Colonic motor dysfunction in human diabetes is associated with enteric neuronal loss and increased oxidative stress.

BACKGROUND: Gastrointestinal dysfunction is very common in diabetic patients. We assessed the changes in the colonic enteric nervous system using colectomy specimens and intestinal biopsies from diabetic subjects and age-matched controls. METHODS: In control and diabetic colons, we determined the total ganglion area (hematoxylin-eosin staining), changes in neuronal markers-protein gene product 9.5, peripherin, neuronal nitric oxide synthase (nNOS), neuropeptide Y (NPY), choline acetyl transferase (ChAT) and vasoactive intestinal peptide (by immunostaining), apoptosis (cleaved caspase-3 staining) and reduced glutathione levels. Superoxide dismutase mRNA was determined in enteric ganglia isolated by laser capture micro dissection. Isometric muscle recording was used to assess contraction and relaxation responses of colonic circular muscle strips. Apoptosis in enteric neurons under hyperglycemia in vitro was determined by cleaved caspase-3 Western blotting and protective effects of lipoic acid were evaluated. KEY RESULTS: Diabetic subjects had higher incidence of lower gastrointestinal symptoms like constipation and diarrhea at baseline prior to surgery. Diabetic ganglia displayed significant decrease in ganglion size due to enhanced apoptosis and loss of peripherin, nNOS, NPY, and ChAT neurons. Reduced glutathione levels in the diabetic colon (HbA1C > 7%) were significantly less than the control, indicating increased oxidative stress. Colonic circular muscle strips from diabetic subjects showed impaired contraction and relaxation responses compared with the healthy controls. Hyperglycemia-induced cleaved caspase-3 in enteric neurons was reversed by lipoic acid. CONCLUSIONS & INFERENCES: Our data demonstrate loss of enteric neurons in the colon due to increased oxidative stress and apoptosis which may cause the motility disturbances seen in human diabetes. Antioxidants may be of therapeutic value for preventing motility disorders in diabetes.

Respiratory manifestations of chronic granulomatous disease; a clinical survey of patients from Iranian primary immunodeficiency registry.

Chronic granulomatous disease represents a group of inherited disorders of phagocytic system wherein recurrent infections are seen at different sites especially in the respiratory system. To determine the clinical spectrum of respiratory manifestations in chronic granulomatous disease patients, in this retrospective study, we used data from Iranian Primary Immunodeticiency Registry. The diagnosis was based upon WHO criteria for chronic granulomatous disease. We reviewed the records of 38 patients (26 males, 12 females), related to 33 families, 73% of whom were consanguineous. The median age at the time of the study was 12yrs (3 months-22 years). The median onset age of symptoms was 4 months (l month-12 years), and that of diagnostic age was 5 years (l month-20 years), with a diagnostic delay of 4.15 years, on an average. Sixty three percent of our patients had respiratory involvement in the course of their illness, including pneumonia (18 pts, 75%), tuberculosis (llpts, 46%), aspergillosis (3 pts, 12.5%), pulmonary abscess (3 pts, 12.5%), and bronchiectasis (1 pt, 4%). Only 4 of our patients presented with respiratory problems as their first manitestation. Lymph nodes were the first common site and the lungs were the second sites of involvement in chronic granulomatous disease patients; however, it is noteworthy that only in a few of our patients, it was the first manifestation of the disease. Thus special attention should be paid to the pulmonary complications while managing this disease.