considered: (a) suppression of the ASO response, the magnitude of which has been correlated with the risk of developing rheumatic fever after streptococcal infection of the throat, and (b) inhibition of the toxicity of SO, which has been shown to have a direct toxic effect on the mammalian heart and on isolated beating myocytes.


Assuntos
Anticorpos Antibacterianos/biossíntese , Terapia de Imunossupressão , Lipídeos/farmacologia , Pele/imunologia , Streptococcus pyogenes/imunologia , Estreptolisinas/imunologia , Animais , Formação de Anticorpos/efeitos dos fármacos , Colesterol/farmacologia , Desoxirribonucleases/imunologia , NAD+ Nucleosidase/imunologia , Coelhos , Estreptolisinas/antagonistas & inibidores
2.
J Clin Invest ; 49(11): 2146-9, 1970 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-5475987

RESUMO

In man, oral administration of 1 g of phosphorus resulted in a 60-125% increase in serum immunoassayable parathyroid hormone (PTH) concentration. Peak PTH levels were attained in 1 hr, and PTH returned to base line levels in 2 hr. This increase in PTH appeared to be initiated by a very small decrease of total and ionized calcium and was abolished by a calcium infusion. There was no correlation between serum phosphorus and PTH. The experiments show that oral phosphorus administration initiates a calcium-mediated control system for PTH secretion and that this system operates very sensitively in man.


Assuntos
Cálcio/metabolismo , Hormônio Paratireóideo/metabolismo , Fosfatos/fisiologia , Adulto , Feminino , Humanos , Masculino , Hormônio Paratireóideo/sangue , Fosfatos/administração & dosagem , Fósforo/sangue , Radioimunoensaio , Fatores de Tempo
3.
J Clin Invest ; 48(9): 1697-704, 1969 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-5822578

RESUMO

Prospective studies in a population of American Indian children during an outbreak of acute nephritis associated with the Type 49 Group A streptococcus permitted a comparison of attack rates of renal complications after infection at different sites and at different ages. Acute nephritis or unexplained hematuria developed in 10 of 42 children (23.8%) with Type 49 streptococcal skin infection, in 2 of 44 (4.5%) with Type 49 throat infection, and in 3 of 16 (18.8%) with simultaneous Type 49 infection at both sites. The higher attack rate of nephritis and hematuria in children with pyoderma indicates that skin lesions played a direct and quantitatively greater role than respiratory infection in the pathogenesis of acute nephritis during this outbreak. Skin infections with the Type 49 strain were followed by evidence of renal complications more often in children younger than 6.5 yr (9 of 21 or 43%) than in older children (1 of 21 or 5%). Attack rates of renal complications after Type 49 skin infection were approximately equal in males and females.


Assuntos
Nefrite/epidemiologia , Infecções Respiratórias/complicações , Dermatopatias/complicações , Infecções Estreptocócicas/complicações , Doença Aguda , Adolescente , Fatores Etários , Criança , Pré-Escolar , Surtos de Doenças , Feminino , Humanos , Indígenas Norte-Americanos , Masculino , Minnesota , Nefrite/etiologia , Estudos Prospectivos , Fatores Sexuais , Streptococcus/classificação
4.
J Clin Invest ; 49(7): 1405-14, 1970 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-5432372

RESUMO

The immune response after streptococcal infection of the skin and of the upper respiratory tract (URT) was studied prospectively in a group of normal children, ages 3-6 yr. The children were examined and cultures for group A streptococci were obtained weekly from the throat, nose, and skin lesions (when present). Paired sera were collected at the beginning and end of the study, and the changes in antibody titers were measured for three different streptococcal antigens: streptolysin O, deoxyribonuclease B (DNAse B), and nicotinamide adenine dinucleotidase (NADase). The findings suggest that in contrast to infection of the URT antibody response to streptolysin O is relatively feeble after streptococcal infection which is limited to the skin. The response to NADase is also poor after cutaneous infection. Antibody responses to DNAse B are generally good regardless of the site of the infection. These and other studies indicate that anti-DNAse B is the antibody of choice in studying streptococcal infection of the skin and its complications.


