Differential modulation by dopamine of responses evoked by excitatory amino acids in human cortex.

The responses of human neocortical neurons to iontophoretic application of excitatory amino acids and their modulation by dopamine (DA) were studied in vitro. Brain slices were obtained from children undergoing surgery for intractable epilepsy. Application of N-methyl-D-aspartate (NMDA) to the slices induced slow depolarizations accompanied by decreased input conductances and sustained action potentials in cortical neurons. Glutamate produced rapid depolarizations and firing with few changes in input conductances. Quisqualate also induced depolarization and firing, but input conductances increased during the rising phase of the membrane depolarization. Iontophoretic application of DA alone produced no change in membrane potential or input conductance. However, when DA was applied in conjunction with the excitatory amino acids, it produced contrasting effects. With either bath application of DA or when iontophoresis of DA preceded application of NMDA, the amplitude of the membrane depolarizations and the number of action potentials were increased, whereas the latency of these responses decreased. In contrast, DA decreased the amplitude of the depolarizations and the number of action potentials evoked by glutamate or quisqualate. The fact that DA affects responses to NMDA and glutamate or quisqualate in opposite directions is of considerable importance to the understanding of cellular mechanisms of neuromodulation and the role of DA in cognitive processing and in epilepsy.     

Long-term follow-up and the role of surgery in adolescents with morbid obesity

PURPOSE: Obesity has become a health-care crisis in the United States. Adolescent obesity is now one of the most common childhood disorders, with 4.7 million American adolescents having a body mass index (BMI) greater than the 95th percentile. Most patients do not respond to diet modification or exercise programs and attention is now turning toward surgery as a source of weight loss in adolescents. Few studies have looked at the overall morbidity and mortality of weight loss surgery in this patient population. METHODS: This is a retrospective study of medical charts of 15 bariatric surgical procedures performed on 14 adolescents without known genetic syndromes associated with severe childhood obesity from 1971 to 2001 at the University of Minnesota. Procedures performed on these patients included vertical banded gastroplasty (n = 7), Roux-en-Y gastric bypass (n = 5), and jejunoileal bypass (n = 3). Jejunoileal bypass procedures were performed from 1971 to 1977, after which time this procedure was abandoned. Patient age ranged from 13 to 17 years (mean, 15.7 years). Mean follow-up time was 6 years, with 9 patients available for long-term follow-up. RESULTS: All procedures were performed using an open technique by 1 surgeon. There were no perioperative deaths; complications included 1 case of wound infection, 2 episodes of dumping syndrome that resolved without revision, 1 episode of hypoglycemia, and 1 case of short-term electrolyte imbalance in a patient who underwent jejunoileal bypass. The average BMI dropped from 58.5 +/- 13.7 to 32.1 +/- 9.7 kg/m(2) (P < .01)--a 45% reduction. CONCLUSIONS: Surgery for morbid obesity is safe and results in significant weight loss in adolescents who fail medical therapy.     

Ultrastructural alterations in caudate nucleus in aged cats

These studies provide information on the changes in the ultrastructure in the caudate nucleus of aged cats. The major findings was that there was a decrease in the density of synapses in caudate neuropil. This decrease occurred in animals after 3 years of age and remained relatively constant in older animals. In conjunction with this change a population of unusually long synapses also occurred. These larger synaptic appositions were associated with enlarged spine heads. The caudate also showed a number of qualitative ultrastructural alterations. Many neurons contained accumulations of lipofuscin or lipopigment granules in aged animals. These inclusions occurred in both soma and dendrites of neurons and all types of glial cells. A unique configuration of collapsed agranular cisterns also was observed in aged animals. The present results indicate that decreases in synaptic density may by one morphological event underlying functional alterations observed in caudate neurons in aged cats.     

Differences in the glucocorticoid to progesterone receptor selectivity of inhaled glucocorticoids.

