Neural transplantation for Parkinson's disease: a critical appraisal

Abstract :The medical treatment of severe Parkinson's disease is presently problematical and neural transplantation has been proposed as an additional therapy. While functional improvement in animal models of Parkinson's disease has been reported following neural grafting, the treatment of human Parkinsonian patients by adrenal medulla autografting into the neostriatum has produced little clinical improvement overall, and is associated with significant morbidity. Although recent grafting of human foetal dopaminergic neurons has shown more promise, many of the case reports lack rigorous assessment and long term follow-up. Further laboratory experimentation in animal models, particularly primates, to ascertain the mechanism of action of the grafts, the optimal sites for grafting, and the immunological responses to grafting, is essential. The future success of neural transplantation for Parkinson's disease may depend on the development of novel strategies such as the use of growth factors to aid cell survival, regulate neurotransmitter levels and promote connectivity. However, at present, the clinical application of neural transplantation for Parkinson's disease is premature. (Aust NZ J Med 1991; 21: 477–484.)     

Chronic treatment with clozapine, unlike haloperidol, does not induce changes in striatal D-2 receptor function in the rat

Comparison has been made of the effects on brain dopamine function of chronic administration of haloperidol or clozapine to rats for up to 12 months. In rats treated for 1-12 months with haloperidol (1.4-1.6 mg/kg/day), purposeless chewing jaw movements emerged. These movements were only observed after 12 months' treatment with clozapine (24-27 mg/kg/day). Apomorphine-induced (0.125-0.25 mg/kg) stereotyped behaviour was inhibited during 12 months treatment with haloperidol. Clozapine treatment was without effect. After 12 months, stereotypy induced by higher doses of apomorphine (0.5-1.0 mg/kg) was enhanced in haloperidol, but not clozapine, treated rats. Bmax for striatal 3H-spiperone binding was elevated throughout 12 months of haloperidol administration, but was not altered by clozapine treatment. Bmax for striatal 3H-NPA binding was only elevated after 12 months of haloperidol treatment; clozapine treatment was without effect. Bmax for 3H-piflutixol binding was not altered by haloperidol treatment, but was increased after 9 and 12 months of clozapine treatment. Dopamine (50 microM)-stimulated adenylate cyclase activity was inhibited after 1 month's haloperidol treatment but normal thereafter. Adenylate cyclase activity was not altered by chronic clozapine treatment. Striatal acetylcholine content was increased after 3 and 12 months of haloperidol or clozapine intake. These findings indicate that the chronic administration of the atypical neuroleptic clozapine does not produce changes in brain dopamine function which mirror those of the typical neuroleptic haloperidol. In particular, chronic administration of clozapine, unlike haloperidol, does not appear to induce striatal D-2 receptor supersensitivity. Unexpectedly, clozapine treatment, unlike haloperidol, altered D-1 receptor function.     

Induction of the maternal pheromone by cholic acid in the virgin rat

Based on the hypothesis that an elevation in the synthesis of cholic acid underlies emission of the maternal pheromone in the rat, we augmented, through dietary supplement, the biliary level of cholic acid in nulliparous females. In other groups of nulliparae, chenodeoxycholic- and deoxycholic-acid were augmented, respectively. Only the group fed cholic acid came to emit the pheromone. We conclude that cholic acid is critically involved in pheromonal release.     

An outbreak of type A viral hepatitis at the Naval Training Center, San Diego: epidemiologic evaluation.

In October 1974, a large foodborne outbreak of hepatitis occurred among naval personnel undergoing basic training at the Naval Training Center, San Diego, California. Of the 2781 recruits eating at the implicated dining hall on the day disease transmission occurred, 133 developed clinical or laboratory evidence of hepatitis for an attack rate of 47.8/1000. The epidemiologic investigation suggested that hepatitis A virus was the etiologic agent, and this was subsequently confirmed by laboratory examination. The index and source case was a recuit food-handler who experienced prodromal symptoms of hepatitis while preparing salads and fresh fruit 32 days prior to the outbreak. A food preference questionnaire implicated tossed salad and fresh grapefruit as the specific vehicles of transmission.     

Modulation of central noradrenergic function by RS-15385-197.

1. RS-15385-197, a highly potent and selective alpha 2-adrenoceptor antagonist, was examined in a variety of in vitro and in vivo functional tests to assess the selectivity of its interaction with central noradrenergic neurones in the rat. 2. In hypothalamic slices, RS-15385-197 was potent in augmenting K(+)-evoked release of [3H]-noradrenaline, with an EC50 of 9 nM. Idazoxan and yohimbine showed 100 fold less activity. This was due to its antagonist action at presynaptic alpha 2-adrenoceptors, as RS-15385-197 (10 microM), did not directly release [3H]-noradrenaline from cortical slices unlike reserpine (10 microM), and did not inhibit noradrenaline re-uptake into cortical synaptosomes. 3. In vivo, RS-15385-197 (0.5 mg kg-1, p.o.) increased levels of 3-methoxy-4-hydroxy-phenylglycol (MHPG) in the cerebral cortex without modifying levels of 5-hydroxyindoleacetic acid (5-HIAA). This dose, but not a lower dose (0.1 mg kg-1, p.o.) caused beta-adrenoceptor down-regulation in the cortex when administered once daily for 14 days whereas 5-HT2 receptor number was unaltered, indicating a selective effect on noradrenergic transmission. 4. Selective depletion of cortical 5-HT by administration of p-chlorophenylalanine (PCPA; 100 mg kg-1, i.p. for 14 days) or 5,7-dihydroxytryptamine (5,7-DHT; 150 micrograms i.c.v.) prevented the beta-adrenoceptor down-regulation caused by RS-15385-197, indicating that a tonic 5-hydroxytryptaminergic input was required for it to elicit beta-adrenoceptor down-regulation.(ABSTRACT TRUNCATED AT 250 WORDS)     

The morbidity related to atrial fibrillation at a tertiary centre in one year: 9.0% of all strokes are potentially preventable.

Atrial fibrillation is a major risk factor for stroke. Anticoagulant therapy reduces this risk but increases the risk of haemorrhage. We aimed to compare the morbidity related to the treatment of atrial fibrillation with warfarin seen in one year at our hospital, with the morbidity in those patients in whom embolism was potentially preventable. There were 111 patients admitted to our hospital in a 12 month period with nonvalvular atrial fibrillation (NVAF) who had stroke, TIA or peripheral embolism. Atrial fibrillation was identified prior to admission in 87 of these 111 (78%) patients with thromboembolism, yet only 14 of these (16%) were receiving warfarin for stroke prophylaxis. Through chart review, a further 56 (64%) patients with embolism could have been receiving anticoagulant therapy if published clinical guidelines(1) were applied. Therefore, 40 episodes of thromboembolism were potentially preventable. Over the same period, there were 18 patients admitted with haemorrhage related to warfarin therapy for stroke prophylaxis in NVAF, including 10 gastrointestinal, five intracerebral, and three peripheral haemorrhages. Most haemorrhages were associated with a high International Normalized Ratio (INR) and the patients were left less disabled than those with embolism. Only one patient with haemorrhage had an absolute contraindication to warfarin therapy (6%). We conclude that the number of preventable strokes far outweighed the morbidity due to warfarin use in the management of NVAF.