Cladribine in aggressive forms of multiple sclerosis.

Cladribine (2-chlorodeoxyadenosine) is an immunosuppressant drug previously evaluated in multiple sclerosis (MS) with variable results. We report six patients with aggressive relapsing MS who despite a poor response to other therapies had a favourable clinical evolution after cladribine. Four women and two men with a rapid increase in the number and severity of relapses leading to increasing disability [mean Expanded Disability Status Scale (EDSS) 6.42, standard deviation +/- 0.58, mean relapse rate per year in the 2 years prior to study entry 2.67 +/- 0.75] were retrospectively evaluated. Brain magnetic resonance imaging (MRI) performed in five patients showed active disease with gadolinium-enhancing lesions. Cladribine was given at 0.07 mg/kg/day for five consecutive days once monthly with a total of 2- to 4-monthly courses. After 6 months, mean EDSS decreased to 3.75 +/- 1.64 and MRIs showed a decrease or suppression in the number of gadolinium-enhancing lesions. After 1 year from first dose, cladribine dosage was repeated in four patients because of recurrence of relapses with subsequent similar positive clinical results. In the follow-up period (49.33 +/- 39.66 months), the mean relapse rate decreased to 0.71 +/- 0.55 and no unexpected or serious adverse events were observed.

Cytotoxic activity of a polyamine analogue, monoaziridinylputrescine, against the PC-3 human prostatic carcinoma cell line.

We have previously demonstrated that prostate and prostate-derived rodent tumors can be manipulated into increasing their accumulation of radiolabeled putrescine by alpha-difluoromethylornithine (DFMO)-induced depletion of intracellular putrescine and spermidine. As methods which increase intracellular accumulation of cytotoxic agents often increase the chemotherapeutic effectiveness of the agent, we examined whether an alkylating derivative of putrescine would be cytotoxic to tumor cells. We present here our findings on the cytotoxicity of the aziridinyl derivative of putrescine (AZP) against prostatic cancer cells. The apparent Km for putrescine was 2.5 microM with or without DFMO pretreatment and the apparent Ki for AZP was 1 microM with or without DFMO pretreatment. Intracellular polyamine depletion by DFMO pretreatment resulted in a 3.7-fold greater accumulation of AZP compared to non-DFMO-treated cells. The growth inhibitory activity of AZP was increased with prior polyamine depletion by DFMO with the 50% effective dose decreasing from 18 microM to 2.1 microM. Putrescine was able to block the cytotoxic effect of AZP. Putrescine was also able to rescue the AZP-treated PC-3 cells for up to 6 h following a 1-h exposure to AZP. It appears that aziridinylputrescine behaves like putrescine in that it competes with putrescine for uptake into the cell and, like putrescine, has its uptake into the cell increased by prior polyamine depletion. It differs from putrescine in that it expresses cytotoxic activity and inhibits the growth of the human prostate-derived PC-3 cell line. This cytotoxic activity is also increased by prior polyamine depletion. The cytotoxic behavior of AZP is dependent both on the concentration and duration of exposure. Putrescine can rescue the cells from the effect of AZP. AZP is a potentially useful cytotoxic analogue that utilizes the polyamine transport system for its uptake into the cell.

Fibromyalgia and major affective disorder: a controlled phenomenology and family history study.

Fibromyalgia is a form of nonarticular rheumatism characterized by diffuse musculoskeletal pain. To investigate the relationship between fibromyalgia and major affective disorder, the authors evaluated 31 patients with fibromyalgia and 14 patients with rheumatoid arthritis for rates of current or past major affective disorder and family history of major affective disorder. Both the rate of major affective disorder and the familial prevalence of major affective disorder were significantly higher in the fibromyalgia patients than the rheumatoid arthritis patients. The results suggest that fibromyalgia may be related to major affective disorder.

