Cholinergic immunolesions by 192IgG-saporin--useful tool to simulate pathogenic aspects of Alzheimer's disease

Alzheimer's disease, the most common cause of senile dementia, is characterized by intracellular formation of neurofibrillary tangles, extracellular deposits of beta amyloid as well as cerebrovascular amyloid accumulation and a profound loss of cholinergic neurons within the nucleus basalis Meynert with alterations in cortical neurotransmitter receptor densities. The use of the cholinergic immunotoxin 192IgG-saporin allows for the first time study of the impact of cortical cholinergic deafferentation on cortical neurotransmission, learning, and memory without direct effects on other neuronal systems. This model also allows the elucidation of contributions of cholinergic mechanisms to the establishment of other pathological features of Alzheimer's disease. The findings discussed here demonstrate that cholinergic immunolesions by 192IgG-saporin induce highly specific, permanent cortical cholinergic hypoactivity and alterations in cortical neurotransmitter densities comparable to those described for Alzheimer's disease. The induced cortical cholinergic deficit also leads to cortical/hippocampal neurotrophin accumulation and reduced amyloid precursor protein (APP) secretion, possibly reflecting the lack of stimulation of postsynaptic M1/M3 muscarinic receptors coupled to protein kinase C. This immunolesion model should prove useful to test therapeutic strategies based on stimulation of cortical cholinergic neurotransmission or amelioration of pathogenic aspects of cholinergic degeneration in the basal forebrain. Application of the model to animal species that can develop beta-amyloid plaques could provide information about the contribution of cholinergic function to amyloidogenic APP processing.     

Effect of vitamin E and mannitol on renal calcium oxalate retention in experimental nephrolithiasis

STUDY OBJECTIVE: To assess the efficacy of laser laparoscopic photocoagulation of endometriomas (2-18 cm) in patients with pain, infertility, or a combination of the two. DESIGN: Retrospective review of all patients with endometriomas from June 1, 1983, to December 31, 1993. SETTING: Department of gynecology and obstetrics at a district general hospital and national training center in minimal access surgery. PATIENTS: One hundred sixty-five women with large endometriomas present at the time of laser laparoscopy. INTERVENTIONS: Carbon dioxide laser or potassium-titanyl-phosphate laser laparoscopic surgery. MEASUREMENTS AND MAIN RESULTS: Ninety (74%) of 122 patients reported improvement or resolution of pain; and 30 of 66 achieved a pregnancy, for a cumulative conception rate of 45%. CONCLUSION: Laser laparoscopy is a practical, safe, and effective technique for the management of large ovarian endometriomas.     

Erysipelothrix rhusiopathiae bacteremia after dog bite

A case of erysipeloid with bacteraemia caused by Erysipelothrix rhusiopathiae (ER) in a previously healthy 41-year old man is presented. The bacterium was probably introduced by the bite of a dog. He was treated successfully with penicillin V. The ER bacteraemia occurred without complications of endocarditis.     

Modulation characteristic of waveguide-type optical frequency combgenerator

We report the modulation characteristics of a waveguide-type optical frequency comb generator (WG-OFCG) with the advantages of compactness, high modulation index and low driving power. The characteristics of the optical frequency comb (OFC) generated when the modulation index exceeds 2π are discussed. The power of the modulation sidebands was measured by the optical heterodyne method with an external-cavity laser as a local oscillator. The dependence of the modulation index of the WG-OFCG on the modulation frequency up to 40 GHz was measured. The generation span of the OFC at the modulation frequency detuned from an integer multiple of the free spectral range (FSR) is discussed     

Polarization control in a vertical cavity surface emitting laser submitted to optical feedback

We study experimentally and theoretically two polarization effects in a vertical cavity surface emitting laser submitted to optical feedback. In a first experiment, we obtain flips between two linearly polarized laser modes up to a frequency of 50 MHz using an external cavity with a polarizer. In a second experiment, polarization self modulation is demonstrated up to a frequency of 2.6 GHz, using a quarter wave plate instead. Numerical calculations, based on a four levels model for the active medium, show a good agreement with the experiments.     

The crystal structure of HIV-1 Nef protein bound to the Fyn kinase SH3 domain suggests a role for this complex in altered T cell receptor signaling

BACKGROUND: Human immunodeficiency virus (HIV) Nef protein accelerates virulent progression of acquired immunodeficiency syndrome (AIDS) by its interaction with specific cellular proteins involved in signal transduction and host cell activation. Nef has been shown to bind specifically to a subset of the Src family of kinases. The structures of free Nef and Nef bound to Src homology region 3 (SH3) domain are important for the elucidation of how the affinity and specificity for the Src kinase family SH3 domains are achieved, and also for the development of potential drugs and vaccines against AIDS. RESULTS: We have determined the crystal structures of the conserved core of HIV-1 Nef protein alone and in complex with the wild-type SH3 domain of the p59fyn protein tyrosine kinase (Fyn), at 3.0 A resolution. Comparison of the bound and unbound Nef structures revealed that a proline-rich motif (Pro-x-x-Pro), which is implicated in SH3 binding, is partially disordered in the absence of the binding partner; this motif only fully adopts a left-handed polyproline type II helix conformation upon complex formation with the Fyn SH3 domain. In addition, the structures show how an arginine residue (Arg77) of Nef interacts with Asp 100 of the so-called RT loop within the Fyn SH3 domain, and triggers a hydrogen-bond rearrangement which allows the loop to adapt to complement the Nef surface. The Arg96 residue of the Fyn SH3 domain is specifically accommodated in the same hydrophobic pocket of Nef as the isoleucine residue of a previously described Fyn SH3 (Arg96-->lle) mutant that binds to Nef with higher affinity than the wild type. CONCLUSIONS: The three-dimensional structures support evidence that the Nef-Fyn complex forms in vivo and may have a crucial role in the T cell perturbating action of Nef by altering T cell receptor signaling. The structures of bound and unbound Nef reveal that the multivalency of SH3 binding may be achieved by a ligand induced flexibility in the RT loop. The structures suggest possible targets for the design of inhibitors which specifically block Nef-SH3 interactions.     