Assuntos
Formação de Anticorpos , Infecções Respiratórias , Dermatopatias Infecciosas/imunologia , Infecções Estreptocócicas/imunologia , Antígenos , Antiestreptolisina , Criança , Pré-Escolar , Desoxirribonucleases , Humanos , N-Glicosil Hidrolases , Pioderma/imunologia , Infecções Respiratórias/microbiologia , Dermatopatias Infecciosas/microbiologia
5.
J Immunol Methods ; 451: 111-117, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-28939394

RESUMO

Among the four known Streptococcal nucleases comprising of DNase A, B, C and D; DNase B is the most common, and determination of the levels of antibody to DNase B (ADB) is often used to confirm a clinical diagnosis of Streptococcus pyogenes/group A Streptococcal (GAS) infection. The commonly used assays for antibodies that neutralize DNase B or streptolysin O activity use partially purified antigens that often fail to detect antibody changes subsequent to culture documented infections. Therefore, an enzyme-linked immunosorbent assay (ELISA) was developed employing his-tagged recombinant DNase B as plate antigen for comparison to the commonly used DNA methyl green micromethod (DMGM). DNAs from various Streptococcal species were screened for presence of dnaseB gene by PCR. Measurements of ADB in sera collected from subjects belonging to different ages, and ethnic groups were used to compare the two methods. dnaseB was not detected by PCR in DNA samples isolated from different strains of group B (GBS), C (GCS) and G (GGS) Streptococci. The ADB based ELISA proved to be highly sensitive and more responsive to changes in antibody concentration than DMGM. Use of recombinant DNase B eliminates the variability associated with the enzyme, partially purified from Streptococcal culture supernatants from various commercial sources and may provide a more reliable source of antigen to a wider group of laboratories concerned with GAS diagnosis.


Assuntos
Anticorpos Antibacterianos/sangue , Antígenos de Bactérias/imunologia , Corantes/química , Desoxirribonucleases/imunologia , Ensaio de Imunoadsorção Enzimática/métodos , Verde de Metila/química , Infecções Estreptocócicas/diagnóstico , Streptococcus pyogenes/imunologia , Antígenos de Bactérias/genética , Biomarcadores/sangue , Desoxirribonucleases/genética , Humanos , Reação em Cadeia da Polimerase , Valor Preditivo dos Testes , Proteínas Recombinantes/imunologia , Reprodutibilidade dos Testes , Infecções Estreptocócicas/sangue , Infecções Estreptocócicas/genética , Infecções Estreptocócicas/imunologia , Streptococcus pyogenes/enzimologia , Streptococcus pyogenes/genética , Fatores de Tempo
6.
Cardiovasc J Afr ; 28(5): 285-292, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28252675

RESUMO

BACKGROUND: Rheumatic fever (RF) and rheumatic valvular heart disease (RHD) remain important medical, surgical and public health concerns in many parts of the world, especially in sub-Saharan Africa. However, there are no published data from Rwanda. We performed a RHD prevalence study in a randomly selected sample of Rwandan school children using the 2012 World Heart Federation (WHF) criteria. METHODS: Echocardiographic assessment of 2 501 Rwandan school children from 10 schools in the Gasabo district near Kigali was carried out. Resulting data were evaluated by four experienced echocardiographers. Statistical analyses were carried out by statisticians. RESULTS: RHD prevalence was 6.8/1 000 children examined (95% CI: 4.2/1 000-10.9/1 000). Seventeen met WHF criteria for RHD, 13 fulfilled criteria for 'borderline' RHD and four were 'definite' RHD. None of these 17 had been previously identified. CONCLUSION: These data indicate a significant burden of RHD in Rwanda and support a need for defined public health RF control programmes in children there.


Assuntos
Ecocardiografia , Doenças das Valvas Cardíacas/epidemiologia , Febre Reumática/epidemiologia , Cardiopatia Reumática/diagnóstico por imagem , Cardiopatia Reumática/epidemiologia , Adolescente , Criança , Ecocardiografia/métodos , Feminino , Humanos , Masculino , Programas de Rastreamento/métodos , Grupos Populacionais , Prevalência , Febre Reumática/diagnóstico por imagem , Cardiopatia Reumática/classificação , Fatores de Risco , Ruanda/epidemiologia
7.
J Natl Cancer Inst ; 85(24): 2004-7, 1993 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-8246286

