Thylakoids suppress appetite by increasing cholecystokinin resulting in lower food intake and body weight in high‐fat fed mice

Thylakoids are membranes isolated from plant chloroplasts which have previously been shown to inhibit pancreatic lipase/colipase catalysed hydrolysis of fat in vitro and induce short‐term satiety in vivo. The purpose of the present study was to examine if dietary supplementation of thylakoids could affect food intake and body weight during long‐term feeding in mice. Female apolipoprotein E‐deficient mice were fed a high‐fat diet containing 41% of fat by energy with and without thylakoids for 100 days. Mice fed the thylakoid‐enriched diet had suppressed food intake, body weight gain and body fat compared with the high‐fat fed control mice. Reduced serum glucose, serum triglyceride and serum free fatty acid levels were found in the thylakoid‐treated animals. The satiety hormone cholecystokinin was elevated, suggesting this hormone mediates satiety. Leptin levels were reduced, reflecting a decreased fat mass. There was no sign of desensitization in the animals treated with thylakoids. The results suggest that thylakoids are useful to suppress appetite and body weight gain when supplemented to a high‐fat food during long‐term feeding. Copyright © 2009 John Wiley & Sons, Ltd.     

Bioequivalence, pharmacokinetic and pharmacodynamic response to combined extended release formulations of felodipine and metoprolol in healthy volunteers

Objective: The primary aim of this study was to investigate whether bioequivalence is achieved for a new fixed combination of extended-release (ER) felodipine and controlled-release (CR/ZOK) metoprolol␣compared with the free combination of felodipine ER metoprolol CR/ZOK. The second aim was to study whether there was an interaction in pharmacokinetics and pharmacodynamics between felodipine and metoprolol when administered as ER formulation. Methods: Two four-way cross-over studies were performed in 36 young subjects and 24 elderly subjects with frequent measurement of drug plasma concentrations, blood pressures and heart rate. The pharmacokinetic analysis included enantioselective analysis in six subjects. Results: Bioequivalence between the fixed combination and the free combination was observed for the two drugs (mean difference 27%) except for a minor deviation regarding C_max of metoprolol in the elderly. No significant interaction was shown except for a small increase (6%) of metoprolol AUC in the younger subjects. Mean plasma S-/R-enantiomer ratios were almost identical for the different treatments. Blood pressure and heart rate was significantly reduced for the fixed combination compared with felodipine ER in the younger and the elderly subjects. No significant difference regarding pharmacodynamics was detected between the fixed combination and the corresponding free combination. Conclusion: The fixed combination consistently provides fairly constant and effective felodipine and metoprolol concentrations after once-daily administration of one tablet. It is clinically interchangeable with the free combination of metoprolol CR/ZOK tablets and felodipine ER tablets. Finally, felodipine and metoprolol do not interact on a pharmacokinetic level when administered as the fixed combination. Received: 29 October 1996 / Accepted in revised form: 21 March 1997     

Natural killer cell activity and CSF monoamine metabolites in suicide attempters

The aim of this study was to investigate markers of serotonin and immune function in suicidal patients. Cytotoxic activity of natural killer cells (NK) and CD16 lymphocytes were studied in 28 suicide attempters and 26 healthy controls, and related in patients to 5-hydroxyindoleacetic acid (5-HIAA) in cerebrospinal fluid (CSF). Patients with CSF 5-HIAA below the median had significantly lower NK cell activity than other patients. CD16 cell frequency was significantly lower in patients than in controls, and patients also tended to have lower NK cell cytotoxicity than healthy controls. There were no statistically significant correlations between 4-hydroxy-3methoxyphenyl glycol (HMPG), homovanillic acid (HVA), CSF cortisol and NK cell activity. The results support the hypothesis of compromised immune function in suicidal patients with evidence of disordered serotonin function.     

