Studies on levamisole--induced agranulocytosis

Widespread clinical trials of leavo-tetramisole (levamisole) as an immunopotentiating agent in rheumatoid arthritis, metastatic carcinoma, and immunodeficiency states have been complicated by agranulocytosis (AGC) in 2.5%-13% of patients. Other than a relationship with prolonged high dosage, very little is known regarding the pathogenesis of levamisole-induced AGC. Whereas leukoagglutination was negative, fluorochromatic microgranulocytotoxicity (GCY) tests were positive with serum from 10 of 10 acutely neutropenic patients. The antibody was IgM, reacted with 100% of unrelated granulocytes, but not with T or B lymphocytes. Some sera also reacted with monocytes and the myeloid cell line, K-562. Tests for antigen-antibody complexes or cold autoantibodies were negative. Although clinical evidence strongly suggests a haptene (drug) mechanism, in vitro mixing experiments were also negative. An alternative choice parallels the model of aldomet- induced Coombs'-positive hemolytic anemia. Finally, GCY first became positive 2-3 mo prior to the onset of AGC on two patients, suggesting the possibility of identifying those at risk well before the onset of neutropenia.     

Marrow transplantation for children with acute lymphoblastic leukemia in second remission

Fifty-seven children between the ages of 3 and 17 years with acute lymphoblastic leukemia (ALL) in chemotherapy-induced second bone marrow remission were given cyclophosphamide, total body irradiation, and bone marrow transplants from HLA-matched donors. Sixteen died of transplant- related complications. Eighteen relapsed between 56 and 833 days after transplantation, and 16 died of leukemia. Two survive in remission off treatment following chemotherapy. Twenty-three survive in continuous remission from 1.4 to 10.4 years after transplantation and the actuarial analysis shows disease-free survival of 40% with a plateau extending from 2.5 to 10.4 years.     

Dopamine D-1/D-5 receptor activation is required for long-term potentiation in the rat neostriatum in vitro

Dopamine and glutamate are key neurotransmitters involved in learning and memory mechanisms of the brain. These two neurotransmitter systems converge on nerve cells in the neostriatum. Dopamine modulation of activity-dependent plasticity at glutamatergic corticostriatal synapses has been proposed as a cellular mechanism for learning in the neostriatum. The present research investigated the role of specific subtypes of dopamine receptors in long-term potentiation (LTP) in the corticostriatal pathway, using intracellular recording from striatal neurons in a corticostriatal slice preparation. In agreement with previous reports, LTP could be induced reliably under Mg(2+)-free conditions. This Mg(2+)-free LTP was blocked by dopamine depletion and by the dopamine D-1/D-5 receptor antagonist SCH 23390 but was not blocked by the dopamine D-2 receptor antagonist remoxipride or the GABA(A) antagonist picrotoxin. In dopamine-depleted slices, the ability to induce LTP could be restored by bath application of the dopamine D-1/D-5 receptor agonist, SKF 38393. These results show that activation of dopamine D-1/D-5 receptors by either endogenous dopamine or exogenous dopamine agonists is a requirement for the induction of LTP in the corticostriatal pathway. These findings have significance for current understanding of learning and memory mechanisms of the neostriatum and for theoretical understanding of the mechanism of action of drugs used in the treatment of psychotic illnesses and Parkinson's disease.     

Changes in motor activities induced by microinjections of the selective dopamine agonists LY 171555, quinpirole hydrochloride, and SK&F 38393 into the habenula nucleus

The effects on behaviour of microinjections into the habenula complex of selective agonists for dopamine D-1 (SK&F 38393) and D-2 (LY 171555) receptors were documented in a holeboard, open-field test. The D-2 agonist reduced grooming responses, locomotor activity and rearing behaviour. In contrast, the D-1 agonist increased rearing and locomotor activity but was without effect on grooming responses. Neither drug produced significant effects on inspective hole exploration. The data extend findings of behavioural consequences of central D-1 receptor activation and provide direct evidence in support of the functional and behavioural importance of intrahabenular dopamine receptor sites. The findings are consistent with suggestions for feedback regulation of habenular efferents to midbrain dopaminergic neurons. Effects of both receptor agonists on some responses but not others indicates potential complex interactions between D-1 and D-2 receptors within the habenula.     