RESUMO

BACKGROUND: A mutation in c-K-ras (KRAS2) has long been implicated as one of the important early events in the development of a large proportion of human colon cancers. Aberrant crypt foci, putative preneoplastic lesions identified microscopically in wholemounts of colons, have been shown to occur with high frequency in the colons of animals treated with colon carcinogens and in the grossly normal mucosas of patients with colon cancer. PURPOSE: In this study, we asked whether the mutational activation of K-ras occurs in the aberrant crypt foci of human colon. METHODS: Grossly normal colonic mucosas were obtained from seven patients during surgery and were provided to us by the Western Division of the Cooperative Human Tissue Network located at Case Western Reserve University. A total of 42 samples, consisting of aberrant crypt foci and similarly sized normal crypt areas, were microdissected from the grossly normal colonic mucosas. The DNA region containing codon 12 of K-ras was amplified by polymerase chain reaction and analyzed for mutations by dot-blot hybridization with specific oligonucleotide probes complementary to normal or mutant sequences. RESULTS: Mutations in codon 12 of K-ras were found in 11 (73%) of 15 aberrant crypt foci but not in any of 27 morphologically normal crypt areas from the same patients. CONCLUSIONS: The observed high frequency of K-ras mutations in these microscopically identifiable lesions makes mutation in K-ras the earliest identified gene-mutational event in human colon tumorigenesis, establishes that it often occurs prior to the development of polyps, and is consistent with the hypothesis that aberrant crypt foci are the earliest identified precursors of human colon cancer. IMPLICATIONS: Further analysis of aberrant crypt foci may identify yet unknown early genetic events that precede human colon cancer.


Assuntos
Neoplasias do Colo/genética , Genes ras/genética , Mutação , Lesões Pré-Cancerosas/genética , Humanos
8.
Cell Signal ; 7(4): 365-76, 1995 May.
Artigo em Inglês | MEDLINE | ID: mdl-8527305

RESUMO

PI 3-kinase, an enzyme that selectively phosphorylates the 3-position of the inositol ring, is acutely activated by insulin and other growth factors. The physiological significance of PI 3-kinase activation and, more specifically, its role in insulin action is an area under intense investigation. In this study, we have examined the role of PI 3-kinase activation in mediating selected metabolic and mitogenic effects of insulin employing the fungal metabolite wortmannin, a potent inhibitor of PI 3-kinase activity. In isolated rat and cultured 3T3-L1 adipocytes, wortmannin inhibited insulin-stimulated glucose transport (IC50 = 9 nM) without a significant effect on basal transport. Insulin-stimulated translocation of GLUT4 in isolated rat adipocytes was markedly inhibited by wortmannin. Wortmannin had no effect on either basal or insulin-stimulated glucose utilization in L6 myocytes, a skeletal muscle cell line in which GLUT1 is the predominant transporter isoform. Wortmannin also partially antagonized the antilipolytic effect of insulin on adenosine deaminase-stimulated lipolysis in isolated rat adipocytes. Furthermore, wortmannin caused a significant reduction in insulin-stimulated DNA synthesis in Fao rat hepatoma cells. We conclude that PI 3-kinase activation is necessary for maximum insulin-stimulated glucose transport, translocation of GLUT4, antilipolysis and DNA synthesis.


Assuntos
Androstadienos/farmacologia , Inibidores Enzimáticos/farmacologia , Glucose/metabolismo , Insulina/fisiologia , Proteínas Musculares , Fosfotransferases (Aceptor do Grupo Álcool)/antagonistas & inibidores , Células 3T3 , Adipócitos/efeitos dos fármacos , Adipócitos/metabolismo , Animais , Antifúngicos/farmacologia , Transporte Biológico/efeitos dos fármacos , Células Cultivadas , DNA/biossíntese , Replicação do DNA/efeitos dos fármacos , Relação Dose-Resposta a Droga , Transportador de Glucose Tipo 4 , Insulina/farmacologia , Lipólise/efeitos dos fármacos , Neoplasias Hepáticas Experimentais/metabolismo , Camundongos , Proteínas de Transporte de Monossacarídeos/metabolismo , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , Micotoxinas/farmacologia , Fosfatidilinositol 3-Quinases , Ratos , Ratos Sprague-Dawley , Células Tumorais Cultivadas , Wortmanina
9.
Arch Intern Med ; 160(16): 2521-4, 2000 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-10979065