Early pathological changes in progressive multifocal leukoencephalopathy: a report of two asymptomatic cases occurring prior to the AIDS epidemic

Serial sections of formalin-fixed, paraffinembedded blocks from two asymptomatic, non-AIDS cases of progressive multifocal leukoencephalopathy (PML) were stained with a double-label immunocytochemical method for detection of glial fibrillary acidic protein and JC virus (JCV) capsid proteins and with luxol fast blue/hematoxylin-eosin. In case 1 small, rounded lesions of about 1-mm diameter were seen within a restricted area in the posterior part of the superior frontal gyrus of both cerebral hemispheres, suggesting an early manifestation of the disease. Fully developed demyelinated lesions of the classical type with JCV-infected oligodendrocytes appeared in the white matter and along its border with the cortex. Lesswell-developed lesions, believed to be precursors to the fully developed ones, were seen in the gray and white matter. Of special interest were areas which contained small collections of enlarged, glial fibrillary acidic protein (GFAP)-positive astrocytes without capsid antigen and which seemed to lack destruction of myelin as judged from the appearance of matching serial sections stained for myelin. Large lesions in the brain of case 2 showed the well-known features of advanced PML. The close relation between some astrocytes and oligodendrocytes with viral antigen raises the possibility of early intercellular passage of virus. Vacuolation, seen within or near lesions in both cases, has previously been noted in the CNS infected by HIV, but not in PML. It is suggested that PML, a disease of both oligodendrocytes and astrocytes, may actually begin in astroglial cells which, under the influence of a restricted JCV infection, become reactive, express GFAP and pass on virus to the more highly susceptible oligodendrocytes with which they are in contact.Supported in part by a grant N.S.07596 from the National Institute of Neurological Disorders and Stroke. The work was carried out in the Laboratory of Experimental Neurophathology, NINDS, and in the Department of Pathology II, Karolinska Institute, Stockholm     

Manganese induced brain lesions inMacaca fascicularis as revealed by positron emission tomography and magnetic resonance imaging

A series of positron emission tomography scans was made on two monkeys during a 16-month period when they received manganese(IV)oxide by subcutaneous injection. The distribution of [¹¹C]-nomifensine uptake, indicating dopamine terminals, was followed in both monkey brains. The brain distributions of [¹¹C]-raclopride, demonstrating D₂ dopamine receptors, and [¹¹C]-l-dopa, as a marker of dopamine turnover, were followed in one monkey each. The monkeys developed signs of poisoning namely unsteady gait and hypoactivity. The [¹¹C]-nomifensine uptake in the striatum was reduced with time and reached a 60% reduction after 16 months exposure. This supports the suggestion that dopaminergic nerve endings degenerate during manganese intoxication. The [¹¹C]-l-dopa decarboxylation was not significantly altered indicating a sparing of [¹¹C]-l-dopa decarboxylation during manganese poisoning. A transient decrease of [¹¹C]-raclopride binding occurred but at the end of the study D₂-receptor binding had returned to starting values. The magnetic resonance imaging (MRI) revealed that the manganese accumulated in the globus pallidus, putamen and caudate nucleus. There were also suggestions of gliosis/edema in the posterior limb of the internal capsule. MRI might be useful to follow manganese intoxication in humans as long as the scan is made within a few months of exposure to manganese, i. e. before a reversal of the manganese accumulation.     

