Lesion of the Cerebellar Noradrenergic Innervation Enhances the Harmaline-Induced Tremor in Rats

Abnormal synchronous activation of the glutamatergic olivo-cerebellar pathway has been suggested to be crucial for the harmaline-induced tremor. The cerebellum receives two catecholaminergic pathways: the dopaminergic pathway arising from the ventral tegmental area/substantia nigra pars compacta, and the noradrenergic one from the locus coeruleus. The aim of the present study was to examine a contribution of the cerebellar catecholaminergic innervations to the harmaline-induced tremor in rats. Rats were injected bilaterally into the cerebellar vermis with 6-hydroxydopamine (6-OHDA; 8 μg/0.5 μl) either alone or this treatment was preceded (30 min earlier) by desipramine (15 mg/kg ip). Harmaline was administered to animals in doses of 7.5 or 15 mg/kg ip. Tremor of forelimbs was measured as a number of episodes during a 90-min observation. Rats were killed by decapitation 30 or 120 min after harmaline treatment. The levels of dopamine, noradrenaline, serotonin, and their metabolites were measured by HPLC in the cerebellum, substantia nigra, caudate–putamen, and frontal cortex. 6-OHDA injected alone enhanced the harmaline-induced tremor. Furthermore, it decreased the noradrenaline level by ca. 40–80% in the cerebellum and increased the levels of serotonin and 5-HIAA in the caudate–putamen and frontal cortex in untreated and/or harmaline-treated animals. When 6-OHDA treatment was preceded by desipramine, it decreased dopaminergic transmission in some regions of the cerebellum while inducing its compensatory activation in others. The latter lesion did not markedly influence the tremor induced by harmaline. The present study indicates that noradrenergic innervation of the cerebellum interacts with cerebral serotonergic systems and plays an inhibitory role in the harmaline-induced tremor

Effect of obesity on toxicity in women treated with adjuvant chemotherapy for early-stage breast cancer: a systematic review

The purpose of this study is to provide more definite evidence regarding the role of dose modification of chemotherapy in obese women with breast cancer by systematically reviewing current literature regarding chemotherapy-induced toxicity rates in obese and non-obese women with early-stage breast cancer. A systematic search of Pubmed and EMBASE was conducted to identify original studies investigating chemotherapy-induced toxicity in obese women receiving adjuvant chemotherapy treatment for breast cancer. Ten studies were identified. We noted low rates of adjustment for confounders such as prophylactic hematopoietic growth factor use and empirical dose reductions. Seven studies found reduced toxicity in obese compared to non-obese women. Of four studies, where dose capping was precluded or statistically adjusted for, three found reduced toxicity in obese women. These outcomes include less febrile neutropenia (body mass index (BMI) >23.6; odds ratio (OR) 4.4; 95 % confidence interval (CI) 1.65-12.01), fewer hospital admissions (BMI >35; OR 0.61, 95 % CI 0.38-0.97), and fewer neutropenic events (BMI >25; OR 0.49; 95 % CI 0.37-0.66). Only a single study reported higher rates of toxicity in obese women, but this study had significant methodological issues. As a conclusion, we observed that obese patients tolerate chemotherapy better than lean patients. However, this may be confounded by poorly specified dose capping practices and the use of hematopoietic growth factors. Further research should focus on improved documentation of body size, of dose, and of use of growth factors, and analysis of how these affect recurrence rates, toxicity, and survival