Due to the high affinity of new inhaled corticosteroids (ICS) towards the glucocorticoid receptor (GR), and because of the similarities between the binding domains of the GR and the progesterone receptor (PR), the present study focused on assessing the relative binding affinities (RBA) of glucocorticoids (systemic and ICS) to PR (RBAPR). By comparison with the affinities towards the GR (RBAGR) the binding selectivities were also assessed. In general, the selectivity of the investigated glucocorticoids showed a decreasing trend with increasing lipophilicity. When orally administered, less lipophilic glucocorticoids showed the highest selectivity, with RBAGR/RBAPR ratios of 1,375, 760 and 476 for betamethasone, beclomethasone and dexamethasone, respectively. For ICS, mometasone furoate, the most lipophilic steroid, was the least selective (1.1), followed by beclomethasone monopropionate (9), fluticasone propionate (12), triamcinolone acetonide (18), mometasone (25) and budesonide (44), which shows the highest selectivity among inhaled glucocorticoids. In conclusion, the present study revealed that there are differences in selectivity among commercially available glucocorticoids. Future clinical studies are needed to investigate whether the high affinity of some of the investigated glucocorticoids to the progesterone receptor is of clinical relevance.     

Long-latency auditory-evoked potentials: Role of polysensory association cortex in the cat

The objective of this study has been to define the role of polysensory association cortex in the generation of "wave NA" and of "wave C," long-latency auditory-evoked potentials recorded from the vertex of conscious cats as, respectively, a marked negative potential of latency 30-48 msec followed by a broad positive wave of latency 50-75 msec. Wave C may represent the feline analogue of the longer latency human auditory-evoked potential wave P2, insofar as both waveforms are very large amplitude, long duration positivities characterized by long recovery cycles. Based on previous studies of wave C and the generators of other middle-latency evoked potentials, we hypothesized that both wave NA and wave C might reflect, at least in part, the cortical culmination of a nonlemniscal line auditory association system arising in reticulothalamic projections to intralaminar and associated ventral thalamic regions. Relays from these thalamic areas are known to project to polysensory association cortex, including pericruciate gyrus, anterolateral gyrus, and medial suprasylvian gyrus. Therefore we implemented a series of lesion experiments to characterize the role of each of these cortical areas in the production of wave NA and wave C. Our results indicate that all three polysensory association areas contribute significantly to both waves NA and C, although the largest effects followed ablation of the pericruciate area alone. Thus, the generator substrates of waves NA and C appear to involve a long-recovery cycle system which functionally incorporates activation of association cortex.     

Cloning and analysis of the murine Fanconi anemia group C cDNA

Fanconi anemia (FA) is one of a group of disorders characterizedat the cellular level by a combination of hypersensitivity toDNA-damaging agents, chromosomal instability, and defectiveDNA repair. Clinical features of FA include pancytopenia, oftenaccompanied by specific congenital malformations, and a predispositionto leukemia. Since the hematological manifestations are thecritical defect in terms of prognosis, FA is a candidate diseasefor gene replacement therapy, and the development of a mousemodel system is essential for the initial stages of this work.Previously, we have cloned the gene defective in FA group Cby complementation of the intrinsic sensitivity of FA cellsto DNA cross-linking agents. We have now cloned the murine homologueof the human FACC cDNA. The mouse cDNA (Facc) shares 79% aminoacid sequence similarity with the human gene product. The expressionof the mouse cDNA in human FA(C) cells restores the cellulardrug sensitivity to normal levels. Thus, the function of theprotein has been conserved despite the significant sequencedivergence. PCR analysis of mouse tissue RNA reveals that thegene is expressed in all adult tissues, while in situ RNA hybridizationexperiments show tissue specific expression at late stages offetal development. Cross-hybridizing sequences exist in DNAfrom other mammals, chicken and Drosophila. These results supportthe hypothesis that the FACC gene product has a role in a basicaspect of cellular protection against DNA damaging agents andthat this function has been conserved during evolution.     

