Antinociceptive analogs of orphanin FQ/nociceptin(1-11)

The presence of pairs of basic amino acids within the sequence of orphanin FQ/nociceptin (OFQ/N) peptide, the endogenous ligand for the ORL1/KOR-3 receptor, has raised the possibility that processing might generate pharmacologically important truncated peptides, including OFQ/N(1-11). OFQ/N(1-11) is pharmacologically active in vivo with a potency comparable to OFQ/N. Several tyrosine-containing analogs of OFQ/N(1-11) have been synthesized and examined for antinociceptive activity. Like OFQ/N(1-11), [Tyr1]OFQ/N(1-11), [Tyr10]OFQ/N(1-11) and [IodoTyr10]OFQ/N(1-11) given supraspinally in mice were antinociceptive in the tailflick assay in mice. The tyrosine analogs showed similar potencies as OFQ/N(1-11) but longer durations of action. This response was readily reversed by the opioid antagonist naloxone despite poor affinities for these analogs at opioid receptors. Another compound, [Tyr11]OFQ/N(1-11) was highly epileptogenic, inducing naloxone-sensitive seizures in greater than 50% of the mice tested at doses comparable to those examined with the other analogs. These results indicate that it is possible to make analgesic OFQ/N(1-11) analogs. The activity of [IodoTyr10]OFQ/N(1-11) suggests that it may prove useful as a radioligand in exploring potential OFQ/N(1-11) binding sites.     

A prototype Internet autopsy database. 1625 consecutive fetal and neonatal autopsy facesheets spanning 20 years

OBJECTIVE: To demonstrate that cause-of-death statements can be generated by a computer algorithm from an autopsy database composed of diagnostic terms. DATA SOURCES: Over 49 000 autopsy facesheets contributed by over a dozen institutions were collected from a publicly accessible Internet autopsy database. This database is available at the following web site: http:@www.med.jhu.edu/pathology/iad.html STUDY SELECTION: To test the feasibility of creating and using a publicly available autopsy database, and to identify the technical and medicolegal problems that may arise with such a novel resource, a prototype study was designed by selecting autopsy facesheets from fetal and neonatal deaths. An algorithm was developed to determine the cause of death from the listing of anatomic diagnoses. DATA EXTRACTION: One thousand six hundred twenty-five fetal and neonatal autopsy facesheets were selected encompassing fetal and neonatal deaths occurring up to 28 days after birth. DATA SYNTHESIS: The algorithm determined causes of death from autopsy facesheet data in all cases. On review by an experienced pediatric pathologist, these automatically generated cause-of-death statements required no modification or only slight modification in over 90% of cases. CONCLUSIONS: A large multi-institutional autopsy database composed of demographic and diagnostic information has been deposited on the Internet. This information can be freely downloaded and used by any researcher without violating patient confidentiality. As a demonstration of one possible application of the database, fetal and neonatal autopsies generated cause-of-death statements using a computer algorithm. One can anticipate that the wealth of information contained in autopsy facesheets can be assembled into a database that will serve the public interest.     

Mutation frequency declines during spermatogenesis in young mice but increases in old mice

Five percent of live-born human offspring will have a genetic disorder. Of these, 20% are because of germ-line de novo mutations. Several genetic diseases, such as neurofibromatosis and Duchenne muscular dystrophy, are associated with a high percentage of de novo germ-line mutations. Until recently, a direct analysis of spontaneous mutation frequencies in mammalian germ cells has been prevented by technical limitations. We have measured spontaneous mutation frequencies in a lacI transgene by using enriched populations of specific spermatogenic cell types. Similar to previously published results, we observed a lower mutation frequency for seminiferous tubule cell preparations, which contain all stages of spermatogenesis, relative to somatic tissues. We made the unexpected observation of a decline in mutation frequency during spermatogenesis, such that the mutation frequencies of type B spermatogonia and all subsequent stages of spermatogenesis are lower than the frequency for primitive type A spermatogonia. In addition, spermatogenic cells from old mice have significantly increased mutation frequencies compared with spermatogenic cells from young or middle-aged mice. Finally, the mutation frequency was observed to increase during spermiogenesis in postreplicative cell types when spermatogenic cells were obtained from old mice.     

Metastatic papillary thyroid carcinoma presenting as a typical branchial cyst

Two cases of papillary thryoid carcinoma presenting as a cystic lateral neck mass are reported. This tumour characteristically presents in patients under 40-years-old and in the presence of an occult primary tumour may mimic a branchial cyst. In such cases simple aspiration of the cyst will produce a chocolate-brown serous fluid which excludes the diagnosis of a branchial cyst and is characteristic of papillary thyroid carcinoma. Cytological examination of the fluid has a high degree of sensitivity and specificity in the diagnosis of thyroid malignancy and should avoid delay in diagnosis and unnecessary surgical exploration prior to definitive treatment.     

