Local repeated corticotropin-releasing factor infusion exacerbates anxiety- and fear-related behavior: differential involvement of the basolateral amygdala and medial prefrontal cortex.

Increased central corticotropin-releasing factor (CRF) signaling has been associated with various psychiatric symptoms, including anxiety, depression and psychosis. CRF signaling in both the basolateral amygdala (BLA) and medial prefrontal cortex (mPFC) has been implicated in anxiety-like behavior. In addition, repeated activation of CRF receptors within the BLA induces a chronic anxious state. Here we studied the effects of local repeated CRF infusion in the BLA and mPFC on different forms of anxiety, as assessed during light-enhanced startle (LES, general anxiety) and acquisition of fear-potentiated startle (FPS, cue-conditioned fear). In addition, as CRF has been implicated in sensorimotor gating, prepulse inhibition (PPI) was assessed to determine if local CRF infusion within the BLA or mPFC would interfere with the processing of sensory information. To this end, canulas were placed bilaterally in either the BLA or mPFC of Wistar rats. After recovery, animals were infused with h/rCRF (200 ng/side) or vehicle for five consecutive days. Long term effects of local CRF infusion on LES and acquisition of FPS were measured 4 and 10 days post-treatment, respectively. In addition, the acute (day 1), sub-chronic (day 5) and long-term (7 days post treatment) effects on PPI were measured in the same animals. A clear regional differentiation was found on the long lasting effect of CRF on anxiety-like behavior: infusion into the BLA only enhanced acquisition of FPS, whereas infusion into the mPFC only enhanced LES. Sub-chronic CRF infusion into the BLA, but not the mPFC, disrupted PPI. This disturbed PPI was normalized 7 days post-treatment. Together, the current study shows that local repeated CRF receptor activation in the BLA and mPFC is differentially involved in anxiety- and fear-related behavior. In addition, the BLA may be involved in CRF-induced sensorimotor gating deficits. The absence of a long-term effect on these PPI deficits suggests that lasting activation of CRF receptors is a prerequisite for CRF-mediated effects on sensorimotor gating. The long-term effects of repeated CRF infusion on LES and acquisition of FPS on the other hand, show that in case of anxiety-related processes repeated CRF infusion may have lasting effects.

Influences of fat restriction and lipase inhibition on gastric emptying in obesity.

OBJECTIVE: Accelerated gastric emptying of solids may play a role in the pathogenesis of obesity. Orlistat, a potent lipase inhibitor, induces fat malabsorption and body weight loss but might accelerate gastric emptying as a result of suppressed CCK release. The aim was to investigate the role of fat restriction and lipase inhibition in CCK release and gastric emptying. SUBJECTS: A total of 28 patients (three male (M)/25 female (F); mean (s.d.) BMI 37.4(3.9) kg/m2) entering a randomized, double-blind, placebo-controlled study. MEASUREMENTS: CCK release and gastric emptying by scintigraphy at the start (T0), after 1 month of an energy- and fat-restricted diet and placebo (T1), and after 1 month (T2) and 1 year (T3) of randomization to placebo or 120 mg orlistat three times a day. RESULTS: One month of dieting and a weight loss of 2.3 kg (2.1% of initial weight) did not affect gastric emptying of liquids and solids. Basal and meal-stimulated CCK levels remained unaltered. Placebo-treated subjects who continued the diet for 1 month demonstrated a borderline significant suppressed CCK secretion and a weight loss of 1.2 kg (1.0%) without an effect on gastric emptying. After 1 year, the CCK secretion recovered to or beyond values at the start. A significantly slower emptying of solids (17.6 (T3) versus 25.9 (T1)%/h) and a weight loss of 10.4 kg (9.9%) was observed. Subjects on 120 mg orlistat lost 2.5 kg (2.5%) after 1 month, and 9.8 kg (9.9%) after 1 year. Basal and postprandial CCK release decreased significantly after the first month of orlistat treatment but normalized after 1 year. Diet and lipase inhibition did not have any influence on gastric emptying. CONCLUSION: Energy and fat restriction of 1 month did not alter gastric emptying in the whole group. Continuation of the diet for 1 year resulted in a delayed gastric emptying of solids. Lipase inhibition did not result in a sustained depressed CCK release and the anticipated acceleration of gastric emptying did not occur.

Gastric emptying, CCK release, and satiety in weight-stable obese subjects.

Scintigraphic gastric emptying studies are far from conclusive in obesity. The aim was to investigate gastric emptying and CCK release in weight-stable obese subjects on their usual diet and to study the impact of factors known to determine gastric emptying. Patients entering a weight reduction program were asked to participate in a study examining gastric emptying by scintigraphy and CCK release in response to a meal with questionnaires on feelings of satiety. Forty-five patients (9 M, 36 F) with a mean (SD) BMI of 37.0 (4.0) kg/m2 entered the study. The mean T50 (emptying of 50%) of fluids was 20.7 (10.3) min, and that of solids 141.9 (168.3) min. The percentage emptying of solids was 34.5 (19.9)%/hr. CCK values peaked within 42 min and paralleled the subjective ratings of satiety but did not correlate with gastric emptying. Five of 45 subjects (11%) had very prolonged gastric emptying of solids; they showed higher caloric intakes and higher insulin levels. They did not differ in CCK values and ratings of satiety but scored higher in being active and awake. Without these five subjects the T50 of solids was 94.3 (36.1) min, and the percentage of emptying 37.9 (18.4)%/hr. Liquid emptying was faster and solid emptying similar compared with those of normal-weight individuals. Height, fat-free mass, and waist-hip circumference were positively related to solid emptying. In weight-stable obese subjects liquid emptying was faster and solid emptying similar to those in normal-weight subjects. Higher caloric intakes and insulin levels were present in subjects with prolonged solid emptying; they also appeared more vigilant. Body size and composition were the only determinants suggesting a faster solid emptying in taller and muscular subjects or in subjects with more intraabdominal fat.

