TWO NOVEL MUTATIONS IN PHENYLALANINE HYDROXYLASE GENE AND IN VITRO EXPRESSION ANALYSIS ON MUTATION ARG252GLN

INTRoDUCTIoNPhenylketonuria(PKU)isanautosomalrecessivediseasecausedbythedeficiencyofaliver-specificen-zyme,phenylalaninehydroxylase(PAH).Itisoneofthemostcommoninbornerrorsofmetabolismwithaprevalenceof1in17OOOnewbornChinese(l).Recent-ly,theuseofalternativemolecularapproachesforstudy-ingPKUpatientsfromvariousethnicgroupsworldwidehasrevealedatleast14OdifferentpointmutationsinthehumanPAHgene(2,3),andmorethanl3mutationshavebeenreportedinChinesepopulations(4～9)'Tofurtherinvestigatethemol…     

Antipsychotics: Past and Future: National Institute of Mental Health Division of Services and Intervention Research Workshop, July 14, 1998.

A workshop on "Antipsychotics: Past and Future" was convened by the National Institute of Mental Health (NIMH), Division of Services and Intervention Research (DSIR), on July 14, 1998, to review the results of recent antipsychotic drug research, discuss current standards of treatment, and identify areas needing further study. There has been a proliferation of new antipsychotic medications and a rapid increase in their clinical utilization. The new atypicals are beginning to supplant the older typical neuroleptic antipsychotics, and the scientific and ethical issues raised by this transition prompted the workshop. Given the apparent, albeit not fully defined, advantages of atypical drugs, particularly their safety profiles, the question is whether more comparisons with typical antipsychotics are warranted and whether clinical trial designs warrant (or would be justified in) the inclusion of typical drugs as standard active comparators. Workshop participants--including clinical researchers, patient advocates, bioethicists, and NIMH staff--discussed the conclusions drawn from current data, ethical issues for subjects in clinical trials, funding for ongoing studies using typical agents, and appropriate comparators for trials using atypical agents.     

Radiofrequency Ablation of Hepatic Metastases: Factors Influencing Local Tumor Progression

Background

Although radiofrequency ablation (RFA) of nonresectable hepatic metastases has gained wide acceptance by showing survival benefit in selected patients, scattered reports are available regarding risk factors of local control of percutaneous RFA. The purpose of this study was to prospectively evaluate the factors influencing local tumor progression after percutaneous RFA of hepatic metastases.

Methods

Sixty-nine hepatic metastatic lesions in 54 patients were treated by percutaneous RFA. Efficacy was evaluated by contrast-enhanced computed tomography or magnetic resonance imaging at 1 month after ablation, then at 3-month intervals for the first year and biannually thereafter.

Results

The results of the log-rank test showed that tumor size of <3 cm (p = 0.024) and the absence of tumor contiguous with large vessels (p = 0.002) significantly correlated with local control for hepatic metastases. Cox regression analysis showed that the tumor size <3 cm and the absence of tumor contiguous with large vessels were independent factors (p = 0.055 and 0.009, respectively). The results of the log-rank test showed that neither the threshold post-ablation margin of 1.8 cm (p = 0.064) nor the presence of a tumor with subcapsular location (p = 0.134) correlated with the success of local control.

Conclusions

Percutaneous RFA is more effective in achieving local control in patients with hepatic metastases when the tumor size is <3 cm and not contiguous with large vessels.     

Efficiency Improvement of HIT Solar Cells on p-Type Si Wafers

Single crystal silicon solar cells are still predominant in the market due to the abundance of silicon on earth and their acceptable efficiency. Different solar-cell structures of single crystalline Si have been investigated to boost efficiency; the heterojunction with intrinsic thin layer (HIT) structure is currently the leading technology. The record efficiency values of state-of-the art HIT solar cells have always been based on n-type single-crystalline Si wafers. Improving the efficiency of cells based on p-type single-crystalline Si wafers could provide broader options for the development of HIT solar cells. In this study, we varied the thickness of intrinsic hydrogenated amorphous Si layer to improve the efficiency of HIT solar cells on p-type Si wafers.     

Melatonin impedes Tet1‐dependent mGluR5 promoter demethylation to relieve pain

Melatonin (N‐acetyl‐5‐methoxytryptamine)/MT2 receptor‐dependent epigenetic modification represents a novel pathway in the treatment of neuropathic pain. Because spinal ten‐eleven translocation methylcytosine dioxygenase 1 (Tet1)‐dependent epigenetic demethylation has recently been linked to pain hypersensitivity, we hypothesized that melatonin/MT2‐dependent analgesia involves spinal Tet1‐dependent demethylation. Here, we showed that spinal Tet1 gene transfer by intrathecal delivery of Tet1‐encoding vectors to naïve rats produced profound and long‐lasting nociceptive hypersensitivity. In addition, enhanced Tet1 expression, Tet1‐metabotropic glutamate receptor subtype 5 (mGluR5) promoter coupling, demethylation at the mGluR5 promoter, and mGluR5 expression in dorsal horn neurons were observed. Rats subjected to spinal nerve ligation and intraplantar complete Freund's adjuvant injection displayed tactile allodynia and behavioral hyperalgesia associated with similar changes in the dorsal horn. Notably, intrathecal melatonin injection reversed the protein expression, protein‐promoter coupling, promoter demethylation, and pain hypersensitivity induced by Tet1 gene transfer, spinal nerve ligation, and intraplantar complete Freund's adjuvant injection. All the effects caused by melatonin were blocked by pretreatment with a MT2 receptor‐selective antagonist. In conclusion, melatonin relieves pain by impeding Tet1‐dependent demethylation of mGluR5 in dorsal horn neurons through the MT2 receptor. Our findings link melatonin/MT2 signaling to Tet1‐dependent epigenetic demethylation of nociceptive genes for the first time and suggest melatonin as a promising therapy for the treatment of pain.