Serotonergic receptors in the brain of in utero undernourished rats

In this study, we report that 5-HT(1A) receptors are already present in fractions of axonal growth cones, from the normal rat fetal brain (E-17). Also, in utero undernourished (UN) rat pups at birth show a noteworthy enhancement in the B(max) of [3H]5-hydroxytryptamine (5-HT) and [3H]8-hydroxy-(2-N,N-dipropilamin)-tetralin (([3H])8-OH-DPAT), in the brainstem and cerebral cortex up to the second week after birth. Afterwards, there is a significant decrease in the binding of these ligands. [125I]Cyanopindolo binding in the cerebral cortex only showed a decrease in the same period. An elevation of brain serotonin in both regions was also present. These findings together, suggest that the mechanisms of regulation of serotonergic receptors' expression during the period studied, may not depend on the amount of neurotransmitter in the synaptic cleft, because in the early UN brain it would be expected only a lower receptor's density due to the chronic serotonin increase. On this basis, we propose that developmental activation of brain serotonin biosynthesis observed in early UN animals may disrupt the mechanism regulating the expression of 5-HT receptors during development.     

Pattern of deletions of the dystrophin gene in Mexican Duchenne/Becker muscular dystrophy patients: The use of new designed primers for the analysis of the major deletion “hot spot” region

We have analyzed 59 unrelated Mexican Duchenne/Becker muscular dystrophy patients (DMD/BMD) using PCR analysis of the 2 prone deletion regions in the DMD gene. Thirty one (52%) of the patients had a deletion of one or several of the exons. Most of the alterations (87%) were clustered in exons 44–52, this being the highest percentage reported until now. In order to improve the molecular diagnosis in the Mexican population, we designed a new multiplex assay to PCR amplify exons 44–52. This assay allowed for the identification of a greater number of deletions in this region compared with the 9 and 5-plex assays previously described and to determine most of the deletion end boundaries. This is a reliable alternative for the initial screening of the DMD patients in the Mexican population. Am. J. Med. Genet. 70:240–246, 1997. © 1997 Wiley-Liss, Inc.     

Helminth-induced arginase-1 exacerbates lung inflammation and disease severity in tuberculosis

Parasitic helminth worms, such as Schistosoma mansoni, are endemic in regions with a high prevalence of tuberculosis (TB) among the population. Human studies suggest that helminth coinfections contribute to increased TB susceptibility and increased rates of TB reactivation. Prevailing models suggest that T helper type 2 (Th2) responses induced by helminth infection impair Th1 immune responses and thereby limit Mycobacterium tuberculosis (Mtb) control. Using a pulmonary mouse model of Mtb infection, we demonstrated that S. mansoni coinfection or immunization with S. mansoni egg antigens can reversibly impair Mtb-specific T cell responses without affecting macrophage-mediated Mtb control. Instead, S. mansoni infection resulted in accumulation of high arginase-1–expressing macrophages in the lung, which formed type 2 granulomas and exacerbated inflammation in Mtb-infected mice. Treatment of coinfected animals with an antihelminthic improved Mtb-specific Th1 responses and reduced disease severity. In a genetically diverse mouse population infected with Mtb, enhanced arginase-1 activity was associated with increased lung inflammation. Moreover, in patients with pulmonary TB, lung damage correlated with increased serum activity of arginase-1, which was elevated in TB patients coinfected with helminths. Together, our data indicate that helminth coinfection induces arginase-1–expressing type 2 granulomas, thereby increasing inflammation and TB disease severity. These results also provide insight into the mechanisms by which helminth coinfections drive increased susceptibility, disease progression, and severity in TB.     

