HP18THE GOOD,THE FAT AND THE UGLY: METABOLIC HORMONES AND THE HEART

Obesity related cardiovascular disease has assumed epidemic proportions and it is important that we properly understand how hormones of metabolism influence cardiac function. Over the last 15 years a multitude of factors have been discovered that appear to play significant roles in energy balance and metabolism, markedly changing our view of fat and GI cells and their dynamic control and regulation of metabolism. This presentation will focus on how three recently discovered hormones Ghrelin, Leptin and Resistin may directly influence cardiac function. Ghrelin is predominately produced and secreted from the X/A cells of the stomach and studies suggest it can act as a cardioprotective agent. However, Ghrelin also acts to constrict the coronary arteries, which places potential limitations upon its therapeutic use. Leptin is produced by adipose tissue in proportion to fat deposition and appears to drive satiety signals in the body. In contrast, Leptin appears to antagonise cardiac function and it may drive the development of hypertension by impairing renal pressure natriuresis and down regulating endothelium derived vasorelaxant factors. The third factor, Resistin, was originally described from rat adipose tissue and was shown to impair insulin action and glucose control. In humans however, Resistin is primarily produced in inflammatory cells such as monocytes and macrophages. Resistin worsens the recovery of the heart from a period of experimental ischemia and promotes the release of inflammatory agents such as tumour necrosis factor‐alpha. Such actions may be partially responsible for the observed insulin resistance after cardiac surgery.     

Ileal pouch-anal anastomosis for chronic ulcerative colitis. Long-term results.

The aim of this study was to determine the long-term outcome among 390 patients with ulcerative colitis who underwent ileal J pouch-anal anastomosis and whether patient or operative factors influenced results. The combined operative morbidity rate for the pouch-anal anastomosis and the subsequent closure of the temporary ileostomy was 29% (bowel obstruction, 22%; pelvic sepsis, 5%), with one death due to pulmonary embolus. The probability of a successful outcome at 5 years was 94%. Of the 24 patients who failed (6% of total), 18 did so within 1 year (4%), three during year 2 (1%), three during year 3 (1%), and none thereafter. Stool frequency (7 stools/24 h), the occurrence of pouchitis (14%), and satisfactory daytime continence (94% of patients) remained stable over 4 years after operation, whereas nocturnal fecal spotting decreased (51% of patients to 20%). Women had more spotting than men, whereas patients over 50 years old had more stools per day than those 50 years or younger. In conclusion, ileal pouch-anal anastomosis achieved a reasonable stool frequency and satisfactory continence in patients with ulcerative colitis over the long-term. These results support the ileal pouch-anal anastomosis as a safe, satisfactory alternative to permanent ileostomy.     

Congenital thrombophilia among patients with venous thromboembolism.

During a 3-year period we studied 393 adult patients (382 of whom were unrelated) with a history of acute venous thromboembolism. A congenital deficiency state known to predispose to thrombosis was found in 27.2%. Of these, most were due to deficiencies of protein C (9.2%), protein S (7.6%), antithrombin III (5%) or to increased plasma PAI-1 concentration (3.1%) which, in the absence of any known factor that predisposes towards thrombosis, results in a diminished fibrinolytic activity. There was a characteristic pattern between the age of onset (mean 34 years) of thrombosis and individual protein deficiency. Thrombosis appeared spontaneously in 73% of cases with recurrence in 80%. In contrast, in the remaining unrelated patients, 138 (35.1%) in whom venous thromboembolism was secondary and occurred at a mean age of 43 years, and in the other 140 (35.6%) who suffered thromboembolism spontaneously at a later age (mean age 55), there was no permanent protein deficiency state or alteration in fibrinolytic activity and thrombosis recurrence was lower (53.6% and 20.7% respectively). Of the 393 patients, deep vein thrombosis was the most common manifestation; however, in congenital thrombophilia, thrombosis of visceral vessels and Raynaud's syndrome (6%) were also detected.     

The duodenum. Part 1: History, embryogenesis, and histologic and physiologic features

Long before the Christian era, the duodenum was named and its function in controlling gastric emptying was conjectured. It received almost no further attention until the Eighteenth century when its relation to the bile and pancreatic ducts became know. The embryogenesis of the duodenum and the histological features of the organ are described as well as the gross movements that explain the mature relations of the duodenum to the surrounding structures. The "sphincters" of the duodenum are mentioned and evaluated.     

Application of PCR to a clinical and environmental investigation of a case of equine botulism.

