δ Opioid receptor activation is required to induce LTP of synaptic transmission in the lateral perforant path in vivo

The role of opioid receptors in long-term potentiation (LTP) of the medial (MPP) and lateral (LPP) divisions of the perforant path-granule cell projection was investigated in urethane anesthetized rats. A stimulating electrode was positioned in the dorsomedial or ventrolateral aspect of the angular bundle for selective activation of M MPP and LPP, respectively. A p ush-pull cannula served to focally perfuse artificial cerebrospinal fluid (ACSF) across the perforant path terminal zone, while perforant path evoked potentials were monitored in the dentate hilus. Robust LTP of the excitatory postsynaptic potential (EPSP) initial slope and population spike height was induced by high frequency stimulation (400 Hz, 8 bursts of 8 pulses) applied to the medial or lateral perforant path in rats perfused with standard medium. In the lateral perforant path, a putative proenkephalin system, LTP of the EPSP and population spike was blocked when ACSF containing 100 μM of the opioid receptor antagonist naloxone was present during the tetanus, while perfusion with 0.1 μM naloxone prevented EPSP potentiation but only reduced the magnitude of the population spike increase. Naloxone had no effect on LTP induction in the MPP. Importantly, 0.1 μM ICI 174,864, a selective antagonist of δ opioid receptors, blocked LTP of synaptic transmission in the LPP while leaving the population spike increase intact. The results indicate that LTP of synaptic transmission in the LPP requires activation of δ opioid receptors, while ‘non-δ’ opioid receptors may be involved in augmenting granule cell output. This opioid receptor-dependent LTP illustrates peptidergic regulation of synaptic plasticity in the hippocampus.     

Acute cold stress leading to elevated corticosterone neither enhances synaptic efficacy nor impairs LTP in the dentate gyrus of freely moving rats

Exposure to stress has previously been found to impair long-term potentiation (LTP) in the hippocampus. Exposure to stress has also been proposed to induce an LTP-like effect. We examined the effect of acute cold stress on synaptic transmission, neuronal excitability, and LTP induction in the medial perforant path-granule cell synapse of freely moving rats. After obtaining baseline recordings of evoked field potentials at room temperature (23°C), rats were transferred to an environmental cage maintained at 4°C (cold group) or 23°C (control group) and, 90 min later, high-frequency stimulation (HFS) was applied to the medial perforant path. Serum corticosterone measured in trunk blood from rats without implanted electrodes was significantly elevated in cold exposed (28.7 μg/dl) rats relative to control (6.6 μg/dl). Despite increased corticosterone levels indicative of stress activation, cold exposed rats exhibited LTP of the fEPSP slope and population spike of similar magnitude and time course as controls. In addition, there was no stress-specific effect on the fEPSP slope or population spike and no effect on paired-pulse plasticity. Surprisingly, despite extensive cage acclimation, transferring rats to the environmental cage was associated with a reduction in population spike amplitude and an enhancement in paired-pulse facilitation. The results show that acute cold stress leading to elevated serum corticosterone levels neither induces LTP-like increases in synaptic efficacy nor impairs tetanus-evoked LTP in the dentate gyrus of freely moving rats. Thus, impaired working memory during cold stress is not due to an inability of perforant path synapses to express LTP.     

Surgical management of insulinoma associated with multiple endocrine neoplasia type I

