The gastric emptying characteristics of physiological saline (0.9% NaCl) and glucose solutions of three different concentrations (0.05, 0.125, 0.25 g/ml) were examined in order to identify distinctions in the control of the stomach's activity. Saline emptied rapidly and exponentially. Glucose assumed, soon after filling the stomach, a slow and calorie-constant emptying pattern such that 2.13 kcal of glucose were delivered per minute to the duodenum for all three concentrations of glucose. When, by means of a catheter passed beyond the pylorus, glucose was infused into the duodenum in amounts varying from 26.5 to 120 kcal, an inhibition on the gastric emptying of physiological saline of 0.46 min/kcal of intraduodenal glucose was demonstrated. Since 2.13 kcal/min and 0.46 min/kcal are reciprocals, it appeared that in emptying saline, the gastroduodenal system acts as an "open-loop" system passing liquids from the stomach at a rate primarily determined by the volume of gastric contents. With glucose, however, a "closed-loop" system is established that assumes a steady-state balance between the delivery of glucose to the duodenum and the inhibition of this delivery evoked from the duodenum by the glucose that enters it.

The distribution and relative specificity of cholecystokinin (CCK) receptors in the rat brain was mapped by in vitro autoradiography with [125I]CCK-33. We identified two distinct binding patterns, suggesting two CCK receptor types. The first is widespread and relatively non-specific. The second, localized to a few subcortical nuclei, has the specificity demonstrated for pancreatic CCK receptors. Localization of this receptor type to the area postrema provides a possible entry site into brain for circulating CCK that would distinguish between CCK and gastrin and could mediate some of CCK's behavioral effects.

Recent work has suggested a role for an endogenous release of cholecystokinin (CCK) acting at either type A or type B CCK receptors in the control of food intake. In an effort to investigate whether the mechanisms by which exogenously administered and endogenously released CCK inhibits food intake are similar and depend upon interactions with either type A or type B CCK receptors, we examined in rats the ability of the type A (L 364718) and type B (L 365260) CCK receptor antagonists to 1) block the inhibition of glucose consumption produced by an intraperitoneal injection of 4 micrograms/kg of CCK and 2) increase glucose consumption in the absence of exogenous CCK after a 6-h daytime deprivation. Increasing dosages (10-100 micrograms/kg) of the type A CCK antagonist resulted in a dose-related blockade of the inhibition of intake produced by CCK, and the 100 micrograms/kg dose of the A antagonist significantly increased glucose intake above baseline levels. In contrast, no dose (10-1,000 micrograms/kg) of the B antagonist blocked the inhibitory action of exogenous CCK at any time point. In the absence of exogenous CCK, the 32 and 100 micrograms/kg doses of L 364718 increased intake above baseline levels. No dose (3.2-320 micrograms/kg) of the type B antagonist, L 365260, affected intake in this paradigm. These results suggest that the mediation of the feeding-inhibitory effects of exogenous and endogenous CCK are similar and depend upon activation of type A CCK receptors.

In an effort to discern whether cerebral vascular injuries provoke specific emotional disturbances, 20 consecutively admitted stroke patients were compared with 10 orthopaedic patients. Both groups were examined for functional disabilities (Activities of Daily Living) and for psychiatric symptoms. Reliable and valid instruments, the Hamilton Rating Scale, the Visual Analogue Mood Scale, the Present State Exam, and the Mini-Mental State Exam were employed to display the psychopathology. More of stroke patients than orthopaedic patients were depressed (45% versus 10%) even though the level of functional disability in both groups were the same. Patients with right hemisphere stroke seemed particularly vulnerable and and displayed a syndrome of irritability, loss of interest, and difficulty in concentration, in addition to depression of mood (70% of right hemisphere stroke patients versus 0% left hemisphere stroke patients and 0% orthopaedic patients). We conclude that mood disorder is a more specific complication of stroke than simply a response to the motor disability. We suggest that a controlled trial of antidepressant medication is indicated for patients with this complication.