RESUMO

BACKGROUND: Although pheochromocytomas are believed to account for fewer than 0.3% of all cases of hypertension, aggressive diagnostic and surgical intervention is recommended whenever a pheochromocytoma is suspected because uncontrolled catecholamine release from the tumors can lead to catastrophic consequences. Many biochemical diagnostic and imaging localization tests exist for detecting pheochromocytomas. We sought to evaluate the sensitivity of these tests used over a 35-year period at a single institution. METHODS: Thirty-five patients with complete medical records who had pathologically confirmed pheochromocytomas between 1962 and 1997 at the University of Chicago Hospitals were identified. Sensitivity and 95% confidence intervals were calculated for 12 laboratory diagnostic tests and 5 imaging studies. RESULTS: The most sensitive laboratory diagnostic tests in our study were plasma total catecholamines (95%) and urine total metanephrines (100%). Testing for urine vanillylmandelic acid, while less expensive and easier to perform than many other tests, had a slightly lower sensitivity (89%). The most sensitive imaging tests in the study were magnetic resonance imaging (100%) and iodine I-131 metaiodobenzylguanidine scintigraphy (100%). The more often used computed tomography had only 88% sensitivity. Localization was safely and successfully performed on two pregnant patients using magnetic resonance imaging and ultrasound. CONCLUSIONS: By properly choosing from the wide array of laboratory diagnostic and imaging tests, pheochromocytomas can be identified and localized with nearly 100% sensitivity. These tests should be performed in any patient for whom the diagnosis of pheochromocytoma is being considered.


Assuntos
Neoplasias das Glândulas Suprarrenais/diagnóstico , Feocromocitoma/diagnóstico , Complicações Neoplásicas na Gravidez/diagnóstico , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Gravidez , Estudos Retrospectivos , Sensibilidade e Especificidade
10.
Endocrinology ; 96(5): 1217-20, 1975 May.
Artigo em Inglês | MEDLINE | ID: mdl-1122884

RESUMO

Hypocalcemia following gastrin administration occurs in thyroparathyroidectomized (TPTX) as well as thyroid intact rats. Hypophosphatemia does not accompany the hypocalcemia induced by gastrin. These data suggest that a mechanism other than release of calcitonin from the thyroid gland may be involved in this response in the rat. Neither adrenalectomy, nephrectomy, nor excision of the pancreas and small and large intestine altered the hypocalcemic response to gastrin. Gastrectomy, however, eliminated all hypocalcemia following administration of this polypeptide in both thyroid intact and TPTX rats. Removal of the antrum of the stomach did not influence the hypocalcemic response to gastrin. Resection of the proximal 75% of the stomach, however, inhibited the hypocalcemic response to gastrin as did total gastrectomy. Thus, in the rat, the proximal stomach appears to play an important role in mediating this response.


Assuntos
Cálcio/sangue , Gastrinas/farmacologia , Estômago/fisiologia , Glândulas Suprarrenais/fisiologia , Adrenalectomia , Animais , Gastrectomia , Intestinos/fisiologia , Rim/fisiologia , Masculino , Nefrectomia , Pâncreas/fisiologia , Pancreatectomia , Ratos , Suínos , Glândula Tireoide/fisiologia , Tireoidectomia
11.
J Clin Endocrinol Metab ; 71(2): 414-24, 1990 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-2380337

RESUMO

We have analyzed the course of papillary thyroid carcinoma in 269 patients managed at the University of Chicago, with an average follow-up period of 12 yr from the time of diagnosis. Patients were categorized by clinical class; I, with intrathyroidal disease; II, with cervical nodal metastases; III, with extrathyroidal invasion; and IV, with distant metastases. Half of the patients had a history of thyroid enlargement known, on the average, for over 3 yr. In 15% of patients given thyroid hormone, the mass decreased in size. The peak incidence of cancer was when subjects were between 20-40 yr of age. Tumors averaged 2.4 cm in size; 21.6% had tumor capsule invasion, and 46% of patients had multifocal tumors. Sixty-six percent of the patients had near-total or total thyroidectomy. The overall incidence of postoperative hypoparathyroidism was 8.4%, but the incidence was zero in 83 near-total or total thyroidectomies carried out by 1 surgeon. Twenty-five percent of the patients had continuing or recurrent disease, and 8.2% died from cancer. Deaths occurred largely in patients with class III or IV disease. Cervical lymph nodes were associated with increased recurrences, but not increased deaths. Extrathyroidal invasion carried an increased risk of 5.8-fold for death, and distant metastases increased this risk 47-fold. Age over 45 yr at diagnosis increased the risk of death 32-fold. Tumor size over 3 cm increased the risk of death 5.8-fold. Surgical treatment combining lobectomy plus at least contralateral subtotal thyroidectomy was associated, by Cox proportional hazard analysis, with decreased risk of death in patients with tumors larger than 1 cm and decreased risk of recurrence among all patients, including patients in classes I and II, compared to patients who underwent unilateral thyroid surgery or bilateral subtotal resections. By chi 2 analysis, 131I ablation of residual thyroid tissue after operation was associated with decreased risk of recurrence in tumors larger than 1 cm and decreased risk of death in patients in classes I and II with tumors more than 1 cm in size. The data strongly support the use of more extensive initial surgery in class I and II patients with tumors more than 1 cm in size as well as postoperative radioactive 131I ablation of thyroid remnant tissue.