Insulinoma in patients with multiple endocrine neoplasia (MEN) is a rare condition that because of its usual multicentricity presents difficulties not encountered in sporadic patients. In contrast to gastrinoma, which is the most common pancreatic neoplasm associated with MEN I, malignancy and duodenal tumors are much less common for patients with insulinomas, and excellent palliative medication is not available. Accordingly, there is a much greater reliance on surgical therapy for this group of patients. Between 1970 and 1991 a total of 19 patients had surgical treatment of MEN I-related insulinoma. Each patient had hyperinsulinemic hypoglycemia. One patient, with extensive metastases, had unresectable disease. Of the remaining 18, there were 16 (89%) multiple pancreatic tumors. Tumors were located in the neck, body, or tail in 17 cases, 10 of whom also had tumors in the head. Pancreatic resections performed were 1 total, 12 subtotal (7 also had enucleation of tumors from the pancreatic head), and 5 limited distal resections and/or enucleation (conservative resection). There was no operative mortality. One patient developed pancreatitis, fistula, and diabetes following subtotal resection and enucleation. Postoperative cure was achieved in 17 of 18 cases. Recurrent disease occurred in 2 of 5 conservative resections compared to 0 of 12 subtotal resections, with median follow-up times of 10.4 and 10.3 years, respectively. During the follow-up period, four patients died, possibly all due to MEN I-related conditions. Hyperinsulinism in MEN I is associated with the occurrence of multiple, usually benign, pancreatic islet cell tumors, and surgery is an effective treatment modality. Surgical management should be guided by two principles: total removal of gross disease and safe prophylactic pancreatic resection. Acceptable morbidity, low recurrence rates, and a low risk of inducing diabetes lead us to recommend routine subtotal distal pancreatectomy. Meticulous evaluation of the pancreatic head using intraoperative ultrasonography to locate tumors and to locate the pancreatic duct, followed by precise enucleation of residual tumors, is essential to ensure cure.

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Resumen El insulinoma en el síndrome de Neoplasia Endocrina Múltiple (NEM) es una entidad rara que, por su frecuente multicentricidad, presenta dificultades que no se ven en los casos con lesiones de tipo esporádico. En contraste con el gastrinoma, que es el neoplasma más frecuente en el síndrome NEM I, la malignidad y la ubicación duodenal son características mucho menos comunes en los pacientes con insulinoma, y para éste tampoco se halla disponible una excelente medicación paliativa. Es por ello que en este grupo de pacientes hay mayor dependencia del tratamiento quirúrgico.Entre 1970 y 1991 tuvimos 19 pacientes sometidos a tratamiento quirúrgico de insulinomas relacionados con NEM I. Todos los pacientes exhibieron hipoglicemia hiperinsulinémica. Un paciente, con extensas metástasis, presentaba enfermedad no resecable; de los 18 restantes, 16 (89%) tenían tumores pancreáticos múltiples. Los tumores estuvieron ubicados en el cuello, cuerpo o cola del páncreas en 17 casos, 10 de los cuales también los tenían en la cabeza. Los tipos de resección pancreática practicados fueron: total 1, subtotal 12 (7 de los cuales también tuvieron enucleación de tumores ubicados en la cabeza del órgano) y resecciones distales limitadas y/o enucleación (resección conservadora) 5.No se registró mortalidad operatoria. Un paciente desarrolló pancreatitis, fístula y diabetes luego de la resección subtotal y enucleación. Se logró la curación postoperatoria en 17 de 18 casos. Enfermedad recidivante se presentó en 2 de 5 resecciones conservadoras, en comparación con 0 recidivas en 12 resecciones subtotales, con seguimiento medio de 10.4 años y 10.3 años respectivamente. Cuatro pacientes murieron en el período de seguimiento, todos posiblemente por causas relacionadas con NEM-I.El hiperinsulinismo en el NEM-I está asociado con la presencia de tumores pancreáticos de células insulares, múltiples y usualmente benignos; la cirugía es una modalidad terapéutica efectiva. El manejo quirúrgico debe ser guiado por dos principios: la remoción total de la enfermedad macroscópica y una segura resección profiláctica del páncreas.Una aceptable morbilidad, bajas tasas de recidiva y un reducido riesgo de inducir diabetes nos lleva a recomendar el uso rutinario de la pancreatectomía distal subtotal.La valoración meticulosa del estado del páncreas, utilizando ultrasonografía intraoperatoria, tanto para localizar los tumores como para localizar el canal pancreático, seguida de una precisa enucleación de tumores residuales, es esencial para asegurar la curación.