PCR for the detection of botulinum neurotoxin gene types A to E was used in the investigation of a case of equine botulism. Samples from a foal diagnosed with toxicoinfectious botulism in 1985 were reanalyzed by PCR and the mouse bioassay in conjunction with an environmental survey. Neurotoxin B was detected by mouse bioassay in culture enrichments of serum, spleen, feces, and intestinal contents. PCR results compared well with mouse bioassay results, detecting type B neurotoxin genes in these samples and also in a liver sample. Other neurotoxin types were not detected by either test. Clostridium botulinum type B was shown to be prevalent in soils collected from the area in which the foal was raised. Four methods were used to test for the presence of botulinum neurotoxin-producing organisms in 66 soil samples taken within a 5-km radius: PCR and agarose gel electrophoresis (types A to E), PCR and an enzyme-linked assay (type B), hybridization of crude alkaline cell lysates with a type B-specific probe, and the mouse bioassay (all types). Fewer soil samples were positive for C. botulinum type B by the mouse bioassay (15%) than by any of the DNA-based detection systems. Hybridization of a type B-specific probe to DNA dot blots (26% of the samples were positive) and PCR-enzyme-linked assay (77% of the samples were positive) were used for the rapid analysis of large numbers of samples, with sensitivity limits of 3 x 10(6) and 3,000 cells, respectively. Conventional detection of PCR products by gel electrophoresis was the most sensitive method (300-cell limit), and in the present environmental survey, neurotoxin B genes only were detected in 94% of the samples.     

Ionic basis of the resting membrane potential and action potential in the pharyngeal muscle of Caenorhabditis elegans

The pharynx of C. elegans is a rhythmically active muscle that pumps bacteria into the gut of the nematode. This activity is maintained by action potentials, which qualitatively bear a resemblance to vertebrate cardiac action potentials. Here, the ionic basis of the resting membrane potential and pharyngeal action potential has been characterized using intracellular recording techniques. The resting membrane potential is largely determined by a K(+) permeability, and a ouabain-sensitive, electrogenic pump. As previously suggested, the action potential is at least partly dependent on voltage-gated Ca(2+) channels, as the amplitude was increased as extracellular Ca(2+) was increased, and decreased by L-type Ca(2+) channel blockers verapamil and nifedipine. Barium caused a marked prolongation of action potential duration, suggesting that a calcium-activated K(+) current may contribute to repolarization. Most notably, however, we found that action potentials were abolished in the absence of external Na(+). This may be due, at least in part, to a Na(+)-dependent pacemaker potential. In addition, the persistence of action potentials in nominally free Ca(2+), the inhibition by Na(+) channel blockers procaine and quinidine, and the increase in action potential frequency caused by veratridine, a toxin that alters activation of voltage-gated Na(+) channels, point to the involvement of a voltage-gated Na(+) current. Voltage-clamp analysis is required for detailed characterization of this current, and this is in progress. Nonetheless, these observations are quite surprising in view of the lack of any obvious candidate genes for voltage-gated Na(+) channels in the C. elegans genome. It would therefore be informative to re-evaluate the data from these homology searches, with the aim of identifying the gene(s) conferring this Na(+), quinidine, and veratridine sensitivity to the pharynx.     

The elderly healthcare consumer: a critical review of information source use and advertising recommendations.

A critical review of the literature is undertaken to examine the state of the art and degree of articulation of theories, methods, and findings between health care marketing and the traditional "generic" marketing literature as related to knowledge of information use by and advertising to the elderly consumer. Evaluative criteria suggestive of scientific rigor are applied to this domain as consistencies, discrepancies, and gaps are identified. Recommendations for future research are advanced.     

Long-term functional results and quality of life after ileal pouch-anal anastomosis and cholecystectomy

Among 971 patients with chronic ulcerative colitis who underwent ilealpouch anal anastomosis during an 8-year period from January, 1982 to December 1989, 30 patients were randomly selected from each year (total = 240 patients) for an assessment of their long-term functional results and quality of life as of 1990. Patients undergoing cholecystectomy during each of the same years served as controls (20 patients/year, total = 160 patients). All 400 patients completed a written questionnaire that measured bowel habits, overall quality of life, general health, and performance in sports/recreation, travel, sex life, family relationship, occupational work, social activities, and household activities. Ileo-anal patients had more frequent stools (median, 6 stools/day) and more fecal spotting (68% of patients had episodes) than cholecystectomy patients (median, 1 stool/day, 13% had episodes,p<0.05). In spite of the altered bowel habits, 90% of ileo-anal patients had an excellent overall quality of life, 76% enjoyed good health, and 91% had good performance scores in the areas examined. In fact, quality of life and performance were similar among ileo-anal patients and cholecystectomy patients. Moreover, quality of life and bowel habits remained steady in both groups of patients during the 8-year follow-up. In conclusion, functional results were satisfactory and quality of life was excellent after ileal pouch-anal anastomosis; neither deteriorated as patients aged over an 8-year period after operation.