Assuntos
Carcinoma Papilar/fisiopatologia , Neoplasias da Glândula Tireoide/fisiopatologia , Fatores Etários , Carcinoma Papilar/patologia , Carcinoma Papilar/terapia , Feminino , Seguimentos , Humanos , Radioisótopos do Iodo/uso terapêutico , Masculino , Pessoa de Meia-Idade , Probabilidade , Prognóstico , Recidiva , Neoplasias da Glândula Tireoide/patologia , Neoplasias da Glândula Tireoide/terapia , Tireoidectomia
12.
J Clin Endocrinol Metab ; 80(10): 2946-53, 1995 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-7559879

RESUMO

The natural history and results of treatment have been analyzed in a group of 49 patients with follicular thyroid carcinoma who were followed for an average of 10.7 yr. Striking differences between the course of follicular thyroid carcinoma and the course of papillary carcinoma are evident. Deaths from cancer were double (16% for follicular), age at diagnosis was older, and age at death was younger. All deaths and recurrences happened within 13 yr, in contrast to the continued experience of deaths and recurrences in papillary cancer, even through 40 yr of observation. Adverse outcome correlated with extent of disease at diagnosis and with size of primary tumor, but did not correlate with vessel invasion, extent of capsule invasion, degree of dedifferentiation, extent of primary surgery, or radioactive iodide ablation. These observations are again in striking contrast to experience with papillary cancer. No patient with intrathyroidal disease who was under age 45 at diagnosis and with a primary tumor of less than 2.5 cm died. Our observations suggest that follicular cancer, even if apparently intrathyroidal, carries a high mortality rate in patients over age 45 or in those with tumors larger than 2.5 cm at the time of diagnosis and suggest that we must consider additional therapeutic measures in this group of patients, including larger radioiodine doses for initial therapy, external radiotherapy, and even possibly prophylactic chemotherapy.


Assuntos
Adenocarcinoma Folicular/epidemiologia , Adenoma Oxífilo/epidemiologia , Neoplasias da Glândula Tireoide/epidemiologia , Adenocarcinoma Folicular/mortalidade , Adenocarcinoma Folicular/fisiopatologia , Adenocarcinoma Folicular/terapia , Adenoma Oxífilo/mortalidade , Adenoma Oxífilo/fisiopatologia , Adenoma Oxífilo/terapia , Adolescente , Adulto , Fatores Etários , Idade de Início , Idoso , Criança , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Morbidade , Probabilidade , Estudos Retrospectivos , Análise de Sobrevida , Taxa de Sobrevida , Neoplasias da Glândula Tireoide/mortalidade , Neoplasias da Glândula Tireoide/fisiopatologia , Neoplasias da Glândula Tireoide/terapia , Fatores de Tempo
13.
J Med Chem ; 43(11): 2248-57, 2000 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-10841803

RESUMO

The optimization of a series of anilide derivatives of (R)-3,3, 3-trifluoro-2-hydroxy-2-methylpropionic acid as inhibitors of pyruvate dehydrogenase kinase (PDHK) is described that started from N-phenyl-3,3,3-trifluoro-2-hydroxy-2-methylpropanamide 1 (IC(50) = 35 +/- 1.4 microM). It was found that small electron-withdrawing groups on the ortho position of the anilide, i.e., chloro, acetyl, or bromo, increased potency 20-40-fold. The oral bioavailability of the compounds in this series is optimal (as measured by AUC) when the anilide is substituted at the 4-position with an electron-withdrawing group (i.e., carboxyl, carboxyamide, and sulfoxyamide). N-(2-Chloro-4-isobutylsulfamoylphenyl)-(R)-3,3, 3-trifluoro-2-hydroxy-2-methylpropionamide (10a) inhibits PDHK in the primary enzymatic assay with an IC(50) of 13 +/- 1.5 nM, enhances the oxidation of [(14)C]lactate into (14)CO(2) in human fibroblasts, lowers blood lactate levels significantly 2.5 and 5 h after oral doses as low as 30 micromol/kg, and increases the ex vivo activity of PDH in muscle, kidney, liver, and heart tissues. However, in contrast to sodium dichloroacetate (DCA), these PDHK inhibitors did not lower blood glucose levels. Nevertheless, they are effective at increasing the utilization and disposal of lactate and could be of utility to ameliorate conditions of inappropriate blood lactate elevation.


