RELATIONSHIP BETWEEN PLATELET CYTOSOLIC FREE CALCIUM CONCENTRATION AND PLASMA RENIN ACTIVITY

1. Plasma renin activity (PRA) and platelet cytosolic free calcium concentration ([Ca2+]i) were simultaneously determined in 18 untreated essential hypertensive subjects and 17 normotensive controls. A significant positive correlation was found between [Ca2+]i and PRA (slope = 42 nmol/l/ng/ml/h) in these 35 subjects. 2. Two determinations more than one week apart in nine subjects confirmed the parallel fluctuations of [Ca2+]i and PRA. A strict sodium restriction produced a progressive PRA elevation associated with a parallel rise in [Ca2+]i in one subject. 3. These results are consistent with the hypothesis that angiotensin II causes a concentration-dependent calcium mobilization.     

Variation at the ADAM10 gene locus is not associated with Creutzfeldt-Jakob disease

Prion diseases are characterized by the accumulation in the brain of a misfolded and protease-resistant form of the prion protein (PrP(c)). PrP(c) contains an amyloidogenic, neurotoxic sequence that is essential for conversion into PrP(Sc), the pathological isoform. During normal processing, PrP(c) is cleaved at a site within this sequence, and this cleavage is thought to destroy the amyloidogenic potential of the protein. ADAM10, a disintegrin and metalloprotease that plays a key role in the pathogenesis of Alzheimer's disease, was recently shown to use PrP(c) as a substrate. We investigated whether variability in the ADAM10 gene could contribute to the pathogenesis of Creutzfeldt-Jakob disease (CJD), by analyzing a single nucleotide polymorphism (SNP) within ADAM10, as a genetic marker potentially in linkage disequilibrium with a functional polymorphism, in patients with sporadic or variant CJD. We observed no significant differences in ADAM10 genotype or allele frequencies between CJD patients and healthy individuals. Moreover, the distribution of ADAM10 SNP genotypes and alleles did not differ between groups of patients based on genotype at the polymorphic codon 129 of the prion protein gene--the sole major genetic risk factor for CJD identified to date. Our data indicate that ADAM10 is unlikely to confer genetic susceptibility to CJD.     

Amniocentesis in pregnant HIV-infected patients. Absence of mother-to-child viral transmission in a series of selected patients

Objectives

To assess the risk of vertical transmission in HIV-infected pregnant women undergoing diagnostic amniocentesis, and to identify possible predictive factors.

Study design

This was a single center retrospective study. The records of 330 HIV-infected pregnant women booked in our antenatal clinic from 31 January 2001 to 31 January 2006 were analyzed. Women who actually underwent diagnostic amniocentesis (“amniocentesis performed” group) were compared to those eligible for amniocentesis but who did not undergo the procedure (“amniocentesis withheld” group).

Results

During the time period, 318 liveborn babies were delivered (9 HIV infected (2.8%)). Thirty-four women (35 fetuses) were eligible for diagnostic amniocentesis. Amniocentesis was performed in 11 (32.4%) of these women (12 fetuses, none infected among the 9 liveborns) and withheld in 23 (67.6%) women. Among the 19 liveborn babies in this latter group, 1 (5.3%) was infected. There was no statistical difference in vertical transmission rate between the whole cohort of HIV-infected pregnant women and the group of women eligible for amniocentesis; or between the women who actually had or did not have an amniocentesis.The women who did undergo amniocentesis all received highly active antiretroviral combination therapy with three drugs; all but two had an undetectable HIV viral load, only one had immunosuppression and none had HCV co-infection.

Conclusion

No vertical transmission was observed in a group of nine liveborn babies after amniocentesis performed in selected HIV-infected pregnant women. In the presence of high genetic risk during pregnancy, amniocentesis can be considered after proper patient counselling.     

Long-term pregabalin treatment protects basal cortices and delays the occurrence of spontaneous seizures in the lithium-pilocarpine model in the rat

PURPOSE: To determine whether a pharmacologic treatment could delay or prevent the epileptogenesis induced by status epilepticus (SE) through the protection of some brain areas, we studied the effects of the long-term exposure to pregabalin (PGB) on neuronal damage and epileptogenesis induced by lithium-pilocarpine SE. METHODS: SE was induced in adult and 21-day-old (P21) rats. At 20 min after pilocarpine, rats received 50 mg/kg PGB (pilo-preg) or saline (pilo-saline). PGB treatment was given daily at the dose of 50 mg/kg for 7 days after SE and at 10 mg/kg from day 8 until killing. Neuronal damage was assessed in hippocampus and piriform and entorhinal cortices in brain sections stained with thionine and obtained from adult and P21 animals killed 6 days after SE. The number of glial fibrillary acidic protein (GFAP)-reactive astrocytes was tested by immunohistochemistry in sections adjacent to those used for cell counting. The latency to spontaneous seizures was controlled by visual observation and EEG recording. RESULTS: PGB induced neuroprotection in layer II of piriform cortex and layers III-IV of ventral entorhinal cortex of adult rats, whereas no hippocampal region was protected. In P21 rats, damage was limited to the hilus and similar in pilo-preg and pilo-saline animals. The number of GFAP-positive astrocytes was higher in pilocarpine- than in saline-treated rats. It was decreased in pilo-preg compared with pilo-saline rats in layer II of the piriform cortex. Adult pilo-preg rats became epileptic after a longer latency (39 days) than did pilo-saline rats (22 days). CONCLUSIONS: These data underline the antiepileptogenic consequences of long-term PGB treatment, possibly mediated by the protection of piriform and entorhinal cortices in the lithium-pilocarpine model of epilepsy.     

