Effect produced by acute and chronic administration of the selective 5-HT3 receptor antagonist BRL 46470 on the number of spontaneously active midbrain dopamine cells in the rat

This study examined the effect of acute and chronic administration of the selective 5-HT₃ receptor antagonist BRL 46470A, an analog of granisetron, on the number of spontaneously active dopamine (DA) cells in the substantia nigra pars compacta (A9 or SNC) and the ventral tegmental area (A10 or VTA) in the rat. In the A10 area, the acute administration of BRL 46470A decreased the number of spontaneously active DA cells at a dose of 0.1 mg/kg (0.28 μmol/kg) ip, yet increased the number of spontaneously active DA cells at a dose of 0.3 mg/kg (0.84 μmol/kg). The chronic administration (21 days) of BRL 46470A appeared to produce a multiphasic dose-response curve. Thus, the chronic treatment with BRL 46470A increased the number of spontaneously active A10 DA cells at 0.03 (0.084 μmol) and 0.3 mg/kg, but decreased the number of spontaneously active A10 DA cells at a dose of 0.1 mg/kg. In contrast, BRL 46470A did not decrease the number of spontaneously active A9 DA cells after either acute or chronic administration (0.01-0.3 mg/kg). However, BRL 46470A did increase the number of spontaneously active A9 DA cells at acute and chronic doses similar to those that were effective in A10. The iv administration of (+)-apomorphine (APO) not only failed to reverse the decrease produced by chronic administration of BRL 46470A at 0.1 mg/kg, but further decreased the number of spontaneously active A10 DA cells. Similar to the results obtained with granisetron, the pretreatment of naive rats with either 0.01 or 0.1 mg/kg iv of BRL 46470A significantly potentiated (2-fold) the suppressant action of APO on the basal firing rate of A10, but not A9 DA cells. Overall, our results indicate that similar to granisetron, chronic BRL 46470A at 0.1 mg/kg selectively decreases the number of spontaneously active A10 DA cells, via a mechanism not related to depolarization inactivation. Presently, it is not clear what factors may contribute to the multiphasic dose-response curve of BRL 46470A. © 1994 Wiley-Liss, Inc.     

Normal intracortical excitability in developmental stuttering.

Persistent developmental stuttering (PDS) shares clinical features with task-specific dystonias. In these dystonias, intracortical inhibition is abnormally weak. We therefore sought to determine intracortical inhibition and intracortical facilitation in PDS. In 18 subjects with PDS since childhood (mean age, 39.4 [SD 13.0] years) and 18 speech-fluent controls (43.6 [14.3] years), we investigated resting and active motor thresholds as well as intracortical inhibition and facilitation of the optimal representation of the abductor digiti minimi of the dominant hand using transcranial magnetic stimulation. In PDS, the resting and active motor thresholds were increased, whereas intracortical inhibition and facilitation were normal. Normal intracortical excitability makes a pathophysiological analogy between focal dystonia and PDS less likely. The enhanced motor threshold suggests reduced motor cortical neuronal membrane excitability in PDS.     

AIDS and tuberculosis

The diagnostic and therapeutic implications of human immunodeficiency virus (HIV) infection and tuberculosis in South Africa, where tuberculosis remains a major health problem, are reviewed. Mycobacterium tuberculosis is a high-grade pathogen and is able to establish infection early in immunodeficiency. With HIV infection showing significant entry into the heterosexual population in the RSA, an increasing number of cases with both infections can be expected to occur. The radiological appearance in combined infection is variable, ranging from a formal cavitatory picture to the more common finding of diffuse pulmonary infiltration. Intrathoracic adenopathy is a more specific sign of tuberculosis in HIV infection, since it is not associated with persistent generalised lymphadenopathy and pulmonary opportunistic infections, such as Pneumocystis carinii pneumonia. Intercurrent pneumonic infections and other pulmonary manifestations of HIV disease render the interpretation of new infiltrates on chest radiography problematical. Tuberculin skin testing remains useful in HIV infection and should be performed in all HIV-infected patients. The value of tuberculosis serology still remains questionable. Standard antituberculosis drug regimens are effective, but maintenance treatment must be continued for life and should include isoniazid and rifampicin. BCG vaccination is recommended routinely at birth in infants with HIV infection and for asymptomatic HIV-infected individuals who have not previously been immunised.     

Alternative delivery system for controlled drugs in the surgical intensive care unit

Faced with a serious shortage of qualified nurses for critically ill patients, methods to reduce the time required to deliver care without sacrificing quality are needed. A non-electronic device designed as a patient-controlled analgesic (PCA) was evaluated as a nurse-controlled device (NCA). Twenty-five intubated patients received morphine sulfate (MS) with the nurse-controlled device (NCA) and 12 by standard IV push policy. The average nursing time for narcotic dosing with the standard policy was 5 minutes/unit dose. A total of 1,183 NCA doses were given over 77 patient days. The average doses per patient day were 15 (2-38). The average nursing time was 22 seconds/NCA dose. The NCA saved 85 nursing minutes/patient day. Annual nursing labor costs were reduced by $77,000.00 with NCA. Total costs for standard IV push narcotic use were $36.43/patient day versus $35.45/patient day for NCA. Using this protocol, the NCA system saved $8,500.00 annually. By increasing the duration of PCA use to 72 hours, the annual savings would become $49,500.00. These data indicate that a simple NCA can deliver controlled drugs rapidly and safely, save valuable nursing time, and decrease the cost of ICU care.     

Partial tolerance in rat renal allograft recipients following multiple blood transfusions and concomitant cyclosporine

Multiple prior administrations of donor-strain blood while under limited cyclosporine cover, consistently induce extensive rat renal allograft survival and transplantation tolerance. Yet it was hypothesized that some chronic rejection mechanisms were nevertheless operative since consistent but nonprogressive minor renal dysfunction was observed long-term. A histopathologic study on these putative tolerant rats was undertaken to test this hypothesis. Twenty long-term LEW recipients of BN renal allografts receiving the blood-CsA regimen were examined histopathologically at day 100 post-transplant. Sixteen control LEW recipients receiving only a BN renal allograft were studied acutely at day 7 posttransplant. The control recipients demonstrated a range of lesions consistent with previous studies on acute renal allograft rejection in the rat. However, tolerant recipients demonstrated mild-to-moderate lesions consistent with chronic mechanisms of rejection including the following: moderate focal interstitial mononuclear inflammatory cellular infiltration, with periglomerular and perivascular accumulation; occasional arteriolar luminal obliteration and glomerular atrophy; focal areas of moderate interstitial fibrosis; mild interstitial hemorrhage; mild-to-moderate tubular atrophy; and focal tubular necrosis. Previously our laboratory has documented that tissue-specific renal basement membrane antigens may be responsible for inciting this pattern of focal chronic interstitial inflammation. However, from the present histopathologic studies, it would appear likely that chronic rejection mechanisms in these recipients, which were defined as tolerant by immunologic criteria, involve both tissue-specific and MHC determinants. Therefore, induction of transplantation tolerance in these indefinite survivors is partial or incomplete.