Eating Behavior and the Evolutionary Perspective on Anorexia Nervosa.

On the standard perspective, anorexia nervosa and other eating disorders are caused by genetically determined, neurochemically mediated mental illnesses. Standard treatment, cognitive behavioral therapy (CBT), targets cognitive processes thought to maintain the disorders. Effective neurochemically based treatments are not available and the rate of remission is ≤25% 1 year after CBT, with unknown outcomes in the long-term. With starvation as the major threat in biological history, the evolutionary perspective focuses on foraging for food and eating behavior. A neural network, including hypothalamic arcuate peptide-neurons, brainstem serotonin- and dopamine-neurons and their prefrontal cortical projections, mediates (rather than controls) the behavioral adaptations to variations in food availability; activation of the network is associated with opposing behavioral outcomes depending upon external variations. In the clinic, the control of eating behavior is therefore outsourced to a machine that provides feedback on how to eat. Hundreds of eating disorders patients have recovered by practicing eating; the rate of remission is 75% in on average 1 year of treatment, the rate of relapse is 10% over 5 years of follow-up and no patient has died. A two-parameter asymptotic exponential growth curve modeled the eating behavior of 17 healthy women but not that of 17 women with anorexia nervosa. When in remission, the eating behavior of the anorexic women approached that of the healthy women. It is suggested that the treatment of eating disorders should focus on eating behavior.

Neuropeptide Y facilitates activity-based-anorexia.

The hypothesis that treatment with neuropeptide Y (NPY) can increase running activity and decrease food intake and body weight was tested. Female rats with a running wheel lost more weight than sedentary rats and ran progressively more as the availability of food was gradually reduced. When food was available for only 1h/day, the rats lost control over body weight. Correlatively, the level of NPY mRNA was increased in the hypothalamic arcuate nucleus. This phenomenon, activity-based-anorexia, was enhanced by intracerebroventricular infusion of NPY in rats which had food available during 2h/day. By contrast, NPY stimulated food intake but not wheel running in rats which had food available continuously. These findings are inconsistent with the prevailing theory of the role of the hypothalamus in the regulation of body weight according to which food intake is a homeostatic process controlled by "orexigenic" and "anorexigenic" neural networks. However, the finding that treatment with NPY, generally considered an "orexigen", can increase physical activity and decrease food intake and cause a loss of body weight is in line with the clinical observation that patients with anorexia nervosa are physically hyperactive and eat only little food despite having depleted body fat and up-regulated hypothalamic "orexigenic" peptides.

Cognitive behavior therapy for eating disorders versus normalization of eating behavior.

We examine the science and evidence supporting cognitive behavior therapy (CBT) for the treatment of bulimia nervosa and other eating disorders. Recent trials focusing on the abnormal cognitive and emotional aspects of bulimia have reported a remission rate of about 45%, and a relapse rate of about 30% within one year. However, an early CBT trial that emphasized the normalization of eating behavior had a better outcome than treatment that focused on cognitive intervention. In support of this finding, another treatment, that restores a normal eating behavior using mealtime feedback, has an estimated remission rate of about 75% and a relapse rate of about 10% over five years. Moreover, when eating behavior was normalized, cognitive and emotional abnormalities were resolved at remission without cognitive therapy. The critical aspect of the CBT treatment of bulimia nervosa therefore may actually have been the normalization of eating behavior.

Intake inhibition by NPY and CCK-8: A challenge of the notion of NPY as an "Orexigen".

