AIDS-related Kaposi's Sarcoma: evaluation of potential new prognostic factors and assessment of the AIDS Clinical Trial Group Staging System in the Haart Era--the Italian Cooperative Group on AIDS and Tumors and the Italian Cohort of Patients Naive From Antiretrovirals.

PURPOSE: To assess potential new prognostic factors and to validate the AIDS Clinical Trials Group (ACTG) for AIDS-related Kaposi's sarcoma (AIDS-KS) staging system in the highly active antiretroviral therapy (HAART) era. PATIENTS AND METHODS: We collected epidemiologic, clinical, staging, and survival data from 211 patients with AIDS-KS enrolled in two prospective Italian human immunodeficiency virus (HIV) cohort studies. We included in the analysis all patients with the diagnosis of KS made from January 1996, the time at which HAART became available in Italy. RESULTS: In the univariate analysis, survival was not influenced by sex, age, level of HIV viremia at KS diagnosis, HAART at KS diagnosis (HAART-na?ve v HAART-experienced), or type of HAART combination. Regarding ACTG classification, the 3-year survival rate was 85% for T0 patients and 69% for T1 patients (P =.007), 83% for S0 patients and 63% for S1 patients (P =.003), and 83% for I0 patients and 71% for I1 patients (P =.06). In the multivariate analysis, only the combination of poor tumor stage (T1) and poor systemic disease (S1) risk identified patients with unfavorable prognosis. The 3-year survival rate of patients with T1S1 was 53%, which was significantly lower compared with the 3-year survival rates of patients with T0S0, T1S0, and T0S1, which were 88%, 80%, and 81%, respectively (P =.0001). CONCLUSION: In the era of HAART, a refinement of the original ACTG staging system is needed. CD4 level does not seem to provide prognostic information. Two different risk categories are identified: a good risk (T0S0, T1S0, T0S1) and a poor risk (T1S1).     

Solitary meningeal recurrence in a patient with transitional cell carcinoma of the bladder with locally bulky disease at presentation

Patients with locally advanced transitional cell carcinoma (TCC)of the bladder are at high risk forsystemic relapse, with liver, bone and lung beingthe commonest sites of metastases.We report the case of a 52-year-old womanwith a solitary meningeal relapse, a rare siteof recurrence, after 8 months of complete remissionobtained with M-VEC for locally advanced TCC ofthe bladder. We speculate on the likely riskfactors related to this unusual site of recurrence.     

Nicotine reorganizes cytoskeleton of vascular endothelial cell through platelet-derived growth factor BB

BACKGROUND: Cigarette smoking has been directly linked to atherosclerosis formation and vascular graft failures but the role of nicotine in these processes is not yet completely understood. We investigated the release of platelet-derived growth factor BB (PDGF BB) by the bovine aortic endothelial cell (EC) after nicotine administration at concentrations similar to those found in plasma of active and passive smokers and the role of PDGF BB, autocrinally released, in EC cytoskeletal modification. METHODS: EC were stimulated in a serum-free medium for 72 h with (-)-nicotine (from 6 x 10(-4) to 6 x 10(-8) M). The release of PDGF BB was assessed by inhibition antibody-binding assay and confirmed by Western blotting. Mitogenic activity of nicotine on EC was also determined. The EC cytoskeleton was studied with specific antibodies anti-alpha-actin fibers and anti-vimentin and the modification induced by PDGF BB was assessed by blocking PDGF BB activity with specific antibodies. RESULTS: The greatest PDGF BB release was noted at a (-)-nicotine concentration of 6 x 10(-6) M (P < 0.001). The addition of antibody anti-PDGF BB to EC exposed to (-)-nicotine decreased tritiated thymidine uptake by 20% (P < 0.001). EC exposed to (-)-nicotine concentrations of 6 x 10(-6) and 6 x 10(-8) M had a significant alteration in the expression of alpha-actin fibers and vimentin as compared with control. Administration of the antibody anti-PDGF BB in the culture medium reversed cytoskeletal alteration. CONCLUSIONS: Nicotine enhanced the release of PDGF BB by EC which in turn caused an alteration in cytoskeletal organization.     

Painless fractures and thermoregulation disturbances in sensory-autonomic neuropathy: electrophysiological abnormalities and sural nerve biopsy

We describe the case of a young girl suffering from thermoregulation disturbances, painless fractures and arthropathy since early childhood. The patient was diagnosed as having a hereditary sensory autonomic neuropathy. Although needle EMG, conventional nerve conduction studies and somatosensory evoked potentials gave normal results, sympathetic skin responses (SSRs) were absent. Sural nerve biopsy showed a substantial reduction in the number of small myelinated and unmyelinated fibers. We emphasize the importance of SSR testing in revealing a condition which is otherwise difficult to identify by electrophysiological techniques. The combined evidence of functional and morphological findings is strongly suggestive of selective peripheral nerve involvement.     