Determinants of gallbladder kinetics in obesity.

Obese subjects are at risk of developing gallstones both by being overweight and by reducing their body weight. The aim of the present study was to investigate factors related to disturbances in gallbladder emptying measured by ultrasound. Detailed information about weight loss attempts, age at onset of obesity, parity, presence of menopause, use of contraceptive or hormonal replacement drugs, and phase of menstrual cycle was obtained. Smoking habits, alcohol use, dietary intake, and physical activity were recorded. Body composition and fat distribution were assessed by anthropometry. Blood samples were taken for CCK, lipids, glucose, and insulin. Mean (SD) fasting gallbladder volume was 30.0 (12.6) ml. The residual volume was 12.5 (9.8) ml 90 min after a test meal. CCK levels increased from a basal 1.64 (0.8) pM to a peak value of 2.9 (1.0) pM. Fasting gallbladder volumes were closely related to residual and ejection volumes. Body weight and fasting insulin levels explained 35.2% of the variance in fasting volume, lean body mass and insulin explained 28.1% of the residual volume, and waist circumference 23.6% of the ejection volume. None of the other factors were related to gallbladder emptying. Subjects with the largest fasting gallbladders had the largest residual and least emptying gallbladders, scored the highest in every aspect of body size, composition, and fat distribution, and also had the highest insulin levels. Body weight, lean body mass, central fat distribution, and insulin levels were the main determinants of gallbladder kinetics. Fasting and residual gallbladder volumes were closely related and both determined by obesity and its metabolic complication of hyperinsulinemia.

Lipase inhibition by orlistat: effects on gall-bladder kinetics and cholecystokinin release in obesity.

BACKGROUND: Obese subjects are at risk of developing gallstones as a result of the obese state and during weight reduction. AIM: To study whether orlistat, by lipase inhibition, impairs gall-bladder emptying, thus further predisposing weight-losing obese subjects to gallstone formation. METHODS: Patients entering a randomized clinical trial of 1 month of diet, followed by treatment with placebo, 3 x 60 mg orlistat or 3 x 120 mg orlistat, underwent gall-bladder emptying studies measured by ultrasound. Meal-induced cholecystokinin release and gall-bladder emptying were investigated at the start, at randomization and after 1 and 12 months. RESULTS: One month of dieting did not change gall-bladder emptying and cholecystokinin release. After 1 month, placebo treatment resulted in a decreased fasting volume of 11%, compared with increases of 26% and 47% with 60 and 120 mg orlistat, respectively. Gall-bladder emptying increased by 9% with placebo and decreased by 15% and 53% with 60 and 120 mg orlistat, respectively. Fasting cholecystokinin values and cholecystokinin release decreased significantly in the orlistat group. After 1 year, a persistent but attenuated effect of orlistat on gall-bladder emptying and cholecystokinin release remained. Three of 40 patients developed gallstones, two on placebo with major weight loss and one on 60 mg orlistat. CONCLUSIONS: One month of lipase inhibition by orlistat significantly impaired gall-bladder motility, which persisted to some extent after 1 year. Obese subjects with diabetes or hyperlipidaemia, who are more at risk of gallstones, should be followed carefully.

Glomerular barrier function following conversion from cyclosporine to azathioprine in renal transplant recipients.

The renal side effects are the major limitation of the use of cyclosporine in clinical transplantation. We studied the reversibility of changes in renal hemodynamics and glomerular barrier function in 17 patients with moderately impaired renal function at least 1 year after kidney transplantation. All patients were studied both during cyclosporine treatment and 3 months after conversion to azathioprine. During azathioprine treatment both glomerular filtration rate and effective renal plasma flow increased significantly (from 44.3 +/- 4.2 mL/min to 63.5 +/- 5.4 mL/min and from 192 +/- 12.8 mL/min to 260 +/- 14.6 mL/min, respectively). Despite the marked changes in renal hemodynamics, no significant changes were observed in the fractional clearances of uncharged dextrans. When calculating the characteristics of the filtration barrier, we observed a trend toward an increase in the ultrafiltration coefficient (Kt). This trend was abolished when an increase in net filtration pressure (delta P) was assumed to result from reduced prerenal vasoconstriction. We conclude that despite marked improvement of renal perfusion and glomerular filtration, conversion from cyclosporine to azathioprine did not significantly alter the permeability characteristics of the glomerular filtration barrier in renal transplant recipients with moderately reduced renal function. Improvement in renal function following conversion could result from an increase in either Kf or delta P. Since renal plasma flow was increased significantly, the observed improvement in glomerular filtration rate is likely to be, at least in part, due to an increase in glomerular capillary plasma flow.

Phlegmonous gastritis: an unusual presenting symptom of Sjögren's syndrome.

This case report describes the histological and macroscopic changes seen within a few months in the gastric mucosa of a 28 year old woman patient with upper abdominal symptoms. With hindsight these changes were the first signs of Sjögren's syndrome.

Cortical blindness due to cyclosporin.

We here report the occurrence of cortical blindness in a kidney transplant recipient treated with cyclosporin. The cortical blindness was the result of cyclosporin toxicity and resolved spontaneously after cyclosporin dose reduction.