Impairment of bone turnover in elderly women with hip fracture

Summary Hip fracture is one of the most severe consequences of osteoporosis affecting aged women. However, abnormalities of bone turnover responsible for bone loss in this condition have not been clearly defined. To further evaluate the bone metabolic status of women sustaining hip fracture, we have prospectively measured serum osteocalcin as a marker of bone formation and urinary excretion of pyridinoline (Pyr) and deoxypyridinoline (D-pyr) cross-links as markers of bone collagen degradation in 174 independently living women (80 ± 8 years) within a few hours after a hip fracture. Comparison was made with 77 age-matched controls (80 ± 5 years) and 17 premenopausal women (39 ± 3 years). In addition 15 of the patients were followed with daily measurements during the first postoperative week. At the time of admission osteocalcin was 20% lower in the fractured women compared to the elderly controls (7.6 ± 3.8 vs. 9.5 ± 4.5 nglml,P = 0.001). Pyr and D-pyr were 36% and 40% higher, respectively (P = 0.0001), than in elderly controls and 85% and 76% higher than in premenopausal controls (P = 0.0001). Serum osteocalcin did not correlate with the cortisol level measured at the same time (r = 0.03, ns), nor with serum albumin and creatinine. Serum osteocalcin remained unchanged within 18 hours after fracture, whereafter it progressively decreased until the third postoperative day. No correlation was noted between the excretion of pyridinoline cross-links and the time elapsed from fracture.These data suggest that the abnormal levels of osteocalcin and pyridinolines are unrelated to traumatically induced acute changes, but reflect abnormalities of bone turnover existing prior to the fracture. Thus, hip-fracture patients have biochemical evidence of decreased bone formation and increased bone resorption when compared to age-matched controls. We suggest that these abnormalities may play a role in the decrease of the bone mass and the consequently increased bone fragility that characterize the osteoporotic hip fracture in the elderly.     

Improved differential diagnosis of hypercalcemia by hypocalcemic stimulation of parathyroid hormone secretion

In vitro experiments have indicated that in primary hyperparathyroidism (HPT) the hyperfunctioning glands have a set point error, i.e., they are not autonomous but regulate serum calcium around a hypercalcémie value. In contrast, parathyroid function is suppressed in patients with hypercalcemia of causes other than HPT (e.g., malignancy or sarcoidosis). The basal measurements of serum parathyroid hormone (PTH) levels, however, cannot, alone, separate with precision HPT from other causes of hypercalcemia.Lowering of calcium, in order to stimulate secretion of PTH, was, therefore, achieved by either infusion of Na₂ EDTA (24 mg/kg per hr) for 1 hour, or intramuscular injection of 100 IU salmon calcitonin. All 35 patients with primary HPT displayed a significant increase of serum PTH concentrations, evaluated by a midregion/intact hormone assay, during the EDTA infusion, which lowered plasma ionized calcium by an average of 0.16 mmol/l. The injection with calcitonin reduced the calcium concentrations by 0.10 mmol/l after 8 hours and caused a rise in PTH in 80% of HPT patients. With both tests, the secretory response by PTH to the reduction of plasma calcium was generally evident while the patients were still hypercalcemic. In 32 patients with other causes for hypercalcemia, primarily malignancy and sarcoidosis, similar reductions of plasma ionized calcium were obtained. In contrast to the HPT patients, none of them raised their serum PTH values during the test. Thus, stimulation of PTH secretion by a moderate reduction of serum calcium considerably improves the differential diagnosis of hypercalcemia since a significant secretory response appears to be exclusive for HPT.

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Resumen Experimentos in vitro han señalado que en el hiperparatiroidismo primario (HPT) las glándulas hiperfuncionantes tienen un error en su set point, o sea que no son autónomas sino que regulan el calcio sérico alrededor de un valor hipercalcémico. Por el contrario, la función paratiroidea es suprimida en pacientes con hipercalcemia de causa diferente de HPT (e.g., neoplasias malignas o sarcoidosis). Las mediciones basales de los nivelés séricos de hormona paratiroidea (PTH) de por sí no son capaces de diferenciar con precision entre el HPT y la hipercalcemia de otras causas.La disminución del nivel de calcio sérico, con el objeto de estimular secreciones de PTH, fue lograda con la infusión de Na₂ EDTA (24 mg/Kg por hora) por 1 hora o la inyección i.m. de 100 UI de calcitonina de salmón.Todos los 35 pacientes con HPT primario exhibieron un aumento significativo de las concentraciones séricas de PTH, determinadas mediante la medición de la fraction media/intacta de PTH en el curso de la infusion de EDTA, la cual redujo el nivel plasmático de calcio ionizado en un promedio de 0.16 mmol/l. La inyección de calcitonina redujo las concentraciones de sérico en 0.10 mmol/l a las 8 horas y resultó en un aumento de la PTH en 80% de los pacientes con HPT. Con ambas pruebas la respuesta secretoria de PTH a la reducción del calcio plasmático generalmente apareció evidente aún mientras los pacientes se hallaban hipercalcémicos.En 32 pacientes con hipercalcemia de causa diferente, se lograron reducciones similares de la concentration plasmática del calcio ionizado. Por el contrario de lo observado en los patientes con HPT, ninguno demostró elevatión de sus niveles séricos de PTH en el curso de la prueba. Por consiguiente, el estímulo de la secretión de PTH mediante la reductión moderada de calcio sérico incrementa considerablemente la (ie501-01)acidad de establecer el diagnóstico diferencial de la hipercalcemia, puesto que una significativa respuesta secretoria parece ser caracteristíca exclusiva del HPT.

