From the Cover: Loss of phosphatidylinositol 4-kinase 2α activity causes late onset degeneration of spinal cord axons

Phosphoinositide (PI) lipids are intracellular membrane signaling intermediates and effectors produced by localized PI kinase and phosphatase activities. Although many signaling roles of PI kinases have been identified in cultured cell lines, transgenic animal studies have produced unexpected insight into the in vivo functions of specific PI 3- and 5-kinases, but no mammalian PI 4-kinase (PI4K) knockout has previously been reported. Prior studies using cultured cells implicated the PI4K2α isozyme in diverse functions, including receptor signaling, ion channel regulation, endosomal trafficking, and regulated secretion. We now show that despite these important functions, mice lacking PI4K2α kinase activity initially appear normal. However, adult Pi4k2a^GT/GT animals develop a progressive neurological disease characterized by tremor, limb weakness, urinary incontinence, and premature mortality. Histological analysis of aged Pi4k2a^GT/GT animals revealed lipofuscin-like deposition and gliosis in the cerebellum, and loss of Purkinje cells. Peripheral nerves are essentially normal, but massive axonal degeneration was found in the spinal cord in both ascending and descending tracts. These results reveal a previously undescribed role for aberrant PI signaling in neurological disease that resembles autosomal recessive hereditary spastic paraplegia.     

Hepatocyte steatosis in HCV patients promotes fibrosis by enhancing TGF-beta liver expression.

Aim: The objective of this study was to examine the relationship between TGF-beta expression in steatotic liver and the stage and yearly progression rate of fibrosis in chronic hepatitis C (CHC) patients. Methods: We examined 44 CHC fatty liver patients, using 76 non-steatotic CHC patients as controls. The stage of hepatic fibrosis was assessed on a score scale. TGF-beta expression was determined with the use of monoclonal serum and the ABC three-step method. Results: We demonstrated a positive correlation of steatosis with the stage of fibrosis (P < 0.05). No relationship of thiskind was found with the yearly progression rate of fibrosis (P > 0.09). In steatotic biopsies, TGF-beta expression index in portal spaces and lobules was found to be higher as compared to TGF-beta expression in biopsies without steatosis (P < 0.05). Conclusion: In CHC patients steatosis induces the development of fibrosis by elevating the hepatic expression of TGF-beta.     

Multivariate analysis of risk factors for development of duodenal ulcer in Helicobacter pylori-infected patients

BACKGROUND: Although Helicobacter pylori is a significant etiologic factor of peptic ulcer disease, it remains unknown why ulcers develop only in the minority of infected individuals. AIM: The aim of this cross-sectional study was to evaluate the association between the presence of duodenal ulcer in H. pylori-infected patients and different risk factors. METHODS: A total of 122 H. pylori-infected patients were enrolled; 79 had duodenal ulcer and 43 gastritis. Univariate analysis was conducted using either Fisher's exact test or exact Cochrane-Armitage trend test. In multivariate analysis the logistic model was used. RESULTS: Univariate analysis indicated six factors (male sex, smoking, antral H. pylori density, CAGA presence in antrum, and VACA s1a presence in antrum and corpus). Four factors (sex, smoking-alcohol index, H. pylori density index, and CAGA index) were found to be significant in multivariate analysis. The best model predicting duodenal ulcer included male sex, smoking, presence of H. PYLORI on histopathology in antrum and CAGA presence in corpus. CONCLUSION: Although several risk factors were significantly associated with duodenal ulcer, we failed in the identification of either a single risk factor or a set of factors that can unequivocally differentiate patients with ulcer from those with gastritis.     

Use of covered Cheatham-Platinum stents in aortic coarctation and recoarctation

We inserted covered Cheatham-Platinum stents in 4 patients, ranging in age from 12 to 19 years, who weighed between 45 and 94 kg. All the patients had aortic coarctation, with surgical repair having been attempted previously in one, and with balloon dilation having been performed as the primary treatment in two, resulting in formation of aneurysms. The fourth patient had not received any treatment. The gradients were reduced from 10 to 40 mmHg before insertion of the stent to 0 to 5 mmHg after stenting. No complications were encountered. All the patients are well at an interval of 3 to 14 months after stenting.     

Beziehungen zwischen Kalium- und Kohlenhydratstoffwechselstörungen bei Diabetes Mellitus

Zusammenfassung Bei 84 Personen mit stabilem Kohlenhydratstoffwechsel wurde die Glucosetoleranz und ihre Beziehung zum Kaliumspiegel im Serum, Plasma und in Erythrocyten untersucht. Bei 43 Fettsüchtigen wurde mehrmals oral 2 mg eines Salureticums Polythiazid-Renese, Pfizer verabreicht. Die danach auftretende Hypokaliämie verursachte eine Verminderung der Glucosetoleranz, die bei 23 Kranken mit Diabetes mellitus am ausgeprägsten war. Bei 12 Kranken mit latentem Diabetes wurde eine mittelstarke und bei 8 Fettsüchtigen ohne Kohlenhydratstoffwechselstörungen nur eine schwache Verschlechterung der Glucosetoleranz gefunden. 36 Patienten mit Hypokaliämie erhielten eine Kaliumacetatund Bromkaliummischung bis zur Erlangung der Normokaliämie. Daraufhin normalisierte sich die Glucosetoleranz. Die gleichzeitige Verabreichung von Renese und der Kaliummischung in 15 Fällen führte zu einer unbedeutenden Erniedrigung des Kaliumspiegels ohne wesentliche Glykämieveränderungen. Beim Altersdiabetes erreichte man nach Anwendung der Kaliummischung allein bei 33 von 36 Behandelten eine deutliche Verbesserung der Glucosetoleranz und gleichzeitig einen geringgradigen Anstieg des Kaliumspiegels im Serum. Bei 5 Gesunden waren die Veränderungen unwesentlich. Sämtliche Ergebnisse sind statistisch gesichert. — Schlußfolgerung: Bei Beurteilung des latenten Diabetes und Diabetes mellitus sollte der mögliche Einfluß einer Störung des Kaliumstoffwechsels mit in Betracht gezogen werden.

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Relationships between disturbances in Potassium and carbohydrate metabolism in diabetes mellitus

Summary The glucose tolerance was measured in 84 patients examined under controlled conditions, and related to the potassium concentration of serum, or plasma and that in erythrocytes. Forty-three obese patients were given 2 mg of Polythiazid-Renese [Pfizer] by mouth for 7 days to promote elimination of salt. The resulting hypokaliaemia caused a reduction in glucose tolerance. This was greatest in 23 patients with diabetes mellitus, moderate in 12 patients with latent diabetes, and least in 8 obese patients with normal carbohydrate metabolism. Thirty-six hypokaliaemic patients were given a mixture of potassium acetate and potassium bromide for several days until serum potassium was normal. This brought about a return to normal of the values obtained in the glucose tolerance test. Simultaneous administration of Renese and the potassium mixture in 15 cases caused only an insignificant fall in serum potassium without any appreciable change in blood glucose. In 33 out of 36 patients with maturity-onset diabetes, the administration of the potassium mixture alone caused a noticable improvement in the glucose tolerance test and at the same time a small rise in serum potassium. In 5 normal subjects the changes were unimportant. The results obtained were statistically significant. — Conclusion: In the assessment of latent diabetes and of diabetes mellitus the role of disturbances in potassium metabolism should not be overlooked.

Nach einer Mitteilung auf der II. Tagung der Europäischen Gesellschaft für Diabetologie in Aarhus am 6. 7. 1966.