We tested the hypothesis that neuropeptide Y (NPY) interacts with cholecystokinin octapeptide (CCK-8) in inhibition of intake of an intraorally infused solution of sucrose, a test of consummatory ingestive behavior. Both intracerebroventricular infusion of NPY (10 microg) and intraperitoneal injection of CCK-8 (0.5 micro/kg) reduced the intake of a 1M solution of sucrose infused intraorally at a rate of 0.5 ml/min in ovariectomized female rats, but the two peptides did not interact in inhibiting intraoral intake. By contrast, NPY increased intake if the sucrose solution was ingested from a bottle, a test demanding both appetitive and consummatory ingestive responses. CCK-8 inhibited intake in this test and its inhibitory effect was increased by simultaneous treatment with NPY. The activity in the nucleus of the solitary tract (NTS), a brainstem relay mediating inhibition of intake, judged by the expression of c-fos-like immunoreactivity, was significantly increased after treatment with CCK-8 or NPY to approximately the same extent. Combined treatment with NPY and CCK-8 did not increase the c-fos-like immunoreactivity in the NTS above treatment with NPY or CCK-8 alone. These results strengthen the hypothesis that NPY, like CCK-8, is an inhibitor of consummatory ingestive behavior and suggest that this inhibition is mediated via the NTS.

Cardiovascular prognosis in relation to apolipoproteins and other lipid parameters in patients with stable angina pectoris treated with verapamil or metoprolol: results from the Angina Prognosis Study in Stockholm (APSIS).

Relationships between apolipoproteins and other lipid parameters and cardiovascular (CV) prognosis were evaluated in the Angina Prognosis Study In Stockholm (APSIS). Out of 809 patients with stable angina pectoris, lipid variables were obtained in 786 patients at baseline, and after one month's double-blind treatment with metoprolol or verapamil, to evaluate treatment effects on these lipid variables. During a median follow-up time of 3.3 years (2663 patient years), 37 patients suffered a CV death, 30 suffered a non-fatal myocardial infarction (MI) and 100 underwent a revascularization. Apolipoprotein (apo) A-I, high-density lipoprotein cholesterol and triglycerides were predictors of CV death or non-fatal MI in univariate analyses, but only apo A-I remained as an independent predictor in multivariate analyses. All lipid variables except low density lipoprotein cholesterol were related to the risk of revascularization in univariate analyses, but only apo A-I and apo B were independent predictors of such events. Triglycerides were weakly, but not independently, associated with prognosis. Verapamil and metoprolol had differential short-term effects on lipids, with a shift towards a more atherogenic profile in metoprolol treated patients. However, there was no significant impact of the treatment given, or of these treatment effects on the risk of CV events. Results of the present study suggest that apolipoprotein levels were better predictors of CV events than other lipid parameters in patients with stable angina pectoris.

Effect of amlodipine versus felodipine extended release on 24-hour ambulatory blood pressure in hypertension.

Amlodipine and felodipine are calcium antagonists of the dihydropyridine type. The elimination half-life of amlodipine is longer than that of felodipine. To study whether the different elimination rates of the drugs were reflected in different duration of blood pressure (BP) control, we compared amlodipine and felodipine extended release (ER) by both conventional clinic BP 24 h after drug intake and 24 h ambulatory BP monitoring (ABPM), with special reference to nighttime and morning blood pressure. Two hundred and sixteen patients with primary hypertension (supine diastolic BP, 95 to 115 mm Hg) were randomized to receive amlodipine or felodipine ER in a multicenter study. The starting dose of both drugs was 5 mg. If the target clinic diastolic BP (90 mm Hg) had not been achieved after 4 weeks the dose was increased to 10 mg. Twenty-four-hour ABPM was performed with the subjects taking placebo medication before randomization and after 4 and 8 weeks undergoing active treatment. Significantly more patients responded after 4 weeks of treatment with amlodipine (50%) as compared with felodipine (33%) (P = .013). ABPM during daytime (07:00 to 23:00) was similar during both treatments, but nighttime systolic (P = .026) and diastolic (P = .019) BP was more effectively reduced by amlodipine than by felodipine. After 8 weeks 82% achieved the target pressure with amlodipine and 69% with felodipine (P = .036 for the difference). Amlodipine seems to be more effective than felodipine when the drugs are compared in the same dose, with regard to the effect on clinic BP 24 h after dosing and to ambulatory BP during the night. The longer elimination half-life of amlodipine as compared to felodipine is the probable reason for this finding.