Gastric emptying in four unanesthetized male Macaca mulatta was studied with the serial test meal method of Hunt and Spurrell. Liquid meals were infused into the stomach through a chronic indwelling Silastic cannula. Saline meals empty rapidly and exponentially. Doubling the volume of saline from 150 to 300 ml increased the emptying rate so that the half-life remained unchanged (15 min). The 150-ml glucose meals (0.05, 0.125, and 0.25 g/ml) emptied more slowly than saline, progressively more slowly with increasing concentrations (0.05--1.8, 0.125--0.78, and 0.25--0.37 ml/min) and linearly through most of their course. Doubling the volume of 0.125 g/ml-glucose meal did not change the rate of emptying. Converting grams of glucose to their caloric content, the emptying rate in kcal/min becomes constant (approx 0.4 kcal/min) in this range of concentrations. Isocaloric casein hydrolysate and medium-chain triglyceride oil meals at 0.5 kcal/ml empty at the same rate as glucose. The precision of this regulation is sufficient to give it a role in preabsorptive satiety and the control of caloric intake.

In a search for the physiological mechanisms that could mediate and characterize a satiety function for the hormone cholecystokinin (CCK), we examined in Macaca mulatta the effect of intraperitoneal injections (0.1-0.8 microgram/kg) and intravenous infusions (60-240 ng.kg-1.h-1) of the C-terminal octapeptide of CCK on gastric emptying of saline test meals. Within these dose ranges, gastric emptying was inhibited by this hormone to a degree comparable with that produced by intraintestinal nutrient. The onset of the inhibition is rapid and its effect brief. At the doses of CCK that produce gastric inhibition, CCK would not affect feeding in a fasted monkey unless the stomach was filled with saline. This result suggests that a satiety influence of circulating CCK is an indirect one. The satiety effect depends upon inhibition of gastric emptying, which then leads to gastric distention with further food injection. CCK thus can be considered a link in a chain of physiological elements producing the short-term satiety that leads to the appropriate interruption of a meal or bout of feeding behavior.

Both gastric preloads and exogenous cholecystokinin (CCK) administration inhibit food intake, and combinations of preloads and CCK suppress feeding to a greater degree than either stimulus delivered alone. A role for the vagus nerve in mediating CCK's inhibition of food intake has been proposed, and gastric vagal afferent fibers respond to both gastric loads and local CCK infusions. To examine whether combined load and CCK stimuli may synergistically augment gastric neural afferent activity at the level of the peripheral vagus, we have examined the gastric vagal afferent responses (n = 8) to a range of gastric saline loads (1, 2, and 3 ml) and exogenous close celiac arterial CCK (10 and 100 pmol) when administered alone or in combination. Gastric loads ineffective in eliciting a significant increase in vagal afferent activity when administered alone became effective when combined with doses of CCK that were subthreshold for the production of a vagal afferent response. Gastric loads that alone were effective in producing a significant vagal afferent response yielded an even greater response when administered in combination with both subthreshold and suprathreshold doses of CCK. These data demonstrate that, in rats, signals produced by combined gastric load and exogenous CCK administration are integrated peripherally and interact synergistically. These results suggest that signals arising from the vagus may provide sufficient information for the synergistic inhibition of food intake produced by combinations of gastric loads and exogenous CCK.

The effects of various vagal lesions on cholecystokinin (CCK) binding sites in the nucleus tractus solitarii (NTS) and area postrema (AP) and the peripheral transport of CCK binding sites in the cervical vagus were examined in rats by in vitro autoradiography with [125I]CCK-8. Unilateral supraganglionic, but not subdiaphragmatic vagotomy significantly reduced CCK binding in the ipsilateral NTS. Specific unilateral afferent, but not efferent, vagal rootlet transections also significantly reduced NTS CCK binding ipsilateral to the transections. None of the vagal lesions altered CCK binding in the AP. Infraganglionic but not supraganglionic vagotomy eliminated the peripheral transport of vagal CCK binding sites. Together these results demonstrate that CCK receptors in the NTS are located on vagal afferent terminals, that CCK receptors in the AP are likely postsynaptic to a vagal afferent input and that the peripheral and central transport of vagal CCK binding sites occurs in afferent fibers.

The neurophysiological responses to 2-ml intragastric saline loads and 100-pmol celiac artery infusions of cholecystokinin (CCK) were obtained from 20 vagal afferent fibers in 14 rats. Two groups of fibers were identified. Discharge rates of group I fibers (n = 16) were significantly increased by gastric loading, adapted slowly to maintained gastric volume, and were inhibited by load withdrawal. CCK elicited a significant increase in the discharge rate of these group I fibers. Prior exposure to CCK nearly doubled the response of these fibers to a subsequent gastric load. In contrast, group II fibers (n = 4) increased firing rate only during infusion of a gastric load and showed rapid adaptation and no response to CCK. CCK failed to alter subsequent responses to gastric loads in these fibers. These results 1) demonstrate an integration of signals elicited by exogenous CCK and gastric loads at the level of vagal afferent fibers and 2) imply that aspects of CCK's inhibition of food intake may derive from CCK's ability to mimic and amplify vagal afferent activity provoked by meal-related gastric events.

