Deadly vasospasm.

A patient with Prinzmetal's variant angina (PVA) developed a cardiac arrest due to coronary vasospasm and subsequent myocardial infarction. After resuscitation postanoxic brain injury was diagnosed. After an initial improvement of consciousness he deteriorated rapidly on the seventh day after admission due to severe brain ischaemia apparently caused by cerebral vasospasm, until ultimately brain death was diagnosed. To our knowledge, the association between PVA and cerebral vasospasm has never been described. The combination suggests that this patient had a generalized vasospastic disorder.

Current awareness of delirium in the intensive care unit: a postal survey in the Netherlands.

BACKGROUND: Delirium in the ICU can compromise the recovery process, prolong ICU and hospital stay and increase mortality. Therefore, recognition of delirium is of utmost importance. METHODS: To ascertain current attitude pertaining to delirium in critically ill patients a simple questionnaire was sent to all intensive care units (ICUs) throughout the Netherlands. RESULTS: Seventy-five questionnaires were sent and 44 returned. A delirium protocol was present in the majority of cases (n=35, 80%), although implementation had occurred in only 22 ICUs (50%). The reported general incidence of delirium varied widely (25% of ventilated patients (n=33, 75%) and in patients older than 70 (n=38, 86%). Most participating centres reported that they could certainly (n=9, 20%) or most certainly (n=22, 50%) identify delirium. A geriatrician or a psychiatrist predominantly diagnosed delirium (n=30, 68%), while a diagnostic instrument such as the CAM -ICU was used in a minority of cases (n=11, 25%). A geriatrician or a psychiatrist was consulted when patients were agitated (n=40, 90%), or when routine pharmacological treatment had failed (n=40, 91%). CONCLUSION: In the Netherlands, delirium is considered an important problem in the ICU, although its incidence is estimated to be low by the ICU team. The diagnosis of delirium is most frequently established by a geriatrician or psychiatrist after consultation, while diagnostic instruments are infrequently used. Efforts should be undertaken to implement delirium protocols and a routinely applied diagnostic instrument in the ICU.

Circadian rhythm of plasma leptin levels in upper and lower body obese women: influence of body fat distribution and weight loss.

Plasma leptin concentrations were measured every 20 min for 24 h in eight normal weight women and in eight upper body and eight lower body obese women matched for body mass index. The circadian rhythm of leptin, which could mathematically be described by a cosine, was characterized by an acrophase just after midnight in all subjects. The amplitude of a cosine fit as well as the average 24-h leptin concentration were increased by 280% and 420%, respectively, in obese compared to normal weight women. All characteristics of leptin concentration profiles were similar in upper body and lower body obese women, except for a significantly higher amplitude in the lower body obese group. Visceral and sc body fat depots were measured using magnetic resonance imaging in all three groups. Average 24-h leptin concentrations were strongly correlated with sc fat (r = 0.84), whereas visceral fat was not an independent predictor of the plasma leptin level. A loss of 50% of the overweight was associated with a 55% decrease in the average 24-h leptin concentrations in obese women (95% confidence interval, 12.3, 26.6), whereas the characteristics of the circadian rhythm of leptin remained unchanged. Finally, it was observed that a fasting plasma leptin concentration is not an acceptable indicator of the average leptin concentration over 24 h.

Insulin and leptin concentrations in obese humans during long-term weight loss.

BACKGROUND: Leptin is likely to be involved in the homeostasis of body weight. Insulin is suggested to regulate both short-term and long-term circulating leptin levels. The present study aims to assess the relation between insulin and leptin levels in obese humans. METHODS: Some 53 obese subjects (body mass index 35.1 +/- 3.9 kg m-2 (mean +/- SD)) were prescribed a hypocaloric diet and randomized to either a placebo or the intestinal lipase inhibitor orlistat for 2 years. Serum leptin and insulin levels were determined repeatedly during these 2 years (5 times in the fasting condition and twice after an oral glucose load). RESULTS: Leptin concentrations appeared to be regulated at a specific level for each individual throughout the weight-loss period. The BMI explained 39.7% of the total variance in leptin levels, the body-fat distribution 17.2%, individual characteristics 30.3%; and the fasting serum insulin concentration 1.0%. After a mean weight loss of 7.7 +/- 4.9 kg, the time-integrated insulin response to an oral glucose load was significantly lower but the leptin response remained unchanged. CONCLUSIONS: The BMI is the main determinant of the circulating leptin concentration in obese humans. Individual characteristics seem to determine the leptin level, given the BMI. In a short-term observational study in obese humans, changes of insulin levels do not appear to be correlated to changes in leptin levels.

Psychological and metabolic responses of carbohydrate craving obese patients to carbohydrate, fat and protein-rich meals.