Cyclin D1 overexpression in malignant lymphomas

Cyclin D1, the regulatory subunit of certain protein kinases thought to advance the G1 phase of the cell cycle, is now established as a proto-oncogene, with evidence indicating that its derangement may contribute to the uncontrolled cell growth characteristic of tumors. The chromosomal translocation t(11;14)(q13:q32), involving rearrangement of the BCL-1 locus, is closely associated with human lymphoid neoplasia affecting mantle cell lymphomas (MCL). Recently, the putative BCL-1 proto-oncogene turned out to be none other than the cyclin D1 gene. Although the observed break points in the BCL-1 locus are not tightly clustered, its rearrangement has been documented in 40-70% of cases of mantle cell lymphoma, whereas it only rarely occurs in other B cell lymphomas. Of note, all of the known break points leave the cyclin D1 coding region structurally intact and result in increased protein expression, implying that this may provide a highly sensitive and specific marker for MCL. Recent studies demonstrated that immunohistochemical detection in paraffin-embedded material, using a monoclonal antibody, is very useful for routine diagnosis. Current knowledge of cyclin D1 overexpression in malignant lymphomas, with emphasis on its clinicopathologic significance, is reviewed.     

Rapid and selective depletion of CD4+ T lymphocytes and preferential loss of memory cells on interaction of mononuclear cells with HIV-1 glycoprotein-expressing cells

Apigenin is a plant flavonoid that has been shown to significantly inhibit ultraviolet-induced mouse skin tumorigenesis when applied topically and may be an alternative sunscreen agent for humans. A long-term goal of our laboratory is to elucidate the molecular mechanism or mechanism by which apigenin inhibits skin tumorigenesis. In a previous publication, we characterized the mechanism by which apigenin induced G2/M arrest in keratinocytes. More recent studies in our laboratory have provided evidence that apigenin can induce G1 arrest in addition to arresting cells at G2/M. Here we describe the mechanism of the apigenin-induced G1 arrest in human diploid fibroblasts (HDF). Treatment of asynchronous HDF for 24 h with 10-50 microM apigenin resulted in dose-dependent cell-cycle arrest at both the G0/G1 and G2/M phases as measured by flow cytometry. The G0/G1 arrest was more clearly defined by using HDF that were synchronized in G0 and then released from quiescence by replating at subconfluent densities in medium containing 10-70 microM apigenin. The cells were analyzed for cell-cycle progression or cyclin D1 expression 24 h later. A dose of apigenin as low as 10 microM reduced the percentage of cells in S phase by 20% compared with control cultures treated with solvent alone. Western blot analysis of apigenin-treated HDF indicated that cyclin D1 was expressed at higher levels than in untreated cells, which signifies that they were arrested in G1 phase rather than in a G0 quiescent state. The G1 arrest was further studied by cyclin-dependent kinase 2 (cdk2) immune complex-kinase assays of apigenin-treated asynchronous HDF, which demonstrated a dose-dependent inhibition of cdk2 by apigenin. Inhibition of cdk2 kinase activity in apigenin-treated cells was associated with the accumulation of the hypophosphorylated form of the retinoblastoma (Rb) protein as measured by western blot analysis. The cdk inhibitor p21/WAF1 was also induced in a dose-dependent manner, with a 22-fold induction of p21/WAF1 in 70 microM apigenin-treated cells. In conclusion, apigenin treatment produced a G1 cell-cycle arrest by inhibiting cdk2 kinase activity and the phosphorylation of Rb and inducing the cdk inhibitor p21/WAF1, all of which may mediate its chemopreventive activities in vivo. To our knowledge this is the first report of a chemopreventive agent inducing p21/WAF1, a known downstream effector of the p53 tumor suppressor protein.     

An experimental pilot study of tacalcitol activities during modulation of parakeratotic skin features

Establishing guidelines and experimental models preclinical and clinical evaluations of new agents for treatment, and/or prevention of human diseases has become a task of crucial importance. Psoriasis is such one disease holding great interest for dermatology owing to its high rate of incidence and complexity of treatment. However the absence of psoriatic lesions in animals and the inability to induce them, calls for experimental techniques both in vitro and in vivo. The purpose of this study was to evaluate experimentally the effects of tacalcitol on cell proliferation and differentiation process. Thereafter a human pilot study on psoriatic patients has been developed.