Assuntos
Anilidas/síntese química , Inibidores Enzimáticos/síntese química , Propionatos/síntese química , Inibidores de Proteínas Quinases , Anilidas/química , Anilidas/farmacologia , Animais , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Fibroblastos/efeitos dos fármacos , Fibroblastos/enzimologia , Humanos , Concentração Inibidora 50 , Propionatos/química , Propionatos/farmacologia , Proteínas Quinases/metabolismo , Proteínas Serina-Treonina Quinases , Piruvato Desidrogenase Quinase de Transferência de Acetil , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade
14.
J Med Chem ; 43(2): 236-49, 2000 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-10649979

RESUMO

N'-methyl-N-(4-tert-butyl-1,2,5,6-tetrahydropyridine)thiourea, SDZ048-619 (1), is a modest inhibitor (IC(50) = 180 microM) of pyruvate dehydrogenase kinase (PDHK). In an optimization of the N-methylcarbothioamide moiety of 1, it was discovered that amides with a small acyl group, in particular appropriately substituted amides of (R)-3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid, are inhibitors of PDHK. Utilizing this acyl moiety, herein is reported the rationale leading to the optimization of a series of acylated piperazine derivatives. Methyl substitution of the piperazine at the 2- and 5-positions (with S and R absolute stereochemistry) markedly increased the potency of the lead compound (>1,000-fold). Oral bioavailability of the compounds in this series is good and is optimal (as measured by AUC) when the 4-position of the piperazine is substituted with an electron-poor benzoyl moiety. (+)-1-N-[2,5-(S, R)-Dimethyl-4-N-(4-cyanobenzoyl)piperazine]-(R)-3,3, 3-trifluoro-2-hydroxy-2-methylpropanamide (14e) inhibits PDHK in the primary enzymatic assay with an IC(50) of 16 +/- 2 nM, enhances the oxidation of [(14)C]lactate into (14)CO(2) in human fibroblasts with an EC(50) of 57 +/- 13 nM, diminishes lactate significantly 2.5 h post-oral-dose at doses as low as 1 micromol/kg, and increases the ex vivo activity of PDH in muscle, liver, and fat tissues in normal Sprague-Dawley rats. These PDHK inhibitors, however, do not lower glucose in diabetic animal models.


Assuntos
Inibidores Enzimáticos/farmacologia , Propionatos/farmacologia , Inibidores de Proteínas Quinases , Proteínas Quinases , Amidas , Animais , Área Sob a Curva , Disponibilidade Biológica , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacocinética , Humanos , Ácido Láctico/sangue , Espectroscopia de Ressonância Magnética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Propionatos/química , Propionatos/farmacocinética , Proteínas Serina-Treonina Quinases , Piruvato Desidrogenase Quinase de Transferência de Acetil , Ratos , Ratos Sprague-Dawley
15.
Pediatrics ; 60(1): 28-32, 1977 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-327423

RESUMO

This study was designed to explore whether the test for C-reactive protein (CRP) is useful in differentiating bona fide streptococcal infection from the symptomatic carrier at the time of the acute visit to the physician. Serial blood samples from 157 children with symptomatic pharyngitis and a positive culture for group A streptococci were analyzed for the presence or absence of CRP. These data were compared with the patients' antibody responses to two streptococcal extracellular antigens (antistreptolysin O and antistreptococcal deoxyribonuclease B). Seventy-eight percent of patients with serologically confirmed streptococcal pharyngitis had a positive CRP test at the initial visit. Conversely, if the CRP test was negative at the acute visit, only about 25% later showed an antibody response. This latter finding held regardless of the degree of positivity of the initial culture, the presence of exudate or adenitis, or the presence of a temperature greater than 38.3 C (101 F) or coryza. These data suggest that the CRP test may be helpful to the clinician, especially if this abnormal protein is absent at the time of the acute visit.


Assuntos
Proteína C-Reativa/análise , Faringite/sangue , Infecções Estreptocócicas/sangue , Portador Sadio/sangue , Criança , Diagnóstico Diferencial , Humanos , Linfadenite/sangue , Streptococcus pyogenes
16.
Pediatrics ; 83(3): 380-4, 1989 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-2645567