[A quantitative histochemical study of alkaline phosphatase isoenzyme kinetics in the thyroid gland, kidney and small intestine of white rats]. / Kolichestvennoe gistokhimicheskoe issledovanie kinetiki izofermentov shchelochnoi fosfatazy v shchitovidnoi zheleze, pochke i tonkoi kishka belykh krys

Microphotometric determination of alkaline phosphatase isoenzyme patterns in morphological structures of rat thyroid gland, kidney and small intestine were performed, using different concentration of L-levamisol and temperature-dependent enzyme inactivation. It was concluded that he constant of inhibition and degree of thermostability are closely connected with heterogeneity of alkaline phosphatase isoenzyme pattern in the organ.

[A microphotometric study of the kinetics of the histochemical reaction to lactate dehydrogenase]. / Mikrofotometricheskoe issledovanie kinetiki gistokhimicheskoi reaktsii na laktatdegidrogenazy

The aim of the work--to ascertain and substantiate concentrations of the main components of the incubation medium used for identification and quantitative evaluation of the activity of lactate dehydrogenase in cryostat sections. Studies were conducted using cryostat sections of the rat's liver as thick as 5, 10, 15 mcM with concentration in the incubation medium of lactate 25--125 mM, NAD 2--12 mM, nitrobleu and tetranitrobleu tetrazoles 0.3--5 mM, and also under conditions with addition of pyruvate in concentrations from 0.3 to 100 mM. The cytospectrophotometric method was used for evaluation of kinetic parameters of the histochemical reaction. The data on the dependence of the rate of tetrazole reduction upon the concentration of substrate, cofactor, thickness of the section and the level of the end product of the pyruvate reaction in the incubation medium were obtained. The main kinetic parameters of the enzymatic reaction in liver sections--value of Michaelis' constant and the concentration of the substrate at which the maximal rate of the reaction was observed--were calculated. Recommendations for selection of an optimal composition of the incubation medium, ensuring the strictly quantitative evaluation of the activity of an enzyme in cryostate sections are suggested.

[Morphological changes in the thyroid gland of rats during various phases of the estral cycle]. / Morfologicheskie izmeneniia shchitovidnoi zhelezy krys v razlichnykh fazakh éstral'nogo tsikla

The functional state of the thyroid gland and the concentration of thyroid hormones in the peripheral blood were studied in 20 mature female albino rats during their estral cycle. Evaluation of the thyroid functional state was made according to data of histological, morphological (the diameter of folliculi, the height of the thyroid epithelium) and histochemical analysis (determination of NAD and NADP-dehydrogenase, succinatedehydrogenase, lactate dehydrogenase, peroxydase, acid and alkaline phosphatase) as well as biochemical determination of iodine bound with protein (IBP) in the blood plasma and investigation of the ratio of the parameters in question under conditions of the sex cycle. The cyclic changes of the morphological state of the thyroid gland attended by the phases of the estral cycle were revealed. The activation of the organ was observed in proestrus and estrus which was evidenced by high levels of activity of the enzymes under study, high concentration of IBP in the blood and increased height of thyreocytes. A decreased function of the thyroid parenchyma was observed at the period of metaestrus-diestrus.

Breast cancer in the inner city: intensive efforts may be succeeding.

Breast cancer is a significant problem in a 518 bed government supported university hospital in New Jersey's largest city. The following records were reviewed: tumor registry abstracts of the 367 analytic breast cancer patients admitted from 1/1/91 to 12/31/92; the 455 participants in the Breast Cancer Detection Awareness Program (BCDAP) from 1987 to 1992; and the 460 breast biopsies performed from 1990 to 1992. Breast cancer is less common at this inner city hospital than in the U.S. in general; the stage is more advanced at presentation than in the U.S. overall; and the overall survival is only 54% at five years. Approximately 40% of the patients were African-American women from the inner city. Their median age was 53, seven years younger than the median age for diagnosis in the U.S. overall, and their five year survival was only 46%. Intensive efforts have recently produced improvement in the proportion of cases diagnosed at early stages (T0 and T1), but a decrease in mortality has not yet been seen.