Dopamine D(2) receptors and ingestive behavior: brainstem mediates inhibition of intraoral intake and accumbens mediates aversive taste behavior in male rats.

RATIONALE: One of the factors that terminate the ingestion of an intraorally infused solution of sucrose may be an increase in the perceived aversiveness of its taste. OBJECTIVES: We tested the hypothesis that dopamine D(2), as opposed to D(1), receptors in the brainstem or nucleus accumbens inhibit intraoral intake by enhancing the aversiveness of the taste of the infused solution. METHODS: Male rats were infused intraorally with a 2 M sucrose solution (1 ml/min) and intake and the display of gapes and chin rubs, i.e. taste-related aversive behavior, was measured. Gapes and chin rubs were also measured in rats during and 40 s after brief intraoral infusion (1 ml/min during 20 s) of a 0.3 mM solution of quinine HCl. The full D(1) receptor agonist dihydrexidine (0.1-3.0 mg/kg) and antagonist SCH-23390 (0.03-0.1 mg/kg), the D(2) receptor agonist quinpirole (0.3 mg/kg) and antagonist raclopride (1.7 mg/kg) were injected IP. Quinpirole (14-55 microg) and raclopride (5 microg) were also infused into the fourth brain ventricle. In addition, quinpirole (2 or 10 microg) was infused into the shell region of the nucleus accumbens. RESULTS: IP dihydrexidine and quinpirole inhibited the intraoral intake of sucrose and pretreatment with raclopride, but (in the case of dihydrexidine) not SCH-23390, attenuated this effect. Injection of quinpirole into the fourth ventricle produced raclopride-reversible inhibition of intraoral intake but did not stimulate the display of gapes and chin rubs. Infusion of quinpirole into the shell region of the nucleus accumbens had the opposite effects. The intake of sucrose was suppressed by the addition of quinine HCl but this suppression was unaffected by dopamine agonist or antagonist treatment. CONCLUSIONS: It is suggested that brainstem dopamine D(2) receptors mediate suppression of consummatory ingestive behavior and that D(2) receptors in the shell region of the nucleus accumbens mediate the display of gapes and chin rubs, but that neither of these D(2) receptor populations mediate the hedonic evaluation of taste.

Carriers and noncarriers of haemophilia A: I. Multivariate analysis of pedigree data, screening blood coagulation tests and factor VIII variables.

From a material of 18 obligate carriers of haemophilia A and 40 healthy females, a discriminant function was created, based on ratio of factor VIII related antigen (electroimmunoassay = EIA) to factor VIII activity (one-stage assay), factor VIII related antigen (radioimmunoassay = RIA) and number of bleeding symptoms. The standard deviation of p-values for carrier- and non-carrier state (less than 0.05) was estimated by a procedure built on the 'jack-knife' method. By combined information of pedigree- and discriminant analysis data, 43 possible carriers were classified as carriers/noncarriers with about 95% confidence. Carriers were significantly older, had more bleeding symptoms, longer APTT, lower factor VIII activity, factor VIII procoagulant antigen, and higher ratio of factor VIII related antigen (EIA) to factor VIII activity (one-stage) and to factor VIII related antigen (RIA) respectively, than classified noncarriers. Individuals with blood group A, B, AB had significantly higher levels of factor VIII related antigen (EIA) and (RIA), and ristocetin cofactor, compared with blood group O. Obligate carriers with severe haemophilia A in their families had more bleeding symptoms than corresponding group with moderate haemophilia.

Statistical analysis of the micronucleus test--a modelling approach.

This paper suggests an approach according to the principle that 'An experimental design is related to a statistical model describing that particular design'. A simple linear model approach is presented as an alternative to earlier proposed multiple single tests which is suitable for situations in which there are just a few dose levels and expression times. Furthermore, the aim is to move from significance testing towards a modelling and estimation procedure in order to find a structure and try to evaluate what is being determined in the experiment.

