Growth hormone resistance in uremia

Growth retardation is a major complication in children with uremia. Protein restriction, calorie deficit, metabolic acidosis, renal osteodystrophy, and endocrinologic disturbances contribute to the growth failure. The effect of these factors on growth retardation can be attenuated in part by therapy with vitamin D metabolites, adequate nutrition, alkalization, and dialysis. Linear growth in children with uremia is markedly retarded despite normal or increased levels of circulating serum growth hormone. An increased growth hormone level in children with uremia is due to normal growth hormone secretion from the pituitary gland and impaired growth hormone clearance in the kidney. However, the elevated growth hormone level does not lead to a commensurate rise in serum insulin-like growth factor I (IGF-I); the serum IGF-I level is decreased or normal in relation to the degree of renal failure. This discrepancy suggests growth hormone resistance in the liver in uremia. Recent molecular techniques open a new era in studying the gene expression for growth hormone or IGF-I. There is no doubt today that growth hormone treatment has the beneficial effect of growth promotion in children with uremia, which also suggests endogenous growth hormone resistance in target organs or target cells in uremia.     

Experimental axonopathy induced by immunization with campylobacter jejuni lipopolysaccharide from a patient with guillain‐barré syndrome

Campylobacter jejuni (C. jejunj) infection is the most common antecedent in the axonal variant of Guillain‐Barré syndrome (GBS). Antibodies against nerve gangliosides found in GBS patients recognize cross‐reactive epitopes in the lipopolysaccharide (LPS) of C. jejuni. This led to the molecular mimicry hypothesis of GBS. We immunized eleven rabbits with a LPS extracted from HS:19 C. jejuni strain isolated from a patient with GBS and complete Freund's adjuvant (CFA)(group I). In a second experiment we immunized seven rabbits with LPS, CFA and keyhole limpet hemocyanin (KLH)(group II). All group I rabbits developed high titers of anti‐LPS, anti‐GM1, anti‐GD1b antibodies and lower titers of anti‐GD1a. One rabbit, 50 days after initial inoculation, showed tremor and weakness. All rabbits of group II developed high titres of antiganglioside antibodies and six animals showed weakness 59–113 days after initial inoculation. Two rabbits died. Pathology showed mild to moderate, tendentially grouped, axonal degeneration in sciatic nerves of four out of five animals. Control rabbits of group I (immunized with CFA only) did not develop antibodies, controls of group II (immunized with CFA + KLH) developed low titers of IgG anti‐GM1. None developed neurological signs or showed axonal degeneration. C. jejuni LPS is a potent B‐cell stimulator capable to induce a strong antiganglioside response in rabbits. However, to induce the neuropathy is crucial to employ KLH, a glycoprotein known to stimulate both humoral and cellular responses. This animal model reproduces the pathogenetic process hypothesized in axonal GBS with antiganglioside antibodies post C. jejuni infection.     

The microbial flora of in-use blood pressure cuffs

The capacity of blood pressure cuffs to act as vehicles of hospital infection has been recognised. We describe the microbial flora of in-use DINAMAP blood pressure cuffs used in the operating theatres and one recovery room in a teaching hospital. Our results show significant microbial contamination of in-use blood pressure cuffs.     

Is the grading of breast carcinomas affected by a delay in fixation?

Summary The effect of delay in fixation on the modified Bloom and Richardson grade of eight breast carcinomas was investigated. Topologically shuffled samples of each tumour were immersed in fixative at times of 0.5, 2, 4, 6, 18 and 24 h after surgical removal. The grade of each tumour was assessed at delays of 0.5 and 6 h. The tubule formation and nuclear pleomorphism components of the grade showed no change with a delay in fixation of 6 h. The number of mitotic figures declined by a mean of 53% over the same period and this resulted in a decrease in the histological grade of one of the tumours. The implications of these findings for the handling of breast specimens in a diagnostic histopathological laboratory are discussed.Some of these data were presented at the 162nd meeting of the Pathological Society of Great Britain and Ireland at Cambridge, 3 January 1991. Published as an abstract in J Pathol (1991) 163:154A     

Phase II trial of PALA in combination with 5-fluorouracil in advanced pancreatic cancer