Autoimmune progesterone dermatitis.

Autoimmune progesterone dermatitis (APD) is a rare disorder characterized by recurrent polymorphous skin manifestations, which appear or are exacerbated during the luteal phase of the menstrual cycle. The hallmarks for diagnosis include premenstrual flare, its prevention with the inhibition of ovulation, and positive skin reaction to intradermal injection of progesterone. The mainstay of treatment is to inhibit the secretion of endogenous progesterone by suppressing ovulation. Bilateral oophorectomy may be necessary in patients with severe and refractory symptoms. We report herein the case of a 38-year-old woman who developed recurrent and cyclic vesiculobullous eruptions clinically suggestive of erythema multiforme or autoimmune bullous diseases. The skin manifestations turned out to be APD. The patient was treated with tamoxifen 20 mg daily with complete symptom remission after 4 months.     

Cloning and distribution of the rat parkin mRNA

We have isolated by RT-PCR and sequenced a partial cDNA coding for the rat homolog of parkin, a gene mutated in autosomal recessive juvenile parkinsonism. The 1.46 kb rat cDNA clone contains a 1376 bp coding sequence that shares strong similarity with the human parkin cDNA. RT-PCR and in situ hybridization revealed widespread expression of parkin in the rat brain and the periphery. The availability of the rat parkin cDNA and the initial elucidation of its distribution should facilitate further research on the pathophysiological role of parkin in the nervous system.     

Nicotine-induced smooth muscle cell proliferation is mediated through bFGF and TGF-beta 1

BACKGROUND: Cigarette smoking influences and enhances the development of atherosclerosis. We investigated if nicotine, an important constituent of cigarette smoking, has a stimulatory effect on bovine smooth muscle cell proliferation in vitro through the mediation of bFGF and TGF-beta 1. METHODS: Bovine aortic smooth muscle cells (SMC) were stimulated with (-)-nicotine at various concentrations ranging from 6 x 10(-4) mol/L to 6 x 10(-8) mol/L. SMC viability and count were assessed. The presence of bFGF and TGF-beta 1 in serum-free conditioned media was determined by the inhibition antibody-binding assay, and the mitogenic activity of (-)-nicotine on SMC was analyzed by the 3H-thymidine uptake. Polymerase chain reaction was used to study the expression of bFGF and TGF-beta 1. RESULTS: The bFGF release after (-)-nicotine stimulation was greater than in the controls, whereas TGF-beta 1 release was lower. The greatest mitogenic activity was found at a (-)-nicotine concentration of 6 x 10(-6) mol/L. The addition of monoclonal antibody anti-bFGF decreased the 3H-thymidine uptake of SMC exposed to (-)-nicotine, whereas the addition of monoclonal antibody anti-TGF-beta 1 increased the 3H-thymidine uptake of stimulated SMC. bFGF mRNA expression was significantly higher in SMC exposed to (-)-nicotine than in the controls, but TGF-beta 1 mRNA expression was significantly lower in SMC exposed to 6 x 10(-6) mol/L (-)-nicotine than in SMC treated with the other concentrations of (-)-nicotine and in controls. CONCLUSIONS: Nicotine is a potent regulator of bFGF and TGF-beta 1 production and release by aortic SMC, and it seems to play an important role in the development and progression of atherosclerosis and neointimal fibrous hyperplasia.     