Plasma renin activity and oxygen content along the renal veins in hypertensive patients.

Plasma renin activity (PRA) and oxygen content in three different locations in the renal veins were studied in 27 patients with suspected renin-dependent hypertension or during post-operative follow-up investigations after renal artery reconstruction. A significant decrease in PRA was found along the right renal vein but not along the left one. The oxygen content simultaneously measured was lower in the central parts of both renal veins than most peripherally, more on the right side than on the left one, indicating dilution of renal venous blood. An erroneous ratio between renal vein PRA of the affected and the contralateral kidney was found in two of 17 patients with unilateral renal artery stenosis when sampling from a central position in the renal vein. This indicates that a peripheral position of the catheter is important when sampling for renal vein PRA.

A statistical model examining repetitive criminal behavior in acts of violence.

A simple statistical model for examining repetitive criminal behavior in acts of violence is described. The units, called "parameters," are nonquestionable data concerning environment of the crime, personal properties, and postmortem findings of the victim, obtained by double-blind investigation performed by two forensic pathologists. Parameters shared by two or more criminal acts allegedly committed by the same assailant were compared with the same parameters recorded from 50 or 100 other mutually independent criminal acts committed by other known assailants. This allowed an evaluation of the probability (p) of a crime pattern expressed as a parameter score to recur in mutually independent cases. The distribution of the score, when plotted on a logarithmic scale in all examples, showed an approximately normal distribution. The relation between probability (p), the estimated mean (means), and standard deviation (SD) yielded a normal curve. Different patterns of action by different perpetrators and patterns indicating repetitive behavior could be obtained. The method is applicable during investigation of crimes in which the perpetrator acts in a repetitive manner, as in serial murders.

The clinical relevance of endoscopic and histologic inflammation of gastroduodenal mucosa in dyspepsia of unknown origin.

Two hundred and ten patients were defined as having dyspepsia of unknown origin. At endoscopy 11% had body gastritis, 46% antral gastritis, and 19% bulbitis (two thirds combined with antral gastritis). Histologically, 22% had chronic corpus gastritis (79% superficial, 21% atrophic), which was combined with chronic antral gastritis in 84%, 33% had chronic antral gastritis (82% superficial, 18% atrophic); and 14% had duodenitis, which was combined with antral gastritis in 65%. Polymorphonuclear leukocytes were found in specimens from the body mucosa in 6%, from the antral mucosa in 13%, and from the duodenal cap in 4%. The endoscopic findings correlated significantly with the histologic findings in the duodenal bulb (kappa = 0.33) but not in the stomach. The frequency of endoscopic antral gastritis and the frequency of histologic chronic body and antral gastritis increased with age. Endoscopic bulbitis and histologic duodenitis and gastric metaplasia were commoner in men than in women. Peak acid output was higher in patients with than in those without endoscopic bulbitis and higher in smokers than in non-smokers when the significant sex differences in peak acid output were taken into account. Gastric metaplasia of the bulb was predominantly correlated to higher peak acid output and to some extent also to sex and smoking. Episodic pain was correlated to histologic duodenitis. Other dyspeptic symptoms and the intragastric bile acid concentration were not associated with any endoscopic or histologic findings. Of the 210 patients, 172 were reexamined after a double-blind 6-week treatment period with cimetidine, antacid, or placebo. The symptomatic outcome of these treatments was not associated with any significant change in endoscopic or histologic findings.

Effect of dipyridamole (Persantin) on blood flow and patency of aortocoronary vein bypass grafts.

