Rearrangement of Valproate Glucuronide in a Patient with Drug-Associated Hepatobiliary and Renal Dysfunction

Formation of beta-glucuronidase-resistant "glucuronides" of valproic acid (VPA) by intramolecular rearrangement of biosynthetic valproate glucuronide in vivo was investigated in a patient diagnosed with VPA-associated hepatobiliary and renal dysfunction. Plasma elimination half-life of VPA following cessation of the drug was 13.9 h. At the time of the toxicity, the concentration of conjugated VPA in plasma was very high (36-54% of nonconjugated VPA levels) relative to that in normal patients (2.9%). The fraction of conjugated VPA resistant to beta-glucuronidase hydrolysis was 0.28-0.47 in plasma and 0.15-0.42 in urine. The corresponding fraction in urine from normal patients receiving VPA therapy was 0.044. The evidence was consistent with retarded elimination of biosynthetic VPA glucuronide caused by renal and hepatobiliary dysfunction. Consequent prolongation of circulation of VPA glucuronide at the slightly alkaline pH of blood would permit extensive intramolecular rearrangement which is known to be pH-, temperature-, and time-dependent. The biological consequences of the presence of such beta-glucuronidase-resistant conjugated VPA in vivo are largely unknown.     

Preeclampsia and reproductive performance in a community of vegans

Studies at "the Farm," a community of spiritually gathered young people in Summertown, Tenn, have shown that it is possible to sustain a normal pregnancy on a vegan diet. The source of dietary protein (ie, animal or vegetable) does not seem to affect birth weight, as long as vegans are health conscious, receive continuous prenatal care, supplement their diets with prenatal vitamins, calcium, and iron, and apply protein-complementing nutritional principles. Preeclampsia may be caused by a relative prostacyclin deficiency in the face of excessive production of thromboxane A2. A vegan diet (one low in arachidonic acid) might provide protection against this condition, especially if the conversion of linoleic acid to arachidonic acid is inhibited by decreased activity of the enzyme delta-6-desaturase. We examined the maternity care records of 775 vegan mothers for symptoms of preeclampsia, and only one case met the clinical criteria. Since preeclampsia in our culture is frequently associated with unrestrained consumption of "fast foods" (foods having high levels of saturated fat) and rapid weight gain, it is possible that a vegan diet could alleviate most, if not all, of the signs and symptoms of preeclampsia.     

Age as a prognostic factor in the malignant melanoma population

Background: The incidence of malignant melanoma is increasing faster than any other cancer, and the state of Florida has one of the highest incidence of melanoma in the United States. This increased incidence is thought to be due to the intense sunlight exposure and ultraviolet radiation exposure in the elderly population. With the increased emphasis on issues of aging, it is appropriate to study the role of age as a prognostic factor for malignant melanoma in the Florida population. Methods: A retrospective, computer-aided search identified 442 consecutively registered patients with malignant melanoma at the Cutaneous Oncology Program. All patients had stage 1 or 2 disease (cutaneous disease only) at diagnosis. Prognostic variables analyzed included the most powerful factors for stage 1 and 2 melanoma, tumor thickness, ulceration, and Clark level of invasion. Other prognostic variables included in the analysis were the clinical variables of sex and primary site (axial vs. extremity). The population was divided into patients 65 and >65 years of age. Results: Significant disease-free survival differences were encountered in the older population, with only 55% of the elderly population being disease free at 5 years compared with 65% for the younger population (p=0.0073). However, a greater percentage of patients with melanoma who were >65 years of age had ulcerated lesions (17.5% vs. 12.9%) and a greater percentage of thick lesions at diagnosis (67.2% vs. 62.7%). Both of these prognostic factors would bias the older population with a poorer survival. A stepwise regression analysis of the entire population was performed, treating age as a continuous variable. Surprisingly, increasing age along with tumor thickness were the only significant predictors for disease-free survival. After inclusion of these two prognostic variables, none of the other prognostic factors, including Clark level, ulceration, sex, and primary site, added to the prognostic model. Conclusions: From this analysis, it is apparent that geriatric patients with melanoma have a worse prognosis than a younger control population, even after the correction for the more commonly cited prognostic factors. This information should be used in mathematical modeling to identify high-risk populations who are candidates for perhaps more aggressive primary or adjuvant therapies.Presented at the 46th Annual Cancer Symposium of The Society of Surgical Oncology, Los Angeles, California, March 18–21, 1993.     