RESUMO

Little information is available about the epidemiology of group A streptococcal upper respiratory tract infections in child day-care centers. During an initial 3-month period, symptomatic upper respiratory tract infections associated with throat cultures or rapid antigen detection tests positive for group A streptococci developed in 55 of 214 (26%) children and adult staff in one day-care center. When the entire day-care center population (except for those receiving antibiotics at the time) was then surveyed, 52 of 146 (36%) children and two of 24 (8%) adult staff had throat cultures positive for group A streptococci. Of the 54 group A streptococcal isolates found during the survey, the three most frequently encountered serotypes were M2,T2/28 (35%), M3,T3/13 (30%), and M-NT, T25 (20%). Rapid antigen detection was performed at the same time as the throat culture in the first 98 individuals examined during the culture survey but was positive in only 11 (35%) of 31 individuals with positive throat cultures. Sensitivity of the rapid antigen test was related to degree of positivity of the throat culture but not to age. The overall group A streptococcal positivity rate was 49% for 187 children and 33% for 27 adult staff; 18 of 66 (27%) children younger than 31/2 years of age were found to have group A streptococci in their upper respiratory tracts. This is the first report of high prevalence rates of group A streptococci associated with upper respiratory tract infections in a day-care center. The group A Streptococcus may represent a significant upper respiratory tract pathogen in the day-care setting.


Assuntos
Creches , Surtos de Doenças , Infecções Respiratórias/epidemiologia , Infecções Estreptocócicas/epidemiologia , Adulto , Antígenos de Bactérias/análise , Técnicas Bacteriológicas , Portador Sadio/microbiologia , Criança , Pré-Escolar , Humanos , Lactente , Faringite/epidemiologia , Infecções Respiratórias/microbiologia , Sorotipagem , Infecções Estreptocócicas/microbiologia , Streptococcus pyogenes/imunologia , Streptococcus pyogenes/isolamento & purificação
17.
Pediatrics ; 89(4 Pt 2): 743-6, 1992 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-1557272

RESUMO

Group A beta-hemolytic streptococci (GABHS) have once again become an important cause of serious suppurative disease in children. A 100% increase in the rate of GABHS bacteremia and an increased frequency in GABHS bacteremia in previously healthy children were observed in 1989 through 1990 compared with 1984 to 1988. Streptococcal isolates were characterized and patient demographic data were tabulated from children hospitalized with GABHS suppurative infections in 1989 through 1990. The differences in clinical manifestations and strains of GABHS were examined in patients with bacteremia, with or without focal site of infection, and in those with focal infections without bacteremia. Bacteremic children were significantly younger and had higher white blood cell counts at admission. No patient had a toxic shock-like syndrome. Although no specific strain was associated with suppurative infections, serum opacity reaction-negative organisms were more frequently associated with focal infections without bacteremia. The data suggest that GABHS may have become more virulent. Physicians should consider GABHS as an important cause of serious suppurative infection in children.


Assuntos
Bacteriemia/epidemiologia , Infecções Estreptocócicas/epidemiologia , Streptococcus pyogenes , Fatores Etários , Bacteriemia/microbiologia , Criança , Infecção Focal/epidemiologia , Infecção Focal/microbiologia , Humanos , Incidência , Missouri/epidemiologia , Estudos Retrospectivos , Sorotipagem , Fatores Sexuais , Infecções Estreptocócicas/microbiologia , Streptococcus pyogenes/classificação , Streptococcus pyogenes/isolamento & purificação
18.
Pediatrics ; 101(1 Pt 1): 86-8, 1998 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-9417157

RESUMO

BACKGROUND: Measurement of antibodies to the extracellular antigens produced by group A streptococci, antistreptolysin O (ASO) and anti-deoxyribonuclease B (anti-DNase B), is often necessary to confirm a clinical diagnosis of a previous group A streptococcal infection, especially in patients suspected of having a nonsuppurative sequel to this infection. Age is among several factors that may influence antibody levels in children. Thus, in contrast to adults, what is considered a normal titer for one age group (infants) is not appropriate for another (older children). Age-related "normal" values for ASO and anti-DNase B are provided in the package inserts of commercially available kits; however, there are no recent comprehensive data to validate such values. OBJECTIVE: Using sera from 1131 children (from 23 states) ages 2 to 12 years, we determined age-specific geometric mean titers (GMT) and upper limits of normal (ULN) of ASO and anti-DNase B. METHODS: ASO and anti-DNase B titers were measured by conventional laboratory methods. RESULTS: Children 7 years of age comprised the largest proportion (14%) of the study population. Approximately two-thirds of the sera were collected during winter and early spring months. For both ASO and anti-DNase B, both GMT values and ULN increased with age. The GMTs for ASO and anti-DNase B for the entire group of subjects were 89 and 112, respectively. The ULN for the entire group for ASO and anti-DNase B were 240 and 640, respectively. CONCLUSION: The age-specific values for GMT and ULN for this group of children from 23 states were slightly higher than previously reported. These values are likely representative of the pediatric population in the United States and should be of clinical value to physicians, epidemiologists, and clinical laboratory personnel.


