Phosphodiesterase 5 Inhibition Improves β-Cell Function in Metabolic Syndrome

OBJECTIVE: This study tested the hypothesis that phosphodiesterase 5 inhibition alone or in combination with ACE inhibition improves glucose homeostasis and fibrinolysis in individuals with metabolic syndrome. RESEARCH DESIGN AND METHODS: Insulin sensitivity, beta-cell function, and fibrinolytic parameters were measured in 18 adults with metabolic syndrome on 4 separate days after a randomized, crossover, double-blind, 3-week treatment with placebo, ramipril (10 mg/day), tadalafil (10 mg o.d.), and ramipril plus tadalafil. RESULTS: Ramipril decreased systolic and diastolic blood pressure, ACE activity, and angiotensin II and increased plasma renin activity. Ramipril did not affect insulin sensitivity or beta-cell function. In contrast, tadalafil improved beta-cell function (P = 0.01). This effect was observed in women (331.9 +/- 209.3 vs. 154.4 +/- 48.0 32 micro x mmol(-1) x l(-1), respectively, for tadalafil treatment vs. placebo; P = 0.01) but not in men. There was no effect of any treatment on fibrinolysis. CONCLUSIONS Phosphodiesterase 5 inhibition may represent a novel strategy for improving beta-cell function in metabolic syndrome

Enterooxyntin release from isolated perfused canine jejunum

A humoral factor may mediate the intestinal phase of gastric acid secretion. An ex vivo perfused segment of canine jejunum maintained by an oxygenated asanguinous physiologic perfusate was used to test for release of an enterooxyntin (EO) in response to balloon distention at 30 mm Hg for 15 min. Gastric acid secretion in guinea pig fundic mucosa was determined indirectly by a quantitative cytochemical bioassay (CBA) of oxyntic cell hydroxyl ion production (HIP). An increase in the optical density (OD) caused by the cytochemical stain in the oxyntic cells reflects HIP, an index of acid secretion. Basal OD for segments with distention was 16.6 +/- 0.53 and for those without 15.5 +/- 0.68 (NS). Results are expressed as mean change of OD from basal (mean [Delta]OD +/- SEM). EO caused greater stimulation of HIP than gastrin or histamine. EO was heat stable. Trichloroacetic acid treatment decreased EO activity as did pronase digestion suggesting that EO is composed of one or more peptides. Conclusion: EO, an acid secretagogue, is a humoral agent probably composed of one or more peptides and is released by small bowel distention. Mechanical distention of the small bowel may be an important mechanism for the perpetuation of gastric acid secretion. The ex vivo perfused jejunal segment in conjunction with the CBA are ideal tools with which to study mechanisms of release of EO and the mechanism of action of EO on the oxyntic cell.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/25235/1/0000677.pd