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Résumé L'expérimentation in vitro a démontré que dans l'hyperparathyroïdisme (HPT), les glandes hyperactives ont un point mort erroné, c'est-à-dire qu'elles ne sont pas autonomes mais règlent la calcémie autour d'une valeur de référence déjà hypercalcémique. En revanche, la fonction parathyroîde est déprimée chez le patient dont l'hypercalcémie est due à une cause autre que l'HPT (cancer ou sarcoïdose par exemple). La mesure des niveaux de base de la parathormone (PTH), cependant, ne permet pas de distinguer l'hypercalcémie de l'HPT des autres causes d'hypercalcémie avec précision.Dans le but de stimuler la sécrétion de PTH, la calcémie était abaissée soit en perfusant les patients avec une solution de Na₂ EDTA (24 mg/Kg) pendant une heure, soit par une injection intramusculaire de 100 U de calcitonine de saumon.Trente-cinq patients ayant un HPT primitif présentaient une augmentation significative des concentrations en PTH sérique, évaluée par l'étude immunologique de la portion moyenne intacte, pendant la perfusion d'EDTA. La portion de calcium plasmatique ionisée a été abaissée en moyenne de 0.16 mmol/l. L'injection de calcitonine a réduit la concentration en calcium par 0.10 mmol/l après huit heures et a provoqué une augmentation en PTH chez 80% des patients à HPT. Quel que soit le test, la réponse de PTH à la réduction de calcium plasmatique était généralement évidente alors que le patient était toujours hypercalcémique.Chez 32 autres patients ayant pour cause d'hypercalcémie cancer ou sarcoïdose, des réductions similaires en calcium plasmatique ionisé ont été obtenues. Aucun malade, contrairement aux patients HPT, n'a vu son niveau de PTH monter pendant le test. Ainsi, la stimulation de sécrétion de PTH par une réduction modérée de calcium sérique améliore considérablement le diagnostic différentiel des hypercalcémies puisque la réponse sécrétoire significative paraît être le fait exclusif des HPT.

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Presented at the International Association of Endocrine Surgeons in Sydney, Australia, September, 1987.

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Supported by the Swedish Medical Research Council.     

The meaning of good sleep: a longitudinal study of polysomnography and subjective sleep quality

SUMMARY  The present study sought to investigate the meaning of subjectively good sleep, using a longitudinal and intraindividual design. Eight subjects slept in an isolation unit according to an irregular schedule of 6h sleeps and 1h naps, designed to give normal amounts of time in bed (1/3 of total), but variable sleep quality. Eight sleeps and eight naps were used for longitudinal simple and multiple regression analyses with standard polysomnographical sleep variables as predictors and subjective sleep quality as dependent variables. The results showed that subjective sleep quality (and related variables) was closely related to sleep efficiency, but not sleep stages. At least 87% efficiency was required for ratings of 'rather good' sleep. In addition, sleep quality ratings improved with closeness (of the awakening) to the circadian acrophase (17.00–21.00 hours) of the rectal temperature rhythm. The subjective ease of awakening differed from most other other variables in that it was related to low sleep efficiency. Objective and subjective homologues of sleep length and sleep latency showed high mean intraindividual correlations ( r = 0.55 and 0.64, respectively). It was concluded that objective measures of sleep continuity were closely reflected in perceived sleep quality and that sleep quality essentially means sleep continuity.