In order to evaluate vagal cholecystokinin (CCK) binding sites as potential target sites for the satiety actions of CCK, their presence, axonal flow and pharmacological specificity in subdiaphragmatic vagal branches were examined by autoradiography utilizing 125I-Bolton Hunter CCK-33. Specific CCK binding and axonal transport were found in vagal trunks and all abdominal vagal branches. Binding was inhibited by unlabelled CCK-8, but not by desulfated CCK-8. The pharmacological specificity and transport of CCK binding sites to subdiaphragmatic branches indicate a potential role in mediating CCK's satiety effect.

Five rhesus monkeys were infused intravenously with partially purified cholecystokinin (CCK) Just prior to a test meal of solid food after overnight food deprivation; CCK produced large, rapid, dose related suppressions of feeding. The lowest dose tested (5 Ivy U/kg body wt) produced a significant inhibition of food intake (26% suppression, P less than 0.05). Equivalent infusions of partially purified CCK or the synthetic COOH-terminal octapeptide of CCK (a pure fragment with all the biological activity of the full molecule) produced equivalent suppressions. In a second experiment, gastric preloads of a potent releaser of endogenous CCK, L-phenylalanine (L-Phe), and a weak releaser, D-phenylalanine (D-Phe) were compared for their relative abilities to suppress food intake at a test meal in nine rhesus monkeys after overnight deprivation. L-Phenylalanine produced large, rapid, dose-related suppressions of feeding, but D-Phe did not. The threshold dose of L-Phe was 0.5 g/kg (32% suppression, P less than 0.01). Neither CCK nor L-Phe caused signs of illness in these experiments. The results demonstrate that intravenous exogenous CCK suppresses feeding in rhesus monkeys and suggest that endogenous CCK has the same effect; they are consistent with the hypothesis that CCK is a satiety signal.

OBJECTIVE

To ascertain the prevalence and type of psychiatric morbidity present in HIV infected patients presenting for the first time to a specialty HIV medical clinic. Also, to develop a way of screening for psychiatric cases in this setting using established self-report questionnaires.

METHODS

Fifty patients who presented consecutively for medical care at the Johns Hopkins Hospital General HIV Clinic participated in this study. These patients were first screened using the General Health Questionnaire and the Beck Depression Inventory and subsequently underwent a comprehensive neuropsychiatric evaluation.

RESULTS

Fifty-four percent were found to suffer from a psychiatric disorder with an additional 22 percent from an active substance use disorder. These rates are one-and-one-half to two times higher than those reported from other medical clinics. The GHQ and BDI used together as screens could identify psychiatric "cases" with a sensitivity of 81 percent and a specificity of 61 percent, an efficacy similar to that found in other clinics.

CONCLUSIONS

Given the high prevalence of psychiatric disorders in HIV infected patients presenting for medical care, screening, evaluating, and treating for these disorders is crucial and should be pursued systematically. This is best done through the presence of a psychiatric team within HIV medical clinics rather than in affiliation with such clinics.

OBJECTIVE

Evidence suggests that the neuropathology of Huntington's disease, a neuropsychiatric disorder due to a mutation on chromosome 4, results from excessive activation of glutamate-gated ion channels, which kills neurons by oxidative stress. Therefore, the authors hypothesized that alpha-tocopherol, which reduces oxyradical damage to cell membranes, might slow the course of Huntington's disease.

METHODS

A prospective, double-blind; placebo-controlled study of high-dose d-alpha-tocopherol treatment was carried out with a cohort of 73 patients with Huntington's disease who were randomly assigned to either d-alpha-tocopherol or placebo. Patients were monitored for changes in neurologic and neuropsychologic symptoms.

RESULTS

Treatment with d-alpha-tocopherol had no effect on neurologic and neuropsychiatric symptoms in the treatment group overall. However, post hoc analysis revealed a significant selective therapeutic effect on neurologic symptoms for patients early in the course of the disorder.