Ileal bypass for hyperlipidemia

Partial ileal bypass (PIB) is a safe, effective, and lasting therapy for the reduction of lipids and lipoproteins in patients with hyperlipidemia. Following PIB, circulating plasma and low-density lipoprotein (LDL) cholesterol fall markedly, while high-density lipoprotein (HDL) cholesterol rises. The average plasma cholesterol lowering is 25% after diet, with a 40% reduction in the LDL-cholesterol fraction; concurrently, the HDL-cholesterol rises about 8%. These effects have been demonstrated to be maintained for up to 20 years. Currently, PIB is being used in the Program on the Surgical Control of the Hyperlipidemias (POSCH), a randomized controlled clinical trial designed to assess the effects of lipid reduction on mortality and morbidity in a postmyocardial infarction population with arteriographically demonstrated coronary atherosclerosis.

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Resumen La derivación (bypass) ileal parcial (DIP) es una modalidad terapéutica segura, efectiva y durable para la reducción de los lípidos y lipoproteínas en pacientes con hiperlipidemia. Después de la DIP, los niveles de colesterol plasmático y de colesterol de baja densidad descienden en forma marcada, en tanto que los de colesterol de alta densidad ascienden. El promedio de reducción del colesterol plasmático es de 25% después de dieta, con una reducción de 40% de la fracción del colesterol de baja densidad; al mismo tiempo, el colesterol de alta densidad asciende alrededor de un 8%. Se ha demostrado que tales efectos perduran hasta por 20 años. Actualmente se utiliza la DIP en el Programa de Control QuirÚrgico de la Hiperlipidemia (POSCH), un ensayo interinstitucional prospectivo y aleatorizado diseñado para evaluar los efectos de la reducción de los niveles de lípidos sobre la mortalidad y la morbilidad en la población que ha sufrido infarto miocárdico con arteriosclerosis coronaria arteriograficamente demostrada.

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Résumé L'opération décrite par l'auteur en 1963, le courtcircuit partiel d l'iléon représente une méthode thérapeutique dénuée de danger, efficace et durable pour obtenir la réduction des lipides et des lipoprotéines chez les malades qui présentent une hyperlipidémie. A la suite de l'intervention la fraction du cholestérol lipoprotéique de haute densité s'élève. La chute moyenne du cholestérol plasmatique est de l'ordre de 25%: la réduction est de 40% en ce qui concerne la fraction LDL du cholestérol (la fraction athérogène) alors que la fraction HDL (la fraction protectrice) s'élève environ de 8%. Ces effets se maintiennent depuis plus de 20 ans. Actuellement, le court-circuit iléal partiel est soumis à un essai clinique randomisé de contrôle destiné à apprécier les effets de la réduction des lipides sur la morbidité et la mortalité chez des malades qui ont subi un infarctus et chez qui l'artériographie a démontré une athérosclérose coronarienne.

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Supported in part by National Heart, Lung, and Blood Institute, NIH, grant #R10 HL15265.     

The free cytoplasmic Ca2+ levels in Duchenne muscular dystrophy lymphocytes

An increased cellular Ca2+ content has been associated with Duchenne muscular dystrophy (DMD). However, estimates of the free cytoplasmic Ca2+ concentration ([Ca2+]i) in cells of DMD patients were not available. We compared the [Ca2+]i levels of normal and DMD peripheral blood lymphocytes and Epstein-Barr virus-transformed lymphoblasts using the novel probe, quin 2, an internally trapped fluorescent indicator. The [Ca2+]i levels of normal and DMD cells were not significantly different.     