Assuntos
Anticorpos/sangue , Desoxirribonucleases/imunologia , Streptococcus pyogenes/imunologia , Estreptolisinas/imunologia , Fatores Etários , Proteínas de Bactérias , Criança , Pré-Escolar , Humanos , Valores de Referência , Infecções Estreptocócicas/diagnóstico , Estados Unidos
19.
Pediatrics ; 91(6): 1166-70, 1993 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-8502522

RESUMO

OBJECTIVE: To determine if it is appropriate to recommend that patients with group A beta-hemolytic streptococcal pharyngitis, who are clinically well by the morning after starting antibiotic treatment, can return to school or day care, or if they should wait until they have completed 24 hours of antibiotics as recommended by the American Academy of Pediatrics Committee on Infectious Diseases. METHODS: We examined the duration of positivity of the throat culture after antibiotics were begun as a means of assessing the potential risk of transmission to close school contacts. Forty-seven children (4 to 17 years of age) with pharyngitis and a positive throat culture for group A streptococci in an outpatient, staff model health maintenance organization clinic were enrolled and were randomly selected to receive therapy with either oral penicillin V, intramuscular benzathine penicillin G, or oral erythromycin estolate. Additional throat cultures were obtained and clinical findings were recorded for each child during three home visits in the 24 hours after their initial clinic visit. Acute and convalescent sera were obtained for determination of anti-streptolysin O and anti-DNase B titers. RESULTS: Seventeen (36.2%) of the 47 patients had a positive culture the morning after initiating antibiotic therapy. However, thirty-nine (83%) of the patients became "culture negative" within the first 24 hours. Neither the time interval to the first negative culture nor the presence or absence of group A streptococcal organisms on any single convalescent culture could be predicted by clinical findings. Six of the eight children who failed to convert to a "negative" throat culture within 24 hours of initiating therapy were receiving erythromycin. We could detect no difference in either time to conversion to a negative culture or the presence of a positive culture 24 hours after starting antibiotics between those who demonstrated a significant antibody increase and those who did not. CONCLUSION: The data from this study strongly suggest that children with group A beta-hemolytic streptococcal pharyngitis should complete a full 24 hours of antibiotics before returning to school or daycare.


Assuntos
Faringite/tratamento farmacológico , Faringite/microbiologia , Faringe/microbiologia , Infecções Estreptocócicas/tratamento farmacológico , Infecções Estreptocócicas/microbiologia , Streptococcus pyogenes/isolamento & purificação , Adolescente , Criança , Pré-Escolar , Estolato de Eritromicina/uso terapêutico , Humanos , Penicilina G Benzatina/uso terapêutico , Penicilina V/uso terapêutico , Estudos Prospectivos , Fatores de Tempo
20.
Pediatrics ; 87(5): 598-603, 1991 May.
Artigo em Inglês | MEDLINE | ID: mdl-2020503

RESUMO

Although several outbreaks of group G beta-hemolytic streptococcal (GGBHS) pharyngitis have been described, doubt still remains regarding the etiologic role of GGBHS in acute pharyngitis beyond a limited number of situations. In the winter/spring of 1986/87, throat cultures were obtained from 222 consecutive children seen at a private pediatric office with acute pharyngitis and group A beta-hemolytic streptococci (GABHS) were recovered from 91 children (41%) and GGBHS from 56 children (25%). One patient had both GABHS and GGBHS isolated. This isolation rate of GGBHS was dramatically greater than in previous and subsequent years, and 67% of the GGBHS isolates occurred during an 8-week period. Results of DNA fingerprinting of the 57 isolates of GGBHS demonstrated that 43 (75%) appeared to be the same strain. The patients with GGBHS were comparable to those with GABHS with respect to clinical findings, antistreptolysin-O titer response, and clinical response to antibiotic therapy. However, patients with GGBHS were significantly older (P less than .05). This is the first well-documented, community-wide outbreak of GGBHS pharyngitis and the first respiratory outbreak of GGBHS pharyngitis in a pediatric population. GGBHS may be a more important cause of acute, treatable pharyngitis than had been previously recognized.


Assuntos
Surtos de Doenças , Faringite/epidemiologia , Infecções Estreptocócicas/epidemiologia , Adolescente , Adulto , Criança , Pré-Escolar , Connecticut/epidemiologia , Feminino , Humanos , Masculino , Faringite/microbiologia , Streptococcus/isolamento & purificação
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