The developmental genetics of Hirschsprung's disease.

Hirschsprung's disease (HSCR), also known as aganglionic megacolon, derives from a congenital malformation of the enteric nervous system (ENS). It displays an incidence of 1 in 5000 live births with a 4:1 male to female sex ratio. Clinical signs include severe constipation and distended bowel due to a non-motile colon. If left untreated, aganglionic megacolon is lethal. This severe congenital condition is caused by the absence of colonic neural ganglia and thus lack of intrinsic innervation of the colon due in turn to improper colonization of the developing intestines by ENS progenitor cells. These progenitor cells are derived from a transient stem cell population called neural crest cells (NCC). The genetics of HSCR is complex and can involve mutations in multiple genes. However, it is estimated that mutations in known genes account for less than half of the cases of HSCR observed clinically. The male sex bias is currently unexplained. The objective of this review is to provide an overview of the pathophysiology and genetics of HSCR, within the context of our current knowledge of NCC development, sex chromosome genetics and laboratory models.

Efficacy of the anti-CD22 recombinant immunotoxin BL22 in chemotherapy-resistant hairy-cell leukemia.

BACKGROUND: Hairy-cell leukemia that is resistant to treatment with purine analogues, including cladribine, has a poor prognosis. We tested the safety and efficacy of an immunotoxin directed against a surface antigen that is strongly expressed by leukemic hairy cells. METHODS: RFB4(dsFv)-PE38 (BL22), a recombinant immunotoxin containing an anti-CD22 variable domain (Fv) fused to truncated pseudomonas exotoxin, was administered in a dose-escalation trial by intravenous infusion every other day for a total of three doses. RESULTS: Of 16 patients who were resistant to cladribine, 11 had a complete remission and 2 had a partial remission with BL22. The three patients who did not have a response received low doses of BL22 or had preexisting toxin-neutralizing antibodies. Of the 11 patients in complete remission, 2 had minimal residual disease in the bone marrow or blood. During a median follow-up of 16 months (range, 10 to 23), 3 of the 11 patients who had a complete response relapsed and were retreated; all of these patients had a second complete remission. In 2 of the 16 patients, a serious but completely reversible hemolytic-uremic syndrome developed during the second cycle of treatment with BL22. Common toxic effects included transient hypoalbuminemia and elevated aminotransferase levels. CONCLUSIONS: BL22 can induce complete remissions in patients with hairy-cell leukemia that is resistant to treatment with purine analogues.

Dietary and exercise interventions for juvenile obesity: long-term effect of behavioral and public health models.

We investigated the influence of nutrition and exercise interventions within cognitive/behavioral and public health formats on weight and blood lipid profiles in obese children. Compliance was also examined as well as the relationship of the compliance measures with clinical outcome variables. Three conditions were compared over 16 sessions: nutrition and eating-habit change followed by exercise (NE), exercise followed by nutrition and eating-habit change (EN), and an information control (INFO). NE and EN were presented in a cognitive/ behavioral framework which focused on the development of self-regulation whereas the INFO condition received the same material in a public health/educational model. NE and EN participants evidenced modest, yet significant, reductions in weight and blood lipids, and the impact of these two interventions endured at a five-year follow-up. In contrast, INFO participants displayed stable weight and blood lipids during the course of the program, and most remained morbidly obese at follow-up. Improved nutrition, increased physical activity and fitness were significantly correlated with weight and lipid reductions.

Macronutrient intake, eating habits, and exercise as moderators of menstrual distress in healthy women.

The present investigation studied the relationship between symptoms of menstrual distress and macronutrient intake, eating behavior, and exercise in healthy women. Twenty-six normally menstruating women with no complaints of menstrual distress completed a disguised questionnaire on menstrual symptoms and monitored the type and amount of food consumed as well as the type and duration of exercise during a full menstrual cycle. Menstrual cycle phases were determined by the presence of menses, ovarian hormonal assays, and basal temperature monitoring. Reports of pain, water retention, negative affect, behavior change, and arousal were significantly higher (p < .05 or better) in the perimenstruum when compared to the follicular and luteal phases. During the perimenstruum, a higher energy intake of carbohydrate was associated with higher ratings of negative affect (p < .01) and impaired performance/decreased activity (p < .05). Lower energy intake of protein was associated with higher ratings of well being (p < .05). Overeating and dieting behavior were related to greater water retention (p < .01), autonomic reactions (p < .05), and appetite (p < .05). The amount of aerobic exercise in contrast to the intensity was related to lower water retention (p < .01), autonomic reactions (p < .05), and appetite (p < .01). Carbohydrate consumption, eating behavior, and regular exercise are reliably associated with menstrual distress and deserving of experimental evaluation as treatment interventions for menstrual distress.

Body image changes over the menstrual cycle in normal women.

Changes in body image across the menstrual cycle and the relationship between these changes and menstrual distress were investigated in an effort to identify determinants of body dissatisfaction. Twenty-six normally cycling women between 18-40 years of age and 90-115% of ideal body weight, with no history of an eating disorder, completed a series of body image measures and a measure of menstrual distress during three menstrual cycle phases: perimenstrual, follicular, and luteal. These phases were identified with serum levels of ovarian hormones and basal body temperature. Results indicated that body dissatisfaction as measured by the number of body-related negative thoughts and anxiety about appearance was significantly highest during the perimenstrual phase. In contrast, measures of body size perception remained stable. Several somatosensory and psychological symptoms of menstrual distress were significantly associated with body dissatisfaction during the perimenstrual phase including, water retention, autonomic reactivity, control, negative affect, and impaired concentration. This association of body dissatisfaction and menstrual distress strongly suggests that menstrual cycle changes play a significant role in body image.

Energy regulation over the menstrual cycle.

To investigate the influence of ovarian hormones on energy regulation, twenty-six normal weight, noneating disordered women recorded their food consumption, exercise, and eating patterns over one menstrual cycle. Serum levels of ovarian hormones were measured to determine three menstrual cycle phases, namely perimenstrual, follicular/ovulatory, and luteal. Energy intake increased 685.9 kJ/day (p < 0.05) from the follicular/ovulatory to the luteal phase. The percent of energy intake as protein and carbohydrate was relatively constant over the three menstrual cycle phases, but the intake from fat increased 2% (p < 0.05) during the luteal phase, representing a 9.2 g/day increment. Variations in energy and fat intake over the menstrual cycle were not attributable to differences in energy expenditure through exercise or dietary restraint, and appear to be related to changes in the estrogen/progesterone ratio.

Prevalence of bulimia among patients in a chemical dependency treatment program.

The present study sought to determine the prevalence of bulimia in a chemically dependent population and to examine the patterns of psychopathology and eating attitudes among chemically dependent patients. Seventy-six male and 62 female consecutive admissions to an impatient treatment facility for chemical dependency were administered the BULIT. Restraint Scale, MMPI and the Marlowe-Crowne Social Desirability Scale. There was no evidence for an increased prevalence of bulimia in this sample. Five of the women (8%) achieved a cutoff score on the BULIT indicative of bulimia. The similarity between mean MMPI profiles of female patients in this sample and those previously obtained for bulimic patients was greater than the similarity between MMPI profiles for the male and female chemically dependent patients in this sample. Findings are discussed within the context of previous research.