Biliary lithotripsy: early observations in 106 patients. Work in progress

One hundred six patients underwent extracorporeal shock wave lithotripsy for cholelithiasis. Of these, 28 patients underwent cholangiographically guided lithotripsy for bile duct stones to assist nonoperative stone removal by endoscopic or radiologic intervention. Fragmentation occurred in 20 of 28 cases (71%) with an average of two lithotripsy sessions. Hemobilia was observed in four patients (14%) for a 24-hour period. Seventy-eight of the 106 were outpatients with symptomatic cholecystolithiasis with one to five calculi who underwent cholecystographic or ultrasound-(US) guided shock wave lithotripsy as definitive therapy. US examination showed stone fragmentation in 86% of cases. With an average of 1.6 treatment sessions and 4,750 shocks, fragments were 4 mm or smaller in 46% of patients. Nine percent of patients had no fragments after an average of 10 weeks, but long-term follow-up is not yet available. Two patients developed acute pancreatitis attributable to fragment passage and one patient acute cholecystitis, likely due to cystic duct obstruction by a fragment.     

Wound tensile strength and contraction rate are not affected by laparotomy or pneumoperitoneum

Background: Many cellular elements responsible for wound healing are affected by laparotomy. The aim of this study was to evaluate the effects of laparotomy and CO₂ pneumoperitoneum on wound healing. Methods: Male Sprague Dawley rats were randomly assigned to one of three experimental groups. Anesthesia control rats underwent no procedure. Pneumoperitoneum group rats were insufflated with CO₂ gas. Laparotomy group rats underwent a 7-cm midline laparotomy incision. The interventions were 30 min long. For the incisional study (n= 30), a 4-cm dorsal full-thickness skin incision was made on each rat and then closed with staples. On postoperative days 7 and 14, an equal number of rats were sacrificed from each group, and wound tensile strength measurements were performed. For the excisional study (n= 45), each group of 15 rats underwent a 2-cm diameter circular dorsal full-thickness skin excision. Blinded measurements of wound area were performed every other day until wounds closed. Results: Wound tensile strength values were not significantly different among experimental groups at either time point. The study had a power of 80% to find a 30% difference at POD 7 and a power of 80% to find a 23% difference at POD 14 to a confidence level of p < 0.05. Wound contraction data from the excisional model were analyzed with the Generalized Estimation Equations statistical approach. When we modeled the treatment group as a covariate, no statistical difference was found between groups, demonstrating equal slopes across time. Conclusions: From the results of these studies, we conclude that wound healing in this model is not significantly diminished following laparotomy or peritoneal insufflation, as compared to anesthesia control. Received: 26 September 1997/Accepted: 27 January 1998     

Two dynamic modes of striatal function under dopaminergic-cholinergic control: simulation and analysis of a model

A neural network model based on the anatomy and physiology of the matrix compartment of the striatum is described. The model consists of a network of neurons which are mutually inhibitory within a defined domain. A membrane potassium conductance (GK) under dopaminergic-cholinergic control is included in the model. Computer simulation results show that changes in GmaxK can modulate the behaviour of the network to produce either competition or coactivation among striatal output neurons. An analysis of a two-neuron system based on the model shows that the maximum steepness of the threshold function plays a decisive role in the dynamics, in particular with regard to the competition that exists between the neurons. Competitive interactions predominate at low GmaxK, while coactivation predominates at high GmaxK. We suggest that the former dynamic governs reciprocal inhibition of antagonistic muscles, while the latter governs cocontraction and rigidity. The model offers insights into the control of striatal neurodynamics by GmaxK which establish closer links between dopaminergic actions in the striatum and the mechanism of Parkinsonian rigidity. A prediction of the model is that acetylcholine should increase GKmax in striatal output neurons.