CONCLUSIONS

Antioxidant therapy may slow the rate of motor decline early in the course of Huntington's disease.

The exogenous administration of the brain/gut peptide cholecystokinin (CCK) inhibits food intake in a variety of species, including subhuman primates and humans. To determine the role of endogenously released CCK in the control of food intake in rhesus monkeys, we examined the ability of the selective type A and type B CCK antagonists devazepide and L-365260 to affect total daily food intake and various meal patterns. Various doses of the antagonists were administered intragastrically 30 min before a daily 4-h feeding period. One-gram food pellets were delivered in response to lever pulls, and intake was computer monitored. Intragastric administration of the type A CCK receptor antagonist devazepide (10-320 micrograms/kg) significantly increased food intake in a dose-related fashion. The threshold for increasing intake was 32 micrograms/kg, and a maximal effect was obtained at a dose of 100 micrograms/kg that increased total 4-h food intake by 47%. The effect of devazepide on food intake was mediated by significant increases in the size and duration of the initial meal, lengthening of the subsequent intermeal interval, and a decrease in the satiety ratio (intermeal interval/1st meal size). In contrast, intragastric administration of the type B CCK receptor antagonist L-365260 (3.2-320 micrograms/kg) did not significantly affect total food intake or any of the meal parameters. These data demonstrate that endogenously released CCK acting through type A CCK receptors plays a role in regulating food intake in rhesus monkeys.

OBJECTIVE

The aims of this study were to estimate the prevalence and investigate the comorbidity and potential consequences of DSM-III personality disorders in the community.

METHODS

A total of 810 adults were examined in the second stage of the Eastern Baltimore Mental Health Survey in 1981, part of the National Institute of Mental Health Epidemiologic Catchment Area program. The subjects were directly examined by psychiatrists using a semi-structured method that allowed diagnosis of all DSM-III personality disorders as well as other DSM-III psychiatric disorders.

RESULTS

The prevalence of personality disorders in these adults was 5.9% (9.3% when provisional cases were included). Men had higher rates than women, and subjects who were separated or divorced had the highest rates. There was little comorbidity among specific personality disorders. Subjects with personality disorders were significantly more likely to have a history of sexual dysfunctions, alcohol use disorders, and drug use disorders as well as suicidal thoughts and attempts. In addition, they reported significantly more life events in the past year. Among subjects with any axis I disorder, those with personality disorders were judged by the psychiatrists to be more in need of treatment; however, only 21% were receiving treatment.

CONCLUSIONS

Personality disorders are relatively common in the community. They are associated with axis I disorders and life events. Only one-fifth of the individuals who qualify for diagnoses of personality disorders in the community are receiving treatment.

In an attempt to identify potential target sites for the satiety action of bombesin (BN), the distribution and pharmacological specificity of bombesin binding sites were examined in the rat gastrointestinal tract by in vitro autoradiography utilizing (125I-Tyr4) bombesin. Specific BN binding was localized to the circular muscle level of the gastric fundus and antrum, submucosal layer of the small intestine and longitudinal and circular muscle and submucosal layers of the colon. Pharmacological studies indicated that gastrin releasing peptide (GRP), Ac-GRP20-27 and BN-like compounds, litorin and ranatensin, inhibited the binding of (125I-Tyr4)BN with high affinity while compounds which lacked COOH-terminal homology with BN demonstrated a low affinity for BN binding sites. The wide distribution of BN binding sites in the gastrointestinal tract provides a number of potential sites for the mediation of the satiety action of BN.

To identify the transduction mechanisms underlying gastric vagal afferent responses to gastric loads and cholecystokinin (CCK), we investigated the ability of specific CCK antagonists, acute pylorectomy, and cholinergic blockade to effect these vagal afferent responses. The CCK-B antagonist L-365,260 (10 pmol-1 nmol) failed to block the gastric vagal afferent response to gastric loads or 100 pmol CCK, while the CCK-A antagonist devazepide (100 pmol-100 nmol) competitively and dose dependently attenuated the response to CCK but not to gastric loads. Application of 100 nmol of the low-affinity CCK receptor antagonist CCK-JMV-180 also completely blocked the gastric vagal afferent response to 100 pmol CCK. Acute pylorectomy failed to block the gastric vagal afferent response to 100 pmol CCK or 2-ml gastric loads. Atropine sulfate administration (15 mg/rat) failed to block the gastric vagal afferent response to 100 pmol CCK or 2-ml gastric loads. These data suggest that 1) the vagal afferent response to CCK is mediated through CCK's interactions with vagal, rather than pyloric, CCK-A receptors, and 2) the vagal afferent responses to CCK and to gastric loads are mediated by dissociable, possibly independent, transduction mechanisms.