The incidental nonhyperfunctioning adrenal mass: an imaging algorithm for characterization

Nonhyperfunctioning adrenal lesions such as cysts, myelolipomas, adrenal haemorrhage, adenoma and metastases are described. Definitive imaging features that help characterize adrenal cysts, myelolipomas and adrenal haemorrhage are illustrated and the differentiation of benign from malignant adrenal lesions using an algorithmic approach based on lipid sensitive imaging is provided.     

Visual marking of moving objects: a role for top-down feature-based inhibition in selection

Recently, the authors presented evidence that new items can be prioritized for selection by the top-down attentional inhibition of old stimuli already in the field (visual marking; D. G. Watson & G. W. Humphreys, 1997). In this article the authors assess whether this inhibition extends to moving old items and test an alternative account of visual marking. Six experiments showed that old moving items could be inhibited provided they did not undergo abrupt property changes. Further, and in contrast to effects with static stimuli, the marking of old moving stimuli was based on inhibition applied at the level of a whole feature map, rather than at their locations. The results also rule out an alternative account of visual marking based on the top-down weighting of dynamic or static processing pathways.     

Green tea polyphenols block endotoxin-induced tumor necrosis factor-production and lethality in a murine model

The effects of arginine on cell proliferation and subsequent T helper (Th) 1 and Th 2 cytokine synthesis by murine Peyer's patch (PP) Th cells in vitro and the influence of arginine on the induction of antigen-specific mucosal and systemic immune responses in vivo were examined. When the PP T cells were stimulated with the anti-alpha beta T cell receptor (TCR) antibody in the presence of different concentrations of arginine, a higher proliferative response was observed in the culture with an optimal concentration of arginine compared with that with a minimum amount of this amino acid. The concentration of cytokines in the supernatant, the number of cytokine-producing cells and the cytokine-specific mRNA expression of PP T cells were also increased in a dose-dependent fashion. Furthermore, when mice fed on an arginine-supplemented liquid diet were orally immunized with tetanus toxoid plus cholera toxin as a mucosal adjuvant, a higher level of antigen-specific fecal IgA was observed when compared with the response in mice fed on an arginine-free diet. Taken together, these results suggest that arginine enhanced antigen-specific mucosal immune response resulting from the supporting activation of cell proliferation and subsequent cytokine synthesis of PP Th cells.     

Increased MPTP neurotoxicity in vesicular monoamine transporter 2 heterozygote knockout mice

The neurotoxic action of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) has been proposed to be attenuated by sequestration into intracellular vesicles by the vesicular monoamine transporter (VMAT2). The purpose of this study was to determine if mice with genetically reduced levels of VMAT2 (heterozygote knockout; VMAT2 +/-) were more vulnerable to MPTP. Striatal dopamine (DA) content, the levels of DA transporter (DAT) protein, and the expression of glial fibrillary acidic protein (GFAP) mRNA, a marker of gliosis, were assessed as markers of MPTP neurotoxicity. In all parameters measured VMAT2 +/- mice were more sensitive than their wild-type littermates (VMAT2 +/+). Administration of MPTP (7.5, 15, or 30 mg/kg, b.i.d.) resulted in dose-dependent reductions in striatal DA levels in both VMAT2 +/- and VMAT2 +/+ animals, but the neurotoxic potency of MPTP was approximately doubled in the VMAT2 +/- mice: 59 versus 23% DA loss 7 days after 7.5 mg/kg dose for VMAT2 +/- and VMAT2 +/+ mice, respectively. Dopaminergic nerve terminal integrity, as assessed by DAT protein expression, also revealed more drastic reductions in the VMAT2 +/- mice: 59 versus 35% loss at 7.5 mg/kg and 95 versus 58% loss at 15 mg/kg for VMAT2 +/- and VMAT2 +/+ mice, respectively. Expression of GFAP mRNA 2 days after MPTP was higher in the VMAT2 +/- mice than in the wild-type: 15.8- versus 7.8-fold increase at 7.5 mg/kg and 20.1- versus 9.6-fold at 15 mg/kg for VMAT2 +/- and VMAT2 +/+ mice, respectively. These observations clearly demonstrate that VMAT2 +/- mice are more susceptible to the neurotoxic effects of MPTP, suggesting that VMAT2-mediated sequestration of the neurotoxin into vesicles may play an important role in attenuating MPTP toxicity in vivo.