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Resumen Se conformó al azar un grupo de 240 pacientes, seleccionando anualmente 30 entre un total de 971 pacientes con colitis ulcerativa crónica que fueron sometidos a resección y recostrucción con anastomosis ileo-bolsa anal en un período de ocho años entre enero de 1982 y diciembre de 1983, con el propósito de valorar los resultados a largo plazo y la calidad de vida en el año 1990. Los pacientes sometidos a colecistectomía en el mismo período sirvieron como controles (20 pacientes año, total = 160 pacientes). Todos los 400 pacientes diligenciaron un cuestionario escrito sobre hábito intestinal, la calidad global de la vida, estado general de salud, rendimiento en cuanto a deportes/recreación, viajes, vida sexual, relación familiar, trabajo ocupacional, actividades sociales y actividades domésticas. Los pacientes con la anastomosis ileoanal presentaron mayor número de defecaciones (6 diarias, medio) y más manchado fecal (68% de los pacientes presentaron tales epísodios) que los pacientes colecistectomizados (1 defecación diaria, medio; 13% presentaron tales epísodios,p<0.05). A pesar de la alteración en el hábito intestinal, el 90% de los pacientes manifestó una excelente calidad global de la vida, el 76% gozó de buena salud y el 91% tuvo un buen rendimiento en las áreas investigadas. En efecto, la calidad de la vida y el rendimiento aparecieron similares entre los pacientes ileoanales y los colecistectomizados; por lo demás, la calidad de la vida y los hábitos intestinales se mantuvieron estables en ambos grupos en el curso de los ocho años de seguimiento. En conclusión, los resultados funcionales fueron satisfactorios y la calidad de la vida fue excelente luego de una anastomosis ileo-bolsa anal, y ésto no pareció deteriorarse con el avance de la edad en el período de seguimiento de ocho años.

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Résumé Parmi 971 patients ayant une rectocolite ulcéreuse chronique et ayant eu une anastomose iléo-anale pendant la période de 8 ans compris entre Janvier 1982 et Décembre 1989, 30 patients ont été sélectionés au hasard chaque année (n=240 patients au total) pour évaluer leur résultats fonctionnels à distance et leur qualité de vie en 1990. Des patients ayant eu une cholécystectomie pendant cette même période de temps ont servi de contrôles (n=20 patients/an pour un total de 160 patients). Les 400 patients inclus dans cette étude ont rempli un questionnaire par écrit qui comportait le nombre et le type des selles, la qualité de vie, l'état général, et l'activité (voyages, vie sexuelle, relations familiales, travail, vie sociale, et vie à la maison). Les patients ayant eu anastomose iléoanale avaient plus de selles (mediane = 6 selles/jour) et plus de pertes fécales (68% des patients avaient des taches fécales) que les patients ayant eu une cholécystectomie (médiane = 1 selle/jour et 13% de patients ayant des taches;p<0.05). Malgré des modification dans les habitudes pour aller à selle, 90% des patients ayant une anastomose iléoanale estimaient avoir une qualité de vie excellente, 76% s'estimaient en bonne santé et 91% avaient de bons scores dans les activités énumérées ci-dessus. La qualité de vie et les scores étaient identiques aux patients cholécystectomisés. La qualité de vie et les selles sont restées stables dans les deux groupes de patients. En conclusion, les résultats fonctionnels étaient satisfaisants et la qualité de vie excellente après une anastomsose iléoanale; elles ne se sont pas détérioriées pendant la période de suivi de huit ans.

     

Pak-1 expression increases with progression of colorectal carcinomas to metastasis.

PURPOSE: The p21-activated kinase-1 (Pak-1) promotes cell motility and invasiveness. Pak-1 is activated by the Rac, Rho, and Cdc42 small GTPases in response to a variety of stimuli including ras and phosphatidylinositol 3'-kinase/AKT pathway activation. Because Pak-1 plays a central role in regulating cell motility and invasiveness, we sought to determine whether Pak-1 may be involved in the malignant progression of colorectal carcinoma. EXPERIMENTAL DESIGN: Pak-1 expression was examined by immunohistochemistry in archived tissues from normal human colons, tubular and tubulovillous adenomas, invasive adenocarcinomas (stages I-III/IV), and lymph node metastases (184 total specimens from 38 patients). Specific cytoplasmic immunostaining was evaluated for overall intensity and uniformity to derive a combined histoscore (stain intensity x percentage of epithelium stained). RESULTS: Pak-1 expression was increased significantly with colorectal cancer progression from normal tissue to lymph node metastases (P < 0.0001). Furthermore, Pak-1 expression was increased significantly in adenomas, invasive carcinomas, and lymph node metastases compared with normal colon (P < 0.0001). Strikingly, Pak-1 expression was significantly higher in lymph node metastases than in invasive cancers, adenomas, or normal colon (P < 0.0001). Moreover, in patients with multiple lesions representing different stages of disease, Pak-1 expression was increased specifically in the most advanced lesions. CONCLUSIONS: This study demonstrates that Pak-1 expression is increased significantly with malignant progression of human colorectal carcinoma. These data, along with numerous functional studies demonstrating a central role for Pak-1 activity in tumor invasiveness and motility, implicate Pak-1 as an exciting target for therapy of colorectal carcinoma.