DNA-based vaccination using Schistosoma japonicum (Asian blood-fluke) genes

We have examined the efficacy of nucleic acid vaccination in inducing immunity to the multicellular parasite, Schistosoma japonicum, a trematode worm responsible for causing schistosomiasis in humans and other mammalian species. A panel of Schistosoma japonicum cDNAs were cloned into eukaryotic expression vectors, injected into animals, and tested for immunogenicity. The cDNAs tested encoded 26- and 28-kDa glutathione-S-transferases, calreticulin, glyceraldehyde-3-phosphate dehydrogenase, a 22.6 kDa membrane-associated antigen, a 14 kDa fatty-acid binding protein, fragments of paramyosin, full-length paramyosin, and a novel gene comprising the 26 kDa glutathione-S-transferase fused to a fragment of paramyosin cDNA. The paramyosin gene constructs, including the fusion, were all able to induce anti-paramyosin antibodies; with the fragments of paramyosin these were of the IgG1, IgG2a and IgG2b isotypes. In contrast, none of the other schistosome cDNAs tested were able to induce detectable antibody responses. The anti-paramyosin antibodies did not protect mice challenged with cercariae of S. japonicum.     

Sphaerechinorhynchus ophiograndis n. sp. (Acanthocephala:Plagiorhynchidae:Sphaerechinorhynchinae), described from the intestine of a king cobra, Ophiophagus hannah

BACKGROUND/AIMS: The mechanism of action of recombinant interferon-alpha (rIFN alpha) treatment in chronic hepatitis C is not fully understood, and may include modulation of the immune system as well as a direct antiviral effect. We have therefore evaluated the plasma concentrations of pro- and anti-inflammatory cytokines in patients with chronic hepatitis C before and during treatment with rIFN alpha. METHODS: Twenty-three patients were studied. Plasma concentrations of IL-1 beta, IL-6, TNF, IL-1 receptor antagonist (IL-1RA) and soluble TNF receptors (sTNFRs) type I and type II were determined twice before rIFN alpha treatment (on day -11 and day 1), and on days 11, 32 and 120 of treatment. RESULTS: IL-1 beta, IL-6 and TNF plasma concentrations were rarely increased before treatment (in one, six and seven patients, respectively), and usually declined during treatment. sTNFRs I and II plasma concentrations were not increased either before or during treatment. This was not the case for IL-1RA. In untreated patients, the plasma concentration of IL-1RA was higher than normal in 16 out of 23 patients. When rIFN alpha treatment was initiated, there was a constant and dramatic increase in IL-1RA levels, which reached 8 times the upper limit of the normal range (p < 0.001 as compared to pretreatment values). This increase was sustained up to day 120. CONCLUSIONS: These results indicate that induction of an anti-inflammatory status through modulation of the IL-1/IL-1RA balance may be a key mechanism of action of rIFN alpha treatment in chronic hepatitis C.     

Uncertainty analysis for wheelchair propulsion dynamics

Nefiracetam is undergoing preclinical and clinical tests as a cognition-enhancing drug in Alzheimer's disease (AD). Nicotinic cholinergic receptors are lost in AD, and nicotinic as well as muscarinic cholinergic receptors are involved in the modulation of eyeblink conditioning. Experiments were carried out using young rabbits to examine the effect of nefiracetam on cholinergic antagonists to nicotinic (mecamylamine) and muscarinic (scopolamine) receptors. Rabbits were tested for 15 days in the 750 ms delay eyeblink classical conditioning paradigm in paired and explicitly unpaired conditions. Nefiracetam at a dose of 15 mg/kg significantly ameliorated the effects of 0.5 mg/kg mecamylamine, and nefiracetam at a dose of 10 mg/kg significantly ameliorated the effect of 1.5 mg/kg scopolamine. The vehicle alone and nefiracetam alone groups performed similarly to the groups treated with mecamylamine or scopolamine and nefiracetam. Reversal by nefiracetam of a nicotinic as well as a muscarinic cholinergic antagonist indicates that the drug may affect deficits specific to AD.     

Somatization in cross-cultural perspective: a World Health Organization study in primary care

OBJECTIVE: The purpose of this study was to examine the phenomenon of somatization in different cultures by determining its frequency and correlates in primary care settings in 14 countries. METHOD: Consecutive primary care patients (N = 25,916) were screened with the 12-item General Health questionnaire, and a stratified sample (N = 5,438) was interviewed with the Composite International Diagnostic Interview. Interviewed patients were also assessed for physical disease burden, self-rated overall health, physician-rated physical health status, number of disability days, and interviewer-rated occupational role functioning. The authors determined center-specific associations with the use of logistic regression analyses in which confounding variables were controlled. RESULTS: ICD-10 defined somatization disorder was relatively uncommon in most primary care settings. A less restrictively defined form was more common. Symptom rates were much higher in South American sites. There was a modest association with low education. Otherwise, frequency of unexplained somatic symptoms did not clearly vary according to geography or level of economic development. Somatizing patients were at elevated risk for self-reported disease burden, negative perception of their health, and comorbid depression and generalized anxiety disorder. Somatization was also commonly associated with disability. Cultures did not differ markedly in the pattern of these associated features. CONCLUSION: Somatization is a common problem in primary care across cultures and is associated with significant problems and disability.     