A pilot clinical study of short-term isoflavone supplements in breast cancer patients

Many laboratory-based studies have shown that soy can suppress breast cancer proliferation. However, given the recent controversy generated by animal experiments that soy may under certain conditions stimulate breast cancer growth, we decided to carry out a pilot clinical trial in order to elucidate any interaction(s) between short-term isoflavone supplement administration and breast cancer growth. After a core-needle biopsy established the diagnosis of breast cancer, 17 patients were administered soy isoflavone tablets for two weeks. This surgically based study provided the unique opportunity to make objective observations based on human breast cancer tissues and blood obtained prior to and after isoflavone supplement treatment in the same patient. Twenty-six historical control cases with similar characteristics to the experimental patients were selected for comparison. We observed that the apoptosis/mitosis ratios in isoflavone-treated cancer specimens were not significantly different from those of control untreated cancer specimens. Furthermore, there appeared to be a statistically nonsignificant trend towards cancer growth inhibition in the isoflavone treatment group, as manifested by higher apoptosis/mitosis ratios compared with those from the control untreated group. Ex vivo/in vitro assays using serum from breast cancer patients prior to and at the conclusion of soy treatment reveal no significant proliferative changes on both breast cancer cells and endothelial cells. We concluded that the effect of soy on breast cancer deserves further studies in larger clinical trials.     

cDNA microarray analysis of endothelial cells in response to green tea reveals a suppressive phenotype

Green tea may prevent cancer, partially by inhibiting tumor angiogenesis. Our previous studies showed that green tea extract was effective in inhibiting breast cancer and endothelial cell proliferation in vitro, and suppressed xenograft size and decreased the tumor vessel density in vivo. Here, we set out to further investigate the molecular mechanisms of this observed angiogenesis suppression. We utilized cDNA microarray technology to profile the global changes in endothelial cellular gene expression in response to green tea. HUVEC (human umbilical vein endothelial cells) were exposed in vitro to green tea for either 6 or 48 h. Only statistically significantly differentially expressed genes were analyzed. Gene profiling demonstrated a global down-regulation of multiple genes involved in endothelial cell growth, signal transduction and oxidation, accompanied by up-regulation of several apoptotic genes. We validated these observations by showing positive correlations with biological assays of cellular proliferation, cell cycle, and apoptosis. The anti-oxidant characteristics of green tea and its metabolites were confirmed in the ORAC (oxygen radical absorbance capacity) assay. cDNA microarray revealed that green tea has an overall suppressive effect on multiple pathways in endothelial cells. This study contributes to the comprehensive analysis of the molecular effects of green tea on endothelial cells, and provides insight into genes that may be important in chemoprevention.     

Improved prevention of moderately emetogenic chemotherapy-induced nausea and vomiting with palonosetron, a pharmacologically novel 5-HT3 receptor antagonist: results of a phase III, single-dose trial versus dolasetron

BACKGROUND: Palonosetron, a highly selective and potent 5-HT(3) receptor antagonist with a strong binding affinity and a long plasma elimination half-life (approximately 40 hours), has shown efficacy in Phase II trials in preventing chemotherapy-induced nausea and vomiting (CINV) resulting from highly emetogenic chemotherapy. The current Phase III trial evaluated the efficacy and safety of palonosetron in preventing acute and delayed CINV after moderately emetogenic chemotherapy. METHODS: In the current study, 592 patients were randomized to receive a single, intravenous dose of palonosetron 0.25 mg, palonosetron 0.75 mg, or dolasetron 100 mg, 30 minutes before receiving moderately emetogenic chemotherapy. The primary efficacy endpoint was the proportion of patients with a complete response (CR; defined as no emetic episodes and no rescue medication) during the first 24 hours after chemotherapy. Secondary endpoints included assessment of prevention of delayed emesis (2-5 days postchemotherapy). RESULTS: In the current study, 569 patients received study medication and were included in the intent-to-treat efficacy analyses. CR rates during the first 24 hours were 63.0% for palonosetron 0.25 mg, 57.1% for palonosetron 0.75 mg, and 52.9% for dolasetron 100 mg. CR rates during the delayed period (24-120 hours after chemotherapy) were superior for palonosetron compared with dolasetron. Adverse events (AEs) were mostly mild to moderate and not related to study medication, with similar incidences among groups. There were no serious drug-related AEs. CONCLUSIONS: A single dose of palonosetron is as effective as a single dose of dolasetron in preventing acute CINV and superior to dolasetron in preventing delayed CINV after moderately emetogenic chemotherapy, with a comparable safety profile for all treatment groups.