Decreased tyrosine hydroxylase content in the dopaminergic neurons of MPTP–intoxicated monkeys: Effect of levodopa and GM1 ganglioside therapy

Parkinson's disease is characterized by the degeneration of melanized dopaminergic neurons of the substantia nigra. The functional capacity of the surviving dopaminergic neurons is affected, as suggested by the subnormal levels of tyrosine hydroxylase messenger RNA and protein found in the remaining cells. The reduced expression of tyrosine hydroxylase may be due to either the evolving neurodegenerative process or its downregulation, possibly secondary to chronic levodopa treatment. The cellular content of tyrosine hydroxylase was determined in the mesencephalon from 16 Macaca fascicularis monkeys, using a semiquantitative immunocytochemical method. Thirteen monkeys were rendered parkinsonian by weekly intravenous injections of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) for 2 (subacute treatment) or 20 (chronic treatment) weeks. Three of the monkeys received levodopa and 3 others received GM1 ganglioside. The loss of dopaminergic neurons in the mesencephalon of the MPTP-intoxicated monkeys was severe in the substantia nigra, intermediate in cell groups A8 and A10, and almost undetectable in the central gray substance. After both subacute and chronic treatment, the cellular content of tyrosine hydroxylase was reduced by 40% in the surviving neurons of the lesioned substantia nigra, but by less in the other mesencephalic dopaminergic regions. Neuronal survival and tyrosine hydroxylase content in monkeys that had received levodopa were not significantly different. The cellular content of tyrosine hydroxylase was increased in the substantia nigra of the monkeys that received GM1 ganglioside injections. The results show that the decreased expression of tyrosine hydroxylase found in nigral dopaminergic neurons after partial degeneration of the mesostriatal dopaminergic system is not influenced by levodopa treatment and is partially reversed by GM1 ganglioside administration.     

Fluoxetine in post-traumatic stress disorder

Fluoxetine was given to five nonveteran patients with post-traumatic stress disorder (PTSD). The maximum doses ranged from 20 to 80 mg/day, and treatment was continued for between 8 and 32 weeks. In contrast to published reports of other drugs, which were noted to improve only the intrusive symptoms of PTSD, fluoxetine was associated with marked improvement of both intrusive and avoidant symptoms. Facilitative effects of fluoxetine were noted on trauma-focused psychotherapy in two adult victims of childhood sexual trauma. In part, these effects were related to modulating effects of the drug upon the intensity of core PTSD symptoms. Serotonergic drugs appear to hold promise for the treatment of PTSD.This work was conducted in the Departments of Psychiatry and Psychology, Duke University, Durham, N.C.     

Liver transplant and hepatitis C in methadone maintenance therapy: a case report

Background

Drug-related death (DRD) figures, published by the national performance management framework, are used to monitor the performance of Drug (and Alcohol) Action Teams (D[A]ATs) in England and Wales with respect to reducing DRDs among drug abusers. To date, no investigation has been made into the types of death included in these figures, the demographic and drug profile of those who died, nor the likelihood of individuals included in DRD figures interacting with services designed to assist drug abusers. The aim of this work was to examine the characteristics of deaths classified as drug-related and to explore their applicability to performance-monitor drug-related services. Liverpool was chosen because it was reported by the national DRD monitoring system to have the highest number of DRDs in 2004.

Methods

Information was retrieved from the Liverpool coroner's records and established monitoring systems on individuals reported by the national performance monitoring system as a DRD between 1^st January 2004 and 30^th June 2005 (n = 70). Analyses assessed differences between those categorised by the national performance monitoring system as 'drug abusers/dependents' and 'non-drug abusers/dependents' using χ², Fisher's exact test and Mann-Whitney U.

Results

Non-drug abusers were significantly older (median age 53.59 vs. 38.23), had no recent contact with drug-related agencies (cv. 31.6% of abusers who had treatment contact) and had different post mortem drug profiles than drug abusers. A significantly greater proportion of non-drug abusers died from drug toxicity – predominantly through anti-depressants, anti-psychotics and analgesics.