Direct demonstration of retroviral recombination in a rhesus monkey

Recombination may be an important mechanism for increasing variation in retroviral populations. Retroviral recombination has been demonstrated in tissue culture systems by artificially creating doubly infected cells. Evidence for retroviral recombination in vivo is indirect and is based principally on the identification of apparently mosaic human immunodeficiency virus type 1 genomes from phylogenetic analyses of viral sequences. We infected a rhesus monkey with two different molecularly cloned strains of simian immunodeficiency virus. One strain of virus had a deletion in vpx and vpr, and the other strain had a deletion in nef. Each strain on its own induced low virus loads and was nonpathogenic in rhesus monkeys. When injected simultaneously into separate legs of the same monkey, persistent high virus loads and declines in CD4+ lymphocyte concentrations were observed. Analysis of proviral DNA isolated directly from peripheral blood mononuclear cells showed that full-length, nondeleted SIVmac239 predominated by 2 weeks after infection. These results provide direct experimental evidence for genetic recombination between two different retroviral strains in an infected host. The results illustrate the ease and rapidity with which recombination can occur in an infected animal and the selection that can occur for variants generated by genetic recombination.     

Routine carotid endarterectomy without a shunt, even in the presence of a contralateral occlusion

A 10-year prospective experience with routine non-shunting, even in the presence of a contralateral internal carotid artery occlusion, is reviewed. METHOD AND RESULTS: Carotid endarterectomy was performed without a shunt in 654 consecutive patients: group 1, 513 patients with contralateral stenosis of less than 79%: group 11, 74 patients with a greater than 80% contralateral stenosis; and group 111, 67 patients with a contralateral occlusion. Average cross-clamp time was 23 min. Neurological complications occurred within 30 days in 20 (3.0%) patients (10 strokes, seven transient ischemic attacks in group I, one transient ischemic attack in group II, and one stroke and one transient ischemic attack in group III). Immediate postoperative strokes, i.e. those five cases that could be implicated as caused by lack of a shunt, were rare (0.76%). There were five perioperative deaths (0.76%). CONCLUSION: Carotid endarterectomy may be performed safely without a shunt even in the presence of a contralateral occlusion. Age, sex, preoperative indication, anesthetic agent and contralateral stenosis were not associated with an increased risk of postoperative neurological deficit.     

c-Met autocrine activation induces development of malignant melanoma and acquisition of the metastatic phenotype

The molecular and genetic events that contribute to the genesis and progression of cutaneous malignant melanoma, a complex and aggressive disease with a high propensity for metastasis, are poorly understood due in large part to the dearth of relevant experimental animal models. Here we used transgenic mice ectopically expressing hepatocyte growth factor/scatter factor (HGF/SF) to show that the Met signaling pathway is an important in vivo regulator of melanocyte function, whose subversion induces malignant melanoma. Tumorigenesis occurred in stages, beginning with the abnormal accumulation of melanocytes in the epidermis and dermis and culminating in the development of metastatic melanoma. Oncogenesis in this model was driven by creation of HGF/SF-Met autocrine loops through forced expression of the transgenic ligand and apparent selection of melanocytes overexpressing endogenous receptor, rather than paracrine stimulation or mutational activation of c-met. Preference for liver as a metastatic target correlated with high HGF/SF-Met autocrine activity, consistent with the notion that such activity may influence colonization. Although basic fibroblast growth factor and its receptor were both weakly expressed in the majority of melanomas examined, high levels were found only in those rare neoplasms with low or undetectable HGF/SF and Met expression, suggesting that these two tyrosine kinase receptor autocrine loops serve a critical overlapping function in melanocytic tumorigenesis. Our data support a causal role for HGF/SF-Met signaling in the development of melanoma and acquisition of the metastatic phenotype. Moreover, this transgenic mouse should serve as a highly useful model, facilitating our understanding of mechanisms by which human melanoma progresses to malignancy and expediting the development of efficacious therapeutic modalities designed to constrain metastasis.     

Nobel Prize of Medicine 1997 awarded for prion theory

The Nobel Prize 1997 for Medicine and Physiology was awarded to S.B. Prusiner, who proposed the prion hypothesis. Prions are small 'proteinaceous infectious particles' that lack nucleic acids and hence genetic information. Prions are normal host encoded proteins but with an abnormal tertiary structure, which makes them extremely resistant to chemical and physical inactivation that would modify nucleic acids. They 'replicate' by forcing their conformation upon the normal prion proteins. Recently it was demonstrated that the prion disease, bovine spongiform encephalopathy (BSE) can be transmitted to man in whom it causes a new variant of Creutzfeldt-Jakob disease.     

Fibronectin type III repeats mediate RGD-independent adhesion and signaling through activated beta1 integrins

Many cell-surface and extracellular matrix proteins contain multiple modular domains known as fibronectin type III (FNIII) repeats. Cells adhere to the extracellular matrix proteins fibronectin and tenascin in part by the interaction of certain integrins with the Arg-Gly-Asp (RGD) sequence, displayed on specific FNIII repeats. We have found that, after experimental activation of beta1 integrins, a number of cell types adhere and spread on FNIII repeats lacking RGD, derived from extracellular matrix proteins and cytokine receptors. Interaction between individual FNIII domains and beta1 integrins mediates focal adhesion kinase phosphorylation and subsequent stress fiber and focal contact formation. These data suggest that many FNIII-containing proteins may bind and signal through activated beta1 integrins, dramatically expanding the potential for integrin-dependent intercellular and cell-matrix communication.