Summary Phosphonacetyl-l-aspartate (PALA), an inhibitor of aspartate transcarbamylase that depletes uridine nucleotide pools, selectively potentiates the antitumor activity of 5-fluorouracil (5-FU) in preclinical models. Due to the promising results we obtained using PALA/5-FU in colorectal cancer, we performed a phase II trial in patients presenting with advanced pancreatic cancer. PALA was given intravenously at 250 mg/m² on day 1, followed 24 h later by 2,600 mg/m² 5-FU given by 24-h infusion. Treatments were repeated weekly. A total of 41 patients who had not previously undergone chemotherapy were entered in the trial; of these, 35 were evaluable for response. Toxicity was generally mild to moderate; neurotoxicity (13/35) and diarrhea (8/35) predominated. Among the 35 patients, 1 achieved a complete response and 4, a partial remission, for an overall response rate of 14%. The median survival was 5.1 months. Pretreatment with PALA alone was not sufficient to enhance the activity of 5-FU in pancreatic cancer.Supported in part by grant CA 06927 from the National Cancer Institute     

Aberrant hormone production from ovarian neoplasms: Strategies for diagnosis and therapy

Syndromes involving peptide or nonsex steroid hormone secretion due to aberrantly located tumors are rare. We report a collected series of 16 patients with ectopic hormone production from ovarian neoplasms, including 3 patients recently encountered at our institution as well as 13 additional cases identified in the recent literature. These tumors included 2 insulin-producing ovarian carcinoids, 1 ACTH-producing pituitary adenoma within a benign ovarian cystic teratoma, 2 cortisol-producing ovarian neoplasms, 8 gastrin-producing ovarian cystadenomata or cystadenocarcinomata, and 3 thyroxine-producing ovarian strumal carcinoids. All patients presented with syndromes of hormone excess. Only 62% of all tumors were localized preoperatively. Following ovarian resection, 87% of patients remained disease-free with a median follow-up period of 1.5 years. In addition to ovariectomy, 8 additional unnecessary ablative procedures were performed in 7 patients. These included distal pancreatectomy, pancreaticoduodenectomy, adrenalectomy, total gastrectomy, selective vagotomy, and subtotal thyroidectomy. Failure to localize the ovarian neoplasm preoperatively was associated with a significantly higher risk of subsequent unnecessary ablative procedures. Because of the potential for the ovary to act as a source of aberrant hormone secretion, we recommend complete preoperative evaluation of the pelvis in female patients presenting with nonlocalizable endocrine tumors.

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Resumen Los síndromes relacionados con la secreción de péptidos o de hormonas esteroideas no sexuales por tumores de ubicación aberrante ocurren infrecuentemente. En este artículo reportamos una serie de 16 pacientes con producción hormonal ectópica por neoplasmas ováricos, la cual incluye 3 pacientes vistos recientemente en nuestra institución y 13 identificados en la literatura médica de los últimos años. El grupo incluye 2 carcinoides ováricos productores de insulina, 1 adenoma pituitario productor de ACTH, 2 neoplasmas ováricos productores de cortisol, 8 cistadenomas o cistadenocarcinomas ováricos productores de gastrina, y 3 carcinoides ováricos estrumales productores de tiroxina. Todas las pacientes se presentaron con síndromes de exceso hormonal. En sólo el 62% de los tumores se pudo establecer la ubicación anatómica en la fase preoperatoria. Después de realizada la resección del ovario, 87% de las pacientes permanecieron libres de enfermedad en el período de seguimiento, que fue de 1.5 años en promedio. Además de la resección ovárica, se practicaron otros 8 procedimientos adicionales innecesarios en 7 pacientes. Estos incluyeron pancreatectomía distal, pancreatoduodenectomía, adrenalectomía, gatrectomía total, vagotomía selectiva, y tiroidectomía subtotal. La falla en la localización preoperatoria del neoplasma ovárico apareció asociada con un riesgo aumentado de ulteriores procedimientos quirúrgicos innecesarios. En vista de la potencialidad del ovario de actuar como fuente de secreción hormonal aberrante, nosotros recomendamos una completa evaluación de la pelvis en las pacientes femeninas en quienes se diagnostiquen tumores endocrinos no localizables.