Postoperative prognosis of pulmonary adenocarcinoma subtypes correlates with HLA-DR expression and the number of tumor-infiltrating cells

Human pulmonary adenocarcinomas (AC) can be divided into two types with special morphologic and immunohistologic properties and a different number of tumor-infiltrating cells as shown by previous investigations. In the present study the relevance of this subdivision for patients' survival was investigated. 42 surgically resected pulmonary AC of stage I and II were subclassified using light and electron microscope. For immunohistologic phenotypization, reactions with monoclonal antibodies against HLA-DR, CD1 and CD3 were studied on fresh tumor specimens. Postoperative survival was evaluated after at least 24 months. AC of type I (N=23) with mucin production and ultrastructural properties of goblet cells showed almost no HLA-DR expression. Infiltration by CD1-positive dendritic cells Langerhans cells and CD3-positive T lymphocytes was significantly lower than in AC of type II (N=19), which expressed HLA-DR homogeneously and showed, ultrastructurally, Clara cell and/or type II pneumocyte properties. Patients' outcome was similar in stage I AC of both types: about 70% of patients were still alive after 24 months. However, significant differences were found between the two types in stage II AC with regional lymph node metastases: survival of patients with AC of type II corresponded roughly with stage I tumors (67%) but only 20% of patients with type I AC were still alive after 24 months. These results indicate that postoperative prognosis for patients with pulmonary AC of type II is more favourable than for mucinous AC of type I. This may be due to the homogeneous HLA-DR expression and higher number of immunologically competent tumor-infiltrating cells which possibly results in better tumor surveillance.     

The history of metabolic surgery for morbid obesity and a commentary

This paper serves as an introduction to a symposium on Surgical Treatment of Morbid Obesity. It offers a brief historical review of the antecedents for and the operative interventions in this field of metabolic surgery. In essence, the procedures can be divided between jejunoileal operations and their derivatives, and gastric operations. The jejunoileal bypasses originated with end-to-end jejunoileostomy; deviated to end-to-side jejunocolic, jejunocecal, and finally jejunoileal bypasses; and returned to end-to-end jejunoileal bypasses with different lengths of functioning bowel and various sites for colonic drainage of the bypassed bowel. More recently, pancreatic-biliary-intestinal bypass operations have been proposed. The gastric operations can be separated into gastric bypasses with closure of the fundic pouch and anastomosis to a segment of small intestine; gastroplasty with separation of the stomach into a small upper pouch communicating via a limiting orifice to the remainder of the stomach; and gastric partitioning, the simplest variation of gastroplasty, consisting of a cross-stapling of the stomach with omission of several central staples. Finally, vagotomy alone has been advocated. We must conclude with the commentary that there is no optimal operation in this field, but that we need not apologize for an 85% cure rate. What we must work toward in the future is the development of therapy based not on circumvention but on an understanding of the satiety factor.

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Résumé Cet article constitue une préface au Symposium consacré à l'obésité morbide. Il offre un bref historique de la question ainsi qu'une revue des différents types d'interventions qui ont pu être proposées pour traiter cette affection.Les méthodes se résument en 2 types d'opérations: les courts circuits jéjuno-iléaux et les interventions gastriques. Les premiers, à l'origine, consistèrent en jéjuno-iléostomies termino-terminales puis ils s'orientèrent vers les jéjuno-colostomies, les jéjuno-caecostomies et les jéjuno-iléostomies termino-latérales avant de revenir aux jéjuno-iléostomies termino-terminales avec segment intestinal fonctionnel de longueur variable. Plus récemment des interventions de dérivation pancréatique et biliaire ont été proposées.Les opérations gastriques sont de 3 types: 1) court-circuits gastriques par anastomose de l'estomac avec un segment de l'intestin grêle après fermeture du réservoir gastrique, 2) gastroplastie réalisant une poche gastrique supérieure de petit volume qui communique par un étroit défilé avec la partie inférieure de l'estomac, 3) division gastrique, la plus simple des gastroplasties, à l'aide des pincesagrafeuses dont la partie centrale des agrafes a été retirée de façon à laisser seulement un petit orifice de communication entre les deux parties de l'estomac. La vagotomie a également été proposée.En fait il n'y a pas d'opération idéale, les meilleures statistiques faisant étant de 83 pour cent seulement de bons résultats. Le champ thérapeutique de l'obésité morbide reste ouvert à la recherche.