Characterization of the epitope recognized by a mAb that reacts differentially with murine suppressor T cells

Although reliable antibodies are available that distinguishhuman suppressor T (T_s) cells from CTL and other T cells, feware available for murine T_s cells. We have developed a mAb (984D4.6.5)that, in the presence of complement, depletes alloantigen-specificT_s cells but not CTL. This antibody recognizes activated TT_scells but not their precursors. In these studies, flow cytometricanalysis demonstrates that 984D4.6.5 reacts with several T_scell hybridomas, cloned T_h cell lines and WEHI-3 (a myelomonocytictumor cell line). Reactivity was not detected with BW5147, T_hcell hybridomas, cloned T_h cells, CTL lines and hybridomas,B cell lines, thymocytes, splenocytes, bone marrow cells nora variety of tumor cells. Among 984D4.6.5 positive lines, expressionis heterogeneous and the number of cells expressing high levelsof the epitope is increased when the hybridomas are maintainedat a relatively high cell density. Neuriminidase and pronasedeplete the epitope recognized by mAb 984D4.6.5. Protein synthesisand glycosylation inhibitors also reduce expression of thisepitope. These observations suggest that the epitope recognizedby 984D4.6.5 is a carbohydrate linked to a polypeptide. Thisantibody was tested by ELISA for binding to a large panel ofcarbohydrates and glycollpids coupled to BSA. The only one thatbound 984D4.6.5 was LS tetrasaccharide c (NeuNAc2-6Galpß1-4GIcNAcß1-3GaIß1-4Glc),an O-linked carbohydrate. Comparative analysis shows that boththe sequence and the linkage of these sugars are essential tothe reactivity with the 984D4.6.5 antibody. This epitope isexpressed by a glycoprotein of-200 kDa, as shown by Westernblots. The identity of this glycoprotein remains to be determined,but indirect evidence suggests that it is not CD45.     

Factors associated with use of community support services in an older Australian population

OBJECTIVE: To assess prevalence and risk factors associated with use of community support services in a representative older Australian population. METHODS: The Blue Mountains Eye Study surveyed 3,654 people aged > or = 49 years, 82.4% of eligible residents from an area west of Sydney during 1992-94. Questions about use of community support services were asked during face-to-face interview. Information on marital and living status, socio-economic status measures, past medical history and self-ranked health status were also collected. RESULTS: 186 (5.4%) persons including 124 women (6.3%) and 62 men (4.2%) reported regular use of community support services, including Meals-on-Wheels (n = 52), Home Care (n = 147) or visits from a community nurse (n = 63). All three services were used by 17 persons and two services by 42 persons. There was a marked age-related increase in use of services from 1.8% in persons aged < 60 years to 25.3% in persons aged 80+ years. Factors significantly associated with use of community services in a multivariate model were: age (OR 1.7 per age decade), living alone (OR 2.5), walking disability (OR 4.1), visual impairment (OR 3.0), stroke history (OR 2.2), arthritis history (OR 1.8), low perceived health status (OR 1.7), cancer history (OR 1.7) and a history of any falls in the past 12 months (OR 1.6). CONCLUSIONS: Our study has found a wide range of health-related factors that impact on the use of community support services, particularly conditions causing difficulty in walking. IMPLICATIONS: These data may assist health planners in identifying target populations for the provision of community support services.     

Receptor tyrosine kinase tie 1 mRNA is upregulated on cerebral microvessels after embolic middle cerebral artery occlusion in rat

Tie 1 is an endothelial specific transmembrane receptor tyrosine kinase and may be required during angiogenesis. Using in situ hybridization, we measured tie 1 mRNA in ischemic brain (n=15). Rats were subjected to middle cerebral artery (MCA) occlusion by a single fibrin rich clot. Expression of tie 1 was not detected in non ischemic brain. Cerebral microvessels expressed tie 1 in the ischemic lesion as early as 2 h after MCA occlusion. The number of microvessels containing tie 1 mRNA decreased in the ischemic lesion at 8 h after MCA occlusion. However, expression of tie 1 increased on microvessels at 24 h and 14 days after ischemia and tie 1 was primarily localized to the microvessels bordering pan necrotic tissue. Ninety-seven percent of cerebral vessels which expressed tie 1 mRNA had diameters of 3.7+/-0.17 microm. Our findings suggest a role for tie 1 in cerebral microvascular remodeling after embolic stroke.     

Novel weight-reducing activity of Galega officinalis in mice

Galega officinalis (galega, Goat's Rue, French Lilac) is well known for its hypoglycaemic action and has been used as part of a plant mixture in the treatment of diabetes mellitus. During pharmacological investigations of an ethanolic extract of a powdered mixture of equal proportions of G. officinalis, Cressa cretica, Mangifera indica and Syzygium jambolanum, a weight reducing effect of galega was discovered. In this study we have investigated the novel weight reducing effect of galega in mice. Galega herb (10% w/w in the diet) caused a significant reduction in body weight in both normal and genetically obese (ob/ob) animals treated for 28 days when compared with respective controls (P < 0.01). In normal mice, the weight loss was reversible and initially associated with a transient reduction in food intake but was then maintained even in the presence of increased eating above the control level. Pair-fed normal mice receiving galega for seven days also showed significant weight loss (P < 0.01, compared with the control) in the presence of increasing food intake. In sharp contrast, weight loss in galega-treated ob/ob mice was accompanied by a persistent reduction in food intake over the 28-day treatment period. Post-mortem examinations of all galega-treated mice revealed a striking absence of body fat. Serum glucose was significantly reduced in both strains of mice receiving galega for 28 days (P < 0.01), whereas serum insulin was significantly reduced only in obese mice (P < 0.01). In summary, together with its established hypoglycaemic effects, galega has a novel weight reducing action that, in normal mice, is largely independent of a reduction in food intake. The mechanism of the weight reducing action of galega is unclear but involves loss of body fat.