MEN I pancreas: A histological and immunohistochemical study

The spectrum and extent of islet cell histopathological findings in patients with multiple endocrine neoplasia, type I (MEN I) syndrome has never been clearly defined. Although some patients have discreet tumors causing clinically evident syndromes, others may have no symptoms until metastatic islet cell carcinoma is apparent. Whether diffuse islet cell disease occurs in all patients with grossly apparent tumors is not known. This study is an attempt to define both the functional and anatomical extent of islet cell disease and its relationship with the clinical course of patients with MEN I syndrome. The resected specimens of pancreas from 14 patients with MEN I syndrome were evaluated for hyperplasia, nesidioblastosis, multiple tumors, and evidence of malignancy. In 12 cases, specimens consisted of distal pancreas and, in 2 cases, the entire pancreas was available. Multiple sections were taken from each specimen. Immunoperoxidase staining was done for gastrin, pancreatic polypeptide, glucagon, serotonin, VIP, somatostatin, and neuron-specific enolase in sections of 24 tumors from 10 patients. Five of the 10 patients with Zollinger-Ellison syndrome underwent total gastrectomy and 3 others underwent only pancreatic procedures to control their acid hypersecretion. The following is concluded. All MEN I patients with pancreatic neoplasms have diffuse islet cell involvement consisting of nesidioblastosis, micro- and macronodular hyperplasia. Some tumors produce multiple hormones and these patients are at risk to develop new tumors, but complete excision of grossly apparent tumors may result in long-term control of the endocrinopathy present. This is particularly true for patients with insulinoma and hypoglycemia. Selected patients with gastrinoma may also be considered for excision of their islet cell tumor(s) without concomitant gastrectomy, especially if transhepatic venous sampling demonstrates a single site of excess gastrin production. However, if transhepatic venous sampling demonstrates diffuse sources of hypergastrinemia, a local pancreatic procedure will invariably be unsuccessful. Total pancreatectomy in MEN I patients with disease localized to the pancreas is the only curative surgical procedure but is rarely indicated. L'histopathologie des cellules insulaires pancréatiques des malades qui présentent un syndrome MEN I n'a jamais été parfaitement définie. Si certains parmi eux sont porteurs de petites tumeurs qui se manifestent par des syndromes cliniques patents, d'autres n'accusent aucun symptôme avant que des métastases néoplasiques ne se manifestent. En particulier, on ne sait pas si les altérations des cellules insulaires sont diffuses quand les malades présentent des tumeurs évidentes. Cette étude a pour but de définir à la fois l'importance anatomique et l'importance fonctionnelle de la maladie insulaire par rapport à son expression clinique chez les sujets concernés par ce syndrome. Pour ce faire, des spécimens provenant de 14 malades atteints du syndrome MEN I ont été étudiés eu égard à l'hyperplasie, à la nésidioblastose, à la multiplicité des îlots tumoraux, à la malignité. Dans 12 cas, les spécimens répondaient au pancréas distal, dans 2 cas à la totalité du pancréas. De multiples coupes furent pratiquées au niveau de chaque pièce soumise à l'examen. L'imprégnation à l'immunoperoxidase concerna les coupes de 24 tumeurs provenant de 10 patients. Cinq des 10 malades qui présentaient un syndrome de Zollinger-Ellison avaient subi une gastrectomie totale et 3 une intervention pancréatique pour contrôler leur hypersécrétion acide. Les conclusions tirées de cette étude furent les suivantes: tous les malades accusant un syndrome MEN I et porteurs d'un néopolasme pancréatique présentaient des lésions insulaires diffuses répondant à une nésidioblastose, à une hyperplasie micronodulaire et macronodulaire. Quelques tumeurs produisaient de multiples hormones: gastrine, polypeptide pancréatique, glucagon, sérotonine, V.I.P., somatostatine, testées par la méthode. Il résulte de ces constatations que les risques de récidive tumorale après exérèse complète des tumeurs évidentes ne sont pas à écarter, encore que l'exérèse permette de contrôler longtemps l'endocrinopathie. Ceci est particulièrement vrai pour les insulinomes hypoglycémiants. En ce qui concerne les gastrinomes, leur exérèse peut être suffisante, en particulier lorsque les prélèvements veineux étagés montrent qu'ils sont uniques; la gastrectomie concomitante est alors inutile. En revanche, lorsque la gastrine est trouvée en excès au niveau de multiples échantillons veineux, l'exérèse tumorale est insuffisante et la pancréatectomie totale représente l'intervention indispensable; en fait, son indication est rare. La variedad del espectro de la histopatología de las células insulares en pacientes con sindrome de neoplasias endocrinas múltiples tipo I (NEM I) todavía no ha sido claramente definido. Aún cuando algunos pacientes poseen tumores discretos que causan síndromes clínicamente evidentes, otros pueden no exhibir sintomatología alguna hasta cuando se hace evidente un carcinoma metastásico de células insulares. No se sabe si hay enfermedad difusa de las células insulares en todo paciente con tumores macroscópicamente aparentes, ni además se conoce con qué frecuencia se desarrollan nuevos tumores en pacientes con síndrome NEM I después de resección local o de pancreatectomía parcial para tumores primarios de células insulares. El presente estudio intenta definir la extensión funcional y anatómica de la enfermedad de las células insulares y su relación con la evolución clínica en pacientes con el síndrome NEM I.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/41313/1/268_2005_Article_BF01654938.pd

Time-Related Risk of Pulmonary Conduit Re-replacement: A Congenital Heart Surgeons’ Society Study

Background Patients receiving a right ventricle to pulmonary artery conduit (PC) in infancy will require successive procedures or replacements, each with variable longevity. We sought to identify factors associated with time-related risk of a subsequent surgical replacement (PC3) or transcatheter pulmonary valve insertion (TPVI) after a second surgically placed PC (PC2). Methods From 2002 to 2016, 630 patients from 29 Congenital Heart Surgeons’ Society member institutions survived to discharge after initial valved PC insertion (PC1) at age ≤ 2 years. Of those, 355 underwent surgical replacement (PC2) of that initial conduit. Competing risk methodology and multiphase parametric hazard analyses were used to identify factors associated with time-related risk of PC3 or TPVI. Results Of 355 PC2 patients (median follow-up, 5.3 years), 65 underwent PC3 and 41 TPVI. Factors at PC2 associated with increased time-related risk of PC3 were smaller PC2 Z score (hazard ratio [HR] 1.6, P < .001), concomitant aortic valve intervention (HR 7.6, P = .009), aortic allograft (HR 2.2, P = .008), younger age (HR 1.4, P < .001), and larger Z score of PC1 (HR 1.2, P = .04). Factors at PC2 associated with increased time-related risk of TPVI were aortic allograft (HR: 3.3, P = .006), porcine unstented conduit (HR 4.7, P < .001), and older age (HR 2.3, P = .01). Conclusions Aortic allograft as PC2 was associated with increased time-related risk of both PC3 and TPVI. Surgeons may reduce risk of these subsequent procedures by not selecting an aortic homograft at PC2, and by oversizing the conduit when anatomically feasible