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Résumé Les syndromes concernant la sécrétion d'hormones peptidique ou stéroïde nonsexuelle due à des tumeurs ectopiques sont rares. Nous rapportons une série de 16 patientes avec une production d'hormone ectopique provenant de néoplasmes ovariens, comprenant 3 patientes récemment soignées dans notre établissement ainsi que 13 cas supplémentaires relevés dans la littérature récente. Ces tumeurs comprennent 2 tumeurs carcinoïdes ovariennes productrices d'insuline, 1 adénome hypophysaire producteur d'ACTH à l'intérieur d'un tératome cystique ovarien bénin, 2 néoplasmes ovariens producteurs de cortisol, 8 cystadénomes ou cystadénocarcinomes ovariens producteurs de gastrine, et 3 carcinoïdes ovariens strumaux producteurs de thyroxine. Toutes les patientes avaient des syndromes d'hyperproduction hormonale. Soixante-deux pour cent seulement des tumeurs avaient été localisées en préopératoire. Après ovariectomie, 87% des patientes étaient apparamment sans récidive avec un suivi médian d'un an et demi. Cependent, outre l'ovariectomie, 8 interventions supplémentaires non nécessaires ont été accomplis chez 7 patientes. Celles-ci comprenaient: pancréatectomie distale, duodénopancréatectomie, surrénalectomie, gastrectomie totale, vagotomie sélective, et thyroïdectomie subtotale. L'impossibilité de localiser le néoplasme ovarien en période préopératoire était associée à un risque notoirement plus grand de faire une résection inutile. Compte tenu de la possibilité pour l'ovaire de se comporter en producteur de sécrétion ectopique d'hormone, nous recommandons un examen complet préopératoire du bassin chez les femmes se présentant avec des tumeurs endocrines non localisables.

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Presented at the International Association of Endocrine Surgeons in Toronto, Ontario, Canada, September, 1989.     

Thalidomide is an inhibitor of angiogenesis.

Thalidomide is a potent teratogen causing dysmelia (stunted limb growth) in humans. We have demonstrated that orally administered thalidomide is an inhibitor of angiogenesis induced by basic fibroblast growth factor in a rabbit cornea micropocket assay. Experiments including the analysis of thalidomide analogs revealed that the antiangiogenic activity correlated with the teratogenicity but not with the sedative or the mild immunosuppressive properties of thalidomide. Electron microscopic examination of the corneal neovascularization of thalidomide-treated rabbits revealed specific ultrastructural changes similar to those seen in the deformed limb bud vasculature of thalidomide-treated embryos. These experiments shed light on the mechanism of thalidomide's teratogenicity and hold promise for the potential use of thalidomide as an orally administered drug for the treatment of many diverse diseases dependent on angiogenesis.     

Severe odontogenic infections, part 2: prospective outcomes study.

PURPOSE: The purpose of this study was to identify significant predictors of 4 outcomes in patients with severe odontogenic infections: abscess formation, penicillin therapeutic failure (PTF), length of hospital stay (LOS), and need for reoperation. PATIENTS AND METHODS: We used a prospective case series study design and enrolled 37 consecutive patients admitted for severe odontogenic infection between March 1996 and June 1999. Treatment consisted of intravenous penicillin (PCN) or clindamycin in PCN-allergic patients, surgical incision and drainage, and extraction(s) as soon as possible. Study variables were categorized as demographic, preadmission, time-related, preoperative, anatomic, treatment, microbiologic, and complications. The primary outcome variables were abscess formation, PTF, LOS, and reoperation. Multivariate linear and logistic regression techniques were used to measure associations between study variables and the outcome variables. RESULTS: The sample consisted of 37 subjects (23 male, 14 female) with a mean age of 34.9 +/- 15.8 years. Multivariate analyses, controlling for confounding variables, indicated that culture of Peptostreptococci was a negative predictor of abscess formation. LOS was predicted by the number of infected spaces and duration of operation. There was no significant predictor of PTF or reoperation on multivariate analysis, although PCN-resistant organisms were isolated in all cases of PTF. CONCLUSION: Increased LOS in severe odontogenic infections is predicted by the anatomic extent and severity of the infection and the occurrence of complications such as PTF and the need for reoperation. PTF is significantly associated with later identification of PCN-resistant organisms. The role of Peptostreptococci in abscess formation warrants further investigation.