RATIONALE: A defective central serotonergic neurotransmission has been suggested to result in the concomitant occurrence of an appetite disorder and a disturbed mood. This syndrome was termed carbohydrate carving (CC) obesity. Excessive consumption of carbohydrate-rich snacks would, through a plasma amino acid mediated mechanism, restore serotonergic neurotransmission and thereby relieve the symptoms of atypical depression. OBJECTIVES: To test whether CC obese patients indeed exhibit symptoms of atypical depression, whether these symptoms can be alleviated by carbohydrate-rich snacks and whether they respond differently to the snacks than non-carbohydrate craving (NC) control subjects. Furthermore, we investigated whether differences between CC and NC patients could be related to peripheral metabolic differences. DESIGN: Double blinded, randomized with cross-over. Patients received three types of snacks (100/0/0, 70/29/1 and 35/3/62 energy percent carbohydrate/fat/protein respectively) on three consecutive test days. Before and after snack administration mood and performance were tested and blood samples were obtained. SUBJECTS: 9 CC and 17 NC obese patients, matched for sex, age and body mass index. MEASUREMENTS: Mood states (Profile of Mood States and Visual Analogue Scales) and performance (Bourdon-Wiersma cancellation test), serum glucose and insulin and plasma amino acid concentrations. RESULTS: Before snack consumption, CC patients had slightly higher anger and fatigue scores and tended to have lower mood scores than NC patients. The efficiency of performance increased in both groups after all snacks. No other psychological effects of the snacks were registered. Psychological and metabolic responses of CC and NC patients to the snacks were similar. CONCLUSION: Although they may have a somewhat disturbed mood, CC obese patients do not improve their mood states through ingestion of a carbohydrate-rich snack. It seems, from a therapeutic point of view, useless to maintain the concept of carbohydrate craving.

Predictors of weight loss during treatment with d-fenfluramine.

OBJECTIVE: To identify parameters predictive of weight loss during treatment with d-fenfluramine. This may provide a tool to recognize patients who are sensitive to the weight-reducing effect of d-fenfluramine and thus prevent unnecessary prescription. DESIGN: An open intervention study during which biweekly control visits were scheduled. The study lasted 12 weeks. SETTING: The General Internal Medicine outpatient clinic of the Leiden University Hospital. Patients were recruited through a newspaper advertisement. SUBJECTS: Forty-eight healthy, obese patients (36 women and 12 men), aged 39 +/- 10 years (mean +/- SD) with a body mass index of 34.3 +/- 4.1 kg/m2 enrolled. INTERVENTIONS: d-Fenfluramine 15 mg twice daily for 12 weeks. MAIN OUTCOME MEASURES: Body weight, height, waist and hip circumference, food intake, smoking habits, obesity history, treatment history, family history of obesity and compliance with the medication scheme were recorded as potential predictors of weight loss. RESULTS: One patient was withdrawn because of depressive symptoms. Thirteen patients did not lose weight. On average, the other 34 patients lost 5.7 +/- 2.9 kg or 18.1 +/- 9.4% of excess body weight. High compliance with the drug regimen was associated with a twofold greater weight loss (17.7 +/- 12.3 vs. 9.0 +/- 9.4% of excess weight, ANOVA, P = 0.0088). Patients with a positive family history of obesity lost twice as much weight as patients without obese relatives (15.8 +/- 11.8 vs. 6.0 +/- 7.3% of excess weight; ANOVA, P = 0.0078). No other potential determinants were predictive for weight loss. CONCLUSIONS: Informing patients that compliance with the medication scheme improves treatment outcome will be useful. Previous failures to lose weight should not exclude patients from treatment. A positive family history of obesity needs further evaluation as a possible determinant of weight loss in forthcoming studies.

Leptin.

A highly conserved protein called 'leptin' was recently discovered to play a role in regulation of the energy balance in humans and rodents. This 167-amino-acid-containing protein is only produced and secreted by mature adipocytes. Absence of the protein in mutant ob/ob mice and resistance to its effects in db/db mice lead to extreme obesity and type II diabetes mellitus. No mutation of the ob-gene encoding for leptin has been found in obese humans so far. ob mRNA in adipocytes and serum leptin levels are positively related to adipose tissue mass. Receptors for leptin have been found in the choroid plexus and hypothalamus. A feedback inhibition of leptin on hypothalamic neuropeptide Y (NY) production is postulated, as hypothalamic NY concentrations are increased in ob/ob mice and NY induces food intake, insulin secretion and autonomic nervous system activity. Insulin increases triglyceride stores in fat cells and could thereby stimulate leptin secretion. The ultimate intracellular pathway within the adipocyte that stimulates or shuts off ob mRNA expression and consequent leptin production and secretion remains to be elucidated. Whether leptin will ever come to play a role in the treatment of human obesity remains an unanswered question at the present time.