We have proposed that cholecystokinin's (CCK) inhibition of gastric emptying contributes to its ability to inhibit food intake. To directly test this hypothesis in rats, the effect of the presence of a 5-ml gastric saline load on the ability of a long-acting cholecystokinin analogue U-67827E (0.1-10.0 nmol/kg) to inhibit intake of a 0.5 kcal/ml glucose solution was measured. The CCK analogue alone inhibited intake at a threshold dose of 2.5 nmol/kg. Although lower doses of the CCK analogue alone had no effect on subsequent glucose intake, when combined with the gastric load such doses did significantly inhibit intake. Thus the presence of a gastric load reduced the threshold dose of the CCK analogue required to inhibit intake. Furthermore, at suprathreshold doses, the peptide-load combination suppressed intake more than the peptide alone. In addition, administration of 0.5 and 5.0 nmol/kg doses of the CCK analogue inhibited gastric emptying at 10, 20, and 30 min in a dose-dependent fashion. The CCK analogue's inhibition of food intake and gastric emptying were reversed by pretreatment with 100 micrograms/kg L364,718, indicating that the analogue was having its effects by interacting with specific type A CCK receptors. Together these data support the notion that CCK satiety derives from an integration of the visceral afferent signals generated by CCK's promotion of gastric distension and those produced directly by CCK.

Psychiatrists used a semi-structured Standardized Psychiatric Examination method to examine 810 adults drawn from a probability sample of eastern Baltimore residents in 1981. Of the population, 5.9% was found to be significantly depressed. DSM-III major depression (MD) had a prevalence of 1.1% and 'non-major depression' (nMD), our collective term for the other depressive disorder categories in DSM-III, had a prevalence of 3.4%. The two types of depression differed by sex ratio, age-specific prevalence, symptom severity, symptom profiles, and family history of suicide. Analyses using a multiple logistic regression model discerned that both types of depression were influenced by adverse life events, and that nMD was influenced strongly by gender, marital status, and lack of employment outside the home. Neither type of depression was influenced by income, education, or race. This study validates the concept of major depression as a clinical entity. Future studies of the aetiology, mechanism, and treatment of depression should distinguish between these two types of depression.

We have studied in Macaca mulatta both the gastric emptying of glucose, D-xylose, and fructose and the effects of these sugars on feeding. Glucose and D-xylose empty in the same fashion, i.e., linearly and more slowly with increasing concentration so that the delivery of solute to the small intestine is constant at 0.1 g/min over time and across concentrations. Fructose empties exponentially and more rapidly than the other sugars. When solutions of each of these sugars (37.5 g in 150 ml) preceded the monkey's daily 4-h feeding period there was a similar total reduction in food intake for each. However, fructose inhibited food intake in the first 2 h of feeding less than did the other sugars just as it inhibited gastric emptying less. D-Xylose, although mimicking glucose in both gastric emptying and feeding on the experimental day, produced, as it is poorly metabolized, a caloric deficit replaced by overeating on the subsequent control day. We conclude from the similarities between glucose and xylose that the stomach, while emptying nutrients, influences feeding and can be at least one source of signals for preabsorptive satiety and caloric homeostasis. The results with fructose require that other sites must be active to permit a similar regulation of feeding to occur despite differing gastric emptying characteristics.

A total of 810 adults were examined by psychiatrists in the second stage of the Eastern Baltimore Mental Health Survey. A semistructured examination, the Standard Psychiatric Examination, was used. The relationships between obsessions and compulsions and personal characteristics, childhood behaviors, family history, and other psychopathology were evaluated. The estimated prevalence of obsessions and compulsions in this population was 1.5%. Cases were significantly more likely to report having had childhood fears, learning disabilities and a family history of alcoholism and suicidal behavior. There were significant positive relationships between scores on compulsive, borderline and histrionic personality disorder scales and the probability of obsessions and compulsions. These exploratory analyses in an epidemiologic sample may identify factors of etiologic importance in this condition.