Conclusion

Our findings suggest that the national DRD performance monitoring system includes deaths of people who are not drug abusers – individuals who are not the current focus of drug prevention, treatment or harm minimisation services. This raises concerns regarding the applicability of these figures to performance monitor D(A)ATs. Furthermore, using the more compact definitions used to monitor trends in DRDs across England, Wales and Europe fails to include a proportion of deaths attributable to drug misuse – such as those attributable blood-borne viruses. Current definitions used to monitor DRDs locally, nationally and across Europe fail to capture the true burden of drug-related mortality.     

Fish consumption and advisory awareness among low-income women in California's Sacramento-San Joaquin Delta

Fishing is a culturally important activity to the ethnically diverse population living in California's Sacramento-San Joaquin Delta. Due to runoff from abandoned gold mines, certain Delta fish are contaminated with methylmercury, a neurodevelopmental toxin. A state health advisory recommends limited consumption of certain Delta fish, to be followed in conjunction with a federal advisory for commercial and sport fish. We conducted a survey of low-income women at a Special Supplemental Nutrition Program for Women, Infants, and Children (WIC) clinic, to characterize commercial and sport fish consumption patterns and advisory awareness. Ninety-five percent of women consumed commercial fish. Thirty-two percent consumed sport fish; this proportion was much higher in Hmong (86%) and Cambodian (75%) women. Ninety-nine percent of sport fish consumers also consumed commercial fish. The overall fish consumption rate among consumers was 27.9 g/day (geometric mean, past 30 days, cooked portion); commercial and sport fish consumption rates were 26.3 and 10.5 g/day, respectively. We found ethnic differences in overall fish consumption rates, which were highest in African Americans (41.2 g/day) and Asians (35.6 g/day), particularly Vietnamese and Cambodians. Pregnant women ate less fish overall than other women (16.8 vs. 30.0 g/day, p=0.0001), as did women who demonstrated specific advisory awareness (23.3 vs. 30.3 g/day, p=0.02). Twenty-nine percent of all women exceeded federal fish consumption advisory limits. These results highlight the need for culturally and linguistically appropriate interventions that address both commercial and sport fish consumption.     

Phase I/II trial of dexverapamil, epirubicin and granulocyte/macrophage-colony-stimulating factor in patients with advanced pancreatic adenocarcinoma

A group of 28 previously untreated patients with locally advanced or metastatic adenocarcinoma of the pancreas were entered in this phase I/II study. Treatment consisted of oral dexverapamil 1000–1200 mg/day for 3 days, epirubicin given as an intravenous bolus injection on day 2 with a starting dose of 90 mg/m², and 400 μg granulocyte/macrophage-colony-stimulating factor (GM-CSF) administered subcutaneously from day 5 through 14. Epirubicin dose escalation levels were 90, 105, 120 and 135 mg/m². Consecutive cohorts of 4–8 patients were planned at each dose level. Treatment cycles were repeated every 3 weeks. Haematological toxicity, specifically granulocytopenia constituted the dose-limiting toxicity with a maximum tolerated dose of 120 mg/m² for epirubicin. Despite routine supportive therapy with GM-CSF, 4, 2, and 5 patients experienced grade 4 granulocytopenia during their first two treatment courses at levels of 105, 120, and 135 mg/m² respectively. Non-haematological toxicity was uncommon, generally modest, and did not demonstrate a clear relationship with the anthracycline dose. Dexverapamil-related cardiovascular symptoms occurred frequently, but they never resulted in serious toxicity requiring active medical intervention or permanent discontinuation of therapy. Of the 28 patients, 9 achieved partial responses to this therapy. The recommended dose of epirubicin for this regimen with dexverapamil and GM-CSF is 120 mg/m² every 3 weeks. Therapeutic results suggest this regimen to be an effective and tolerable treatment strategy in pancreatic cancer, which should be evaluated further.