Citations

Abstract Decoy receptor 3 (DcR3), a soluble receptor belonging to the TNFR superfamily, is a receptor for both Fas ligand (FasL) and LIGHT. It has been demonstrated that DcR3 is up-regulated in lung and colon cancers, thus promoting tumor growth by neutralizing the cytotoxic effects of FasL and LIGHT. In this study, we found that DcR3.Fc profoundly modulated dendritic cell differentiation and maturation from CD14+ monocytes, including the up-regulation of CD86/B7.2, and the down-regulation of CD40, CD54/ICAM-1, CD80/B7.1, CD1a, and HLA-DR. Moreover, DcR3-treated dendritic cells suppressed CD4+ T cell proliferation in an allogeneic MLR and up-regulated IL-4 secretion of CD4+CD45RA+ T cells. This suggests that DcR3.Fc may act not only as a decoy receptor to FasL and LIGHT, but also as an effector molecule to skew T cell response to the Th2 phenotype.

Object Glomus tumors are rare skull base neoplasms that frequently involve critical cerebrovascular structures and lower cranial nerves. Complete resection is often difficult and may increase cranial nerve deficits. Stereotactic radiosurgery has gained an increasing role in the management of glomus tumors. The authors of this study examine the outcomes after radiosurgery in a large, multicenter patient population. Methods Under the auspices of the North American Gamma Knife Consortium, 8 Gamma Knife surgery centers that treat glomus tumors combined their outcome data retrospectively. One hundred thirty-four patient procedures were included in the study (134 procedures in 132 patients, with each procedure being analyzed separately). Prior resection was performed in 51 patients, and prior fractionated external beam radiotherapy was performed in 6 patients. The patients' median age at the time of radiosurgery was 59 years. Forty percent had pulsatile tinnitus at the time of radiosurgery. The median dose to the tumor margin was 15 Gy. The median duration of follow-up was 50.5 months (range 5–220 months). Results Overall tumor control was achieved in 93% of patients at last follow-up; actuarial tumor control was 88% at 5 years postradiosurgery. Absence of trigeminal nerve dysfunction at the time of radiosurgery (p = 0.001) and higher number of isocenters (p = 0.005) were statistically associated with tumor progression–free tumor survival. Patients demonstrating new or progressive cranial nerve deficits were also likely to demonstrate tumor progression (p = 0.002). Pulsatile tinnitus improved in 49% of patients who reported it at presentation. New or progressive cranial nerve deficits were noted in 15% of patients; improvement in preexisting cranial nerve deficits was observed in 11% of patients. No patient died as a result of tumor progression. Conclusions Gamma Knife surgery was a well-tolerated management strategy that provided a high rate of long-term glomus tumor control. Symptomatic tinnitus improved in almost one-half of the patients. Overall neurological status and cranial nerve function were preserved or improved in the vast majority of patients after radiosurgery.

Adenosine monophosphate–activated protein kinase (AMPK) is a major energy sensor that maintains cellular energy homeostasis. Huntington’s disease (HD) is a neurodegenerative disorder caused by the expansion of CAG repeats in the huntingtin (Htt) gene. In this paper, we report that activation of the α1 isoform of AMPK (AMPK-α1) occurred in striatal neurons of humans and mice with HD. Overactivation of AMPK in the striatum caused brain atrophy, facilitated neuronal loss, and increased formation of Htt aggregates in a transgenic mouse model (R6/2) of HD. Such nuclear accumulation of AMPK-α1 was activity dependent. Prevention of nuclear translocation or inactivation of AMPK-α1 ameliorated cell death and down-regulation of Bcl2 caused by mutant Htt (mHtt). Conversely, enhanced expression of Bcl2 protected striatal cells from the toxicity evoked by mHtt and AMPK overactivation. These data demonstrate that aberrant activation of AMPK-α1 in the nuclei of striatal cells represents a new toxic pathway induced by mHtt.

Background Hepatitis B virus (HBV) genotype B and C seem not to affect the therapeutic response to lamivudine (3TC). Whether a given genotype has an earlier emergence of 3TC resistance remains unclear. We thus conducted this study to elucidate the association of HBV genotype with the emergence of 3TC-resistant strains in Taiwanese patients. Methods Forty chronic hepatitis B patients who developed resistance after 3TC therapy were retrospectively enrolled. HBV genotype, serum alanine aminotransferase (ALT) and HBV DNA levels were determined at baseline. The presence of 3TC-resistant mutations was confirmed by direct sequencing whenever biochemical breakthrough developed. Results The distribution of HBV genotype B and C in 40 patients receiving 3TC therapy were 60% and 40%, respectively. The mean interval to detect 3TC- resistant strain was 19.6 ±1.7 months. By using multivariate analysis, HBV genotype B and higher pre-treatment HBV DNA level were independently associated with earlier detection of 3TC-resistant strains. In addition, genotype B was significantly associated with development of 3TC resistance within the first 12 months of 3TC therapy compared with genotype C (odds ratio 8.27; P=0.004). Conclusions Compared with HBV genotype C, genotype B appears to have an earlier biochemical resistance to 3TC than genotype C. Therefore, more frequent monitoring of viral load or genotypical resistance might be needed for patients with HBV genotype B infection receiving 3TC therapy, especially during the first year.

In 1991 the Clinical Trials Subcommittee of the International Headache Society (IHS) developed and published its first edition of the Guidelines on controlled trials of drugs in episodic migraine because only quality trials can form the basis for international collaboration on drug therapy, and these Guidelines would ‘improve the quality of controlled clinical trials in migraine’. With the current trend for large multinational trials, there is a need for increased awareness of methodological issues in clinical trials of drugs and other treatments for chronic migraine. These Guidelines are intended to assist in the design of well-controlled clinical trials of chronic migraine in adults, and do not apply to studies in children or adolescents.