The effect of dipyridamole was investigated in 360 patients undergoing coronary bypass surgery. They were randomly allocated to receive dipyridamole (100 mg orally q.i.d. for 2 days preoperatively, 5 mg/kg body weight/24 h i.v. peroperatively and 100 mg orally q.i.d. for 1 year postoperatively) or placebo. Withdrawn from the study were 48 patients on dipyridamole and 57 on placebo. Cardiovascular and/or cerebrovascular events or need for anticoagulant treatment were the reasons for withdrawal in 22 (13%) of the dipyridamole, and 34 (18%) of the placebo group. Logistic regression analysis of risk factors influencing graft patency showed significant relation to peroperatively measured coronary blood flow. A positive trend of treatment was observed (p = 0.08). Vein graft blood flow measured during bypass surgery (245 patients) was significantly greater in the dipyridamole group (p less than 0.01). The occlusion rate was lower in vessels with peroperative blood flow greater than 30 ml/min (vein-marginal p less than 0.01, vein-dexter p less than 0.05, vein-diagonal 0.05 less than p less than 0.1). Dipyridamole increases coronary blood flow and graft patency following coronary bypass surgery.

Treatment with cimetidine, antacid, or placebo in patients with dyspepsia of unknown origin.

Patients with dyspepsia of unknown origin were randomly allocated to a controlled double-blind study to examine the symptomatic effect of cimetidine and antacid especially on the relief of pain, nausea, and bloating. Two hundred and twenty-two patients with no previous history of peptic ulcer disease and no evidence of other organic causes of dyspepsia were treated for 6 weeks with placebo, cimetidine, or antacid. The results showed that cimetidine was superior to both placebo and antacid in relieving pain and nausea but not bloating. Certain background factors, such as epigastric pain and symptoms relieved by solid food, had a significant positive influence on the outcome of treatment. When the impact of background factors was taken into account, cimetidine was found to be more effective than both placebo and antacid also with regard to the number of patients who improved in general well-being.

Auranofin improves outcome in early rheumatoid arthritis. Results from a 2-year, double blind placebo controlled study.

The effect of early initiation of auranofin (AF) therapy on outcome measures was studied in a controlled 24-month double blind trial in 138 patients with early rheumatoid arthritis (RA) using an intent to treat approach. Patients were randomized to AF or placebo but in case of insufficient effect or intolerable adverse events, they switched to open disease modifying antirheumatic drug therapy. Patients who started AF fared significantly better in improved joint swelling. Stanford Health Assessment Questionnaire index, Keitel functional test, and mental depression, and furthermore, radiologic progression was significantly retarded. Our results support a disease modifying beneficial effect of AF in early active RA.se

Patients with rheumatoid arthritis benefit from early 2nd line therapy: 5 year followup of a prospective double blind placebo controlled study.

OBJECTIVE: To compare 2 treatment strategies in a prospective 5 year study of patients with rheumatoid arthritis (RA): early treatment with slow acting antirheumatic drugs (SAARD) versus a "wait and see" attitude. METHODS: One hundred thirty-seven patients with RA of < 2 years' duration entered a double blind placebo controlled study: patients in the "early" (E) group were treated with auranofin within one year of diagnosis of RA, and SAARD treatment in the initially placebo treated group was delayed 8 months compared with the former group. [The results after 2 years clearly favored early treatment (Borg G, Allander E, Lund B, et al: J Rheumatol 1988; 15:1747-54)]. RESULTS: After a total observation period of 5 years in 75 representative patients, continued improvement in the E group was demonstrated, and differences between the 2 groups were maintained with regard to clinical variables, outcome measures, and radiographic evaluation. CONCLUSION: The results indicate the existence of a therapeutic window in RA within the first 2 years of the disease.

Auranofin treatment in early rheumatoid arthritis may postpone early retirement. Results from a 2-year double blind trial.

The effect of early vs delayed initiation of slow acting antirheumatic drug (SAARD) therapy on the ability to maintain regular work, was evaluated in 83 patients with early rheumatoid arthritis (RA) in a placebo controlled, double blind 24-month study. The estimated probability to maintain working ability was higher in the early treatment group, especially during the second study year. Predicting factors were age, type of work, degree of disability and number of swollen joints. Despite the difficulties in interpreting the results due to the complexity of the underlying socioeconomical and labor market situation, the study supports early treatment in RA with regard to the maintenance of normal life.