Serotoninergic drug-induced weight loss in carbohydrate craving obese patients.

RATIONALE: Serotoninergic neurotransmission, mainly in specific hypothalamic nuclei, plays an important role in the regulation of appetite. Dysfunction of this system has been postulated to result in the clinical picture of carbohydrate craving obesity. This subgroup of obese patients is characterized by a specific preference for high-carbohydrate and low-protein snacks. Centrally acting serotoninergic drugs, such as the serotonin re-uptake inhibitor d-fenfluramine, have been hypothesized to restore serotonin mediated control of food intake. OBJECTIVE: To test the hypothesis that serotoninergic drugs would induce a greater weight loss in carbohydrate craving (CC) than in non-carbohydrate craving (NC) obese patients. DESIGN: A three months open intervention study with d-fenfluramine 15 mg twice daily. In order to be able to study the effect of the drug alone, no dietary restrictions were imposed. Both the medical doctor and the patient were unaware of who was a carbohydrate craving obese patient and who was not. SUBJECTS: 10 CC and 10 NC patients, matched for sex, age, body mass index and family history of obesity. MEASUREMENTS: Height, body weight, food intake (energy intake and macronutrient selection) and patient compliance. RESULTS: CC patients lost 4.8 +/- 3.9 kg body weight or 15.9 +/- 13.5% of their pretreatment overweight, whereas NC patients lost 4.5 +/- 2.9 kg or 16.4 +/- 11.6% of their overweight (t-test for paired samples, P = 0.82 and P = 0.93 respectively). CONCLUSION: We conclude that CC patients do not constitute a subgroup of obese patients that should be treated with a serotoninergic drug preferentially.

Recognition of peptides corresponding to the joining region of p210BCR-ABL protein by human T cells.

In chronic myeloid leukemia (CML) the proto-oncogene c-abl from chromosome 9 q34 is translocated to the breakpoint cluster region (bcr) gene on chromosome 22 q11. This translocation results in a BCR-ABL fusion gene, which encodes chimeric fusion oncoproteins p210BCR-ABL. Here we demonstrate that a peptide with joining region sequence ATGFKQSSKALQRPVAS (eight amino acids (aa) encoded by BCR exon 3; one novel lysine, encoded by the fusion codon; eight aa encoded by ABL exon 2) is immunogenic to human T cells. Primary immune response induction with this peptide resulted in a HLA DR2(DRB1*1501) restricted CD4+ BCR-ABL peptide specific T cell line P1. Responses of P1 were negatively affected by individual aa replacement by alanine at eight aa positions within the 17mer peptide (F4, K5, Q6, K9, L11, Q12, R13, P14). These findings were supported by experiments with a panel of overlapping 11mer b3a2 peptides. Only two of these peptides with an aa sequence encompassing all residues which could not be replaced by alanine induced P1 proliferation. Since presentation of cytosolic oncoproteins as peptides by DR molecules has been observed, the present findings provide a possible explanation for post interferon-alpha persisting remissions in spite of the presence of BCR-ABL PCR positive progenitors.

Insulin-induced decline of plasma amino acid concentrations in obese subjects with and without non-insulin-dependent diabetes.

Obesity-associated hyperaminoacidemia is traditionally interpreted as a consequence of insulin resistance. We performed two different experiments to investigate the effects of both obesity-associated insulin resistance and the insulin resistance of non-insulin-dependent diabetes mellitus (NIDDM) on amino acid metabolism. In the first experiment, we measured postabsorptive amino acid concentrations and their decline in response to an oral carbohydrate load in 19 obese nondiabetic women and 19 normal-weight nondiabetic controls. Obese subjects were more resistant to insulin with respect to its effects on glucose metabolism than normal-weight controls, as calculated by the method described by Matthews. However, postabsorptive plasma concentrations of the so-called large neutral amino acids (LNAA), namely phenylalanine, tyrosine, valine, leucine, and isoleucine, and their decrease in response to carbohydrate consumption were similar in both groups. In the second experiment, we compared the decrease of plasma concentrations of LNAA during a euglycemic, hyperinsulinemic clamp in obese subjects with and without NIDDM. Peripheral glucose uptake (PGU) was more impaired in NIDDM subjects compared with obese controls. Furthermore, hepatic glucose production (HGP) was less attenuated by insulin infusion in NIDDM than in control subjects. Postabsorptive plasma LNAA concentrations were not different in the two groups. Values obtained in either group were not different from the postabsorptive concentrations in the normal-weight control subjects of experiment 1. All amino acid levels decreased substantially in response to insulin infusion. The magnitude of the decrease was not significantly different in the two groups, except for a slightly greater decrease of the plasma isoleucine concentration in obese control subjects.(ABSTRACT TRUNCATED AT 250 WORDS)