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Résumé La présence d'un insulinome au sein du syndrome MEN (multiple endocrine neoplasie) est rare et, en raison de sa multicentricité habituelle, cette tumeur pose des difficultés que l'on ne rencontre pas dans le cas de tumeurs dites sporadiques. Contrastant avec ce que l'on observe dans le gastrinome, la tumeur la plus fréquemment rencontrée dans le syndrome MEN I, la malignité et la présence de tumeurs duodénales sont beaucoup moins fréquentes chez le patient ayant un insulinome et on ne dispose pas de traitement palliatif efficace. Par conséquent, le traitement chirurgical est plus fréquemment envisagé dans ce dernier groupe de patients.Entre 1970 et 1991, 19 patients ont été traités chirurgicalement pour un insulinome dans le cadre d'un syndrome MEN I. Un patient, ayant des métastases massives, avait une tumeur non résecable. Des 18 autres, 16 (89%) avaient des tumeurs multiples du pancréas. Les tumeurs étaient localisées soit dans l'isthme, le corps ou la queue du pancréas pour 17 d'entre elles, et dans 10 cas, associées à des tumeurs de la tête. Le traitement a consisté en une pancréatectomie totale, 12 pancréatectomies subtotales (7 associées à une énucléation de la tumeur céphalique) et 5 résections distales limitées ou énucléations (résections dites conservatrices). Il n'y a eu aucune mortalité opératoire. Un patient a eu une pancréatite postopératoire associée à une fistule et un diabète après pancréatectomie subtotale plus énucléation. La cure postopératoire a été réalisée chez 17 des 18 cas. Une récidive a été observée chez 2 des 5 résections dites conservatrices comparée à 0 des 12 résections subtotales, la médiane de survie étant, respectivement, de 10.4 et de 10.3 ans. Pendant la suivi, il y a eu quatre morts, tous éventuellement en rapport avec le syndrome MEN I. L'hyperinsulinémie dans le syndrome MEN I est associée à de multiples tumeurs pancréatiques, habituellement bénignes et pour lesquelles la chirurgie est une solution efficace. Le traitement chirurgical doit être guidé par deux principes: l'exérèse totale de toute tumeur macroscopiquement visible et une résection pancréatique prophylactique sans prendre de risque pour le malade. Une morbidité acceptable, un taux de récidive bas, et un risque de voir se développer un diabète modéré, nous conduisent à préconiser plutôt une résection distale subtotale de façon systématique. L'évaluation méticuleuse de la tête par échographie peropératoire, afin de localiser les tumeurs et les canaux pancréatiques, suivie d'une énucléation précise des tumeurs restantes, est essentielle à la guérison.

     

Teaching disability and rehabilitation to medical students

Summary. A survey of UK medical schools was undertaken to determine the teaching that was being offered on disability and rehabilitation. In general, teaching on this topic appeared fragmented and inadequate but a number of interesting innovations were identified. These included: a drama workshop run by a group whose members mainly have learning disabilities at St George's Medical School, student-directed learning at the University of Dundee and structured teaching programmes at the Universities of Leeds and Edinburgh. The General Medical Council Education Committee's 1991 discussion document on the undergraduate curriculum specifically mentions disability as an important topic. A number of schools mentioned that they were in the process of revising their curriculum as a consequence. Recommendations arising from the findings of the survey include integration of disability and rehabilitation into clinical teaching, focus of teaching on those types of disability which are common in the community, greater emphasis on functional assessment in teaching the physical examination, and the wider use of standard assessment instruments, for example for activities of daily living, cognitive impairment and locomotor disability. There is a need for improved communication between medical schools to facilitate the spread of educational activities on this topic.     

Twenty-four hour profile of the hypotensive action of felodipine in essential hypertension

Summary Felodipine, 10 mg twice daily, and placebo were administered for 5 weeks to ten untreated essential hypertensives in a double-blind, random-order, crossover study. At the end of each phase patients were assessed by 36 hours of continuous intraarterial blood pressure recordings, both during normal activities and specified activities. Patients were also assessed by 36-hour Holter analysis, maximal exercise testing, radionuclide cardiac scan, and measurement of endogenous creatinine clearance and 2-hourly vasoactive hormones. Arterial pressure was significantly reduced by felodipine, with mean falls in blood pressure of 25.1 mmHg and 12.5 mmHg (systolic and diastolic, respectively) over 24 hours. Blood pressure was reduced by felodipine during moderate and maximal exercise and mental stress. There were no significant changes in heart rate, exercise capacity, ventricular ectopy, endogenous creatinine clearance, or vasoactive hormones.