Proline-rich tyrosine kinase Pyk2 regulates deep vein thrombosis

Deep vein thrombosis results from the cooperative action of leukocytes, platelets, and endothelial cells. The proline-rich tyrosine kinase Pyk2 regulates platelet activation and supports arterial thrombosis. In this study, we combined pharmacological and genetic approaches to unravel the role of Pyk2 in venous thrombosis. We found that mice lacking Pyk2 almost completely failed to develop deep venous thrombi upon partial ligation of the inferior vena cava. Pyk2-deficient platelets displayed impaired exposure of phosphatidylserine and tissue factor expression by endothelial cells and monocytes was completely prevented by inhibition of Pyk2. In human umbilical vein endothelial cells (HUVEC), inhibition of Pyk2 hampered IL-1β-induced expression of VCAM and P-selectin, and von Willebrand factor release. Pyk2-deficient platelets showed defective adhesion on von Willebrand factor and reduced ability to bind activated HUVEC under flow. Moreover, inhibition of Pyk2 in HUVEC strongly reduced platelet adhesion. Similarly, Pyk2-deficient neutrophils were unable to efficiently roll and adhere to immobilized endothelial cells under venous flow conditions. Moreover, platelets and neutrophils from Pyk2-knockout mice showed defective ability to form heterogeneous aggregates upon stimulation, while platelet monocyte interaction occurred normally. Consequently, platelet neutrophil aggregates, abundant in blood of wild-type mice upon inferior vena cava ligation, were virtually undetectable in Pyk2-knockout mice. Finally, we found that expression of Pyk2 was required for NETosis induced by activated platelets. Altogether our results demonstrate a critical role of Pyk2 in the regulation of the coordinated thromboinflammatory responses of endothelial cells, leukocytes and platelets leading to venous thrombosis. Pyk2 may represent a novel promising target in the treatment of deep vein thrombosis.     

Transplacental passage of Pt after treatment with the new triamine complex cis-diaminechloro-[2-(diethylamino) ethyl 4-amino-benzoate,N<Superscript>4</Superscript>]-chloride platinum (II) monohydrochloride monohydrate

Cis-diaminechloro-[2-(diethylamino) ethyl 4-amino-benzoate, N⁴]-chloride platinum (II) monohydrochloride monohydrate (DPR) is a monofunctional Pt triamine complex synthesized starting from cisplatin and procaine hydrochloride, characterized by a good antitumor activity coupled with low toxic effects and able to impair prenatal development of mice but at doses outside or just in the upper range of therapeutic doses. In the present paper the transplacental passage of DPR-derived Pt was investigated in CD1 mice on days 9, 13, 16 and 18 of pregnancy, 24 h after ip administration of 21 mg/kg DPR. For comparison, groups of mice were treated with an equivalent Pt-containing dose of cisplatin (10.7 mg/kg). Similarly to cisplatin, small amounts of Pt were detected in fetuses on day 9. From day 13 of gestation the concentration of DPR- and cisplatin-derived Pt increased up to the highest fetal concentrations detected on day 16. On day 18 the concentration of Pt decreased. Most importantly, on days 13–18 of pregnancy cisplatin-derived Pt was always significantly higher than that assayed after DPR administration. In addition, on day 13 of pregnancy Pt exposure of fetuses was significantly higher when dams were treated with cisplatin (AUC_0.5–24= 3.40 vs. 4.95 g·h/g). Finally, it is worth noting that serum decay of Pt after DPR or cisplatin administration in adult female mice was similar with AUC_0.13–2h s of 7.5 and 6.6 g·h/ml, respectively. When we determined the concentration of Pt into the main organs of fetuses from dams treated with either DPR or cisplatin on day 18 of gestation, we observed a different organ distribution. In fact, while the concentration of DPR-derived Pt was greater in the heart (1.08±0.30 vs. 0.78±0.35 g/g, p <0.10), an opposite situation was found in the kidney (0.51±0.20 vs. 0.69±0.22 g/g, p <0.05). In conclusion, our data show that DPR may pass through the placenta with an efficiency significantly lower than that of cisplatin. This finding may represent one of the possible causes of the lower embryotoxic/teratogenic effect of DPR as compared to cisplatin.     

Risk to human health associated with the environmental occurrence of cyanobacterial neurotoxic alkaloids anatoxins and saxitoxins

Cyanobacteria are ubiquitous photosynthetic micro-organisms forming blooms and scums in surface water; among them some species can produce cyanotoxins giving rise to some concern for human health and animal life. To date, more than 65 cyanobacterial neurotoxins have been described, of which the most studied are the groups of anatoxins and saxitoxins (STXs), comprising many different variants. In freshwaters, the hepatotoxic microcystins represent the most frequently detected cyanotoxin: on this basis, it could appear that neurotoxins are less relevant, but the low frequency of detection may partially reflect an a priori choice of target analytes, the low method sensitivity and the lack of certified standards. Cyanobacterial neurotoxins target cholinergic synapses or voltage-gated ion channels, blocking skeletal and respiratory muscles, thus leading to death by respiratory failure. This review reports and analyzes the available literature data on environmental occurrence of cyanobacterial neurotoxic alkaloids, namely anatoxins and STXs, their biosynthesis, toxicology and epidemiology, derivation of guidance values and action limits. These data are used as the basis to assess the risk posed to human health, identify critical exposure scenarios and highlight the major data gaps and research needs.