Prognostic value of EGF receptor and tumor cell proliferation in bladder cancer: therapeutic implications

Changes in growth factor receptor expression may confer a growth advantage on tumour cells. Epidermal growth factor-receptor (EGF-R) has been associated with the genesis of bladder tumours. We sought a link between EGF-R expression and MIB-1 cell proliferation and examined their prognostic value in the progression of bladder cancer. Fresh frozen samples from 113 transitional cell carcinomas (TCC) of the bladder and 10 healthy bladders were studied by immunohistochemistry, using monoclonal antibodies for EGF-R expression and MIB-1 for cell proliferation. Qualitative and quantitative immunostaining were analyzed in relation to time to progression and compared with clinical and pathologic parameters for prognostic significance in univariate and multivariate analysis (stepwise logistic regression). EGF-R stained more intensively in invasive tumours. Median nuclear over-expression of MIB-1 was 28%. Progression free survival rate estimates (log rank test) were significantly lower in patients EGF-R positive and with MIB-1 score above 28% (P < 0.0001, P < 0.0001, respectively). Multivariate analysis indicated that MIB-1 immunostaining was the most significant independent variable and EGF-R expression had no additional prognostic value over clinical stage and grade and cell proliferation. The MIB-1 proliferation index is a stronger predictor of bladder tumour progression than is EGF-R over-expression. This marker yield significant prognostic information in addition to stage and grade and may be of value for the clinical management of superficial and invasive bladder carcinomas. The pattern of EGF-R immunostaining and its association with tumour progression makes it a candidate for antigrowth factor therapy.     

Sentinel lymph node biopsy in cervical and endometrial cancers: a feasibility study

The sentinel lymph node (SLN) biopsy has been proposed for the cancers of the uterus in order to optimize the diagnosis of lymphatic metastases and micrometastases in early stage tumors. Patients with early invasive cervical (n = 8) or endometrial (n = 15) cancers were enrolled. A lymphoscintigraphy was carried out before the intervention. Intraoperative SLN identification was performed with blue dye combined to a handheld gamma probe detection. Non-sentinel pelvic nodes were separately cleared out. SLNs were examined with frozen sections, permanent sections with hematoxylin-eosin staining and further serial sections with immunohistochemistry if negative. Six cervical cancer patients and 13 endometrial cancer patients had a positive lymphoscintigraphy, showing in 5 patients extra-iliac SLN(s). The intraoperative detection was successful in 6 cervical cancer patients and 14 endometrial cancer patients. The higher detection rate was obtained with the isotopic method. Most of the SLNs were ilio-obturator. Four endometrial cancer patients had a lymphatic spread, only involving the SLN in each case. No false negative SLN has been noted. SLN biopsy appears feasible in cervical and endometrial cancers. This procedure could improve the lymphatic evaluation of these cancers.     

Synthesis and structure-activity relationships of the first ferrocenyl-aryl-hydantoin derivatives of the nonsteroidal antiandrogen nilutamide

We present here the first synthesis of organometallic complexes derived from the nonsteroidal antiandrogen nilutamide, bearing a ferrocenyl substituent at position N(1) or at C(5) of the hydantoin ring; for comparison, we also describe the C(5) p-anisyl organic analogue. All of these complexes retain a modest affinity for the androgen receptor. The N-substituted complexes show a weak or moderate antiproliferative effect (IC 50 around 68 microM) on hormone-dependent and -independent prostate cancer cells, while the C(5)-substituted compounds exhibit toxicity levels 10 times higher (IC 50 around 5.4 microM). This strong antiproliferative effect is probably due to a structural effect linked to the aromatic character of the ferrocene rather than to its organometallic feature. In addition, it seems connected to a cytotoxic effect rather than an antihormonal one. These results open the way toward a new family of molecules that are active against both hormone-dependent and hormone-independent prostate cancer cells.     

Percutaneous cryoablation for advanced and refractory extra-abdominal desmoid tumors

International Journal of Clinical Oncology - To assess efficacy and safety of percutaneous cryoablation (CA) for advanced and refractory extra-abdominal desmoid tumors. This retrospective study...     

Natural paniceins from mediterranean sponge inhibit the multidrug resistance activity of Patched and increase chemotherapy efficiency on melanoma cells

Multidrug resistance has appeared to mitigate the efficiency of anticancer drugs and the possibility of successful cancer chemotherapy. The Hedgehog receptor Patched is a multidrug transporter expressed in several cancers and as such it represents a new target to circumvent chemotherapy resistance. We report herein that paniceins and especially panicein A hydroquinone, natural meroterpenoids produced by the Mediterranean sponge Haliclona (Soestella) mucosa, inhibit the doxorubicin efflux activity of Patched and enhance the cytotoxicity of this chemotherapeutic agent on melanoma cells in vitro. These results are supported by the molecular docking performed on the structure of the bacterial drug efflux pump AcrB and on the Patched model built from AcrB structure. Docking calculations show that panicein A hydroquinone interacts with AcrB and Patched model close to the doxorubicin binding site. This compound thus appears as the first antagonist of the doxorubicin efflux activity of Patched. The use of inhibitors of Patched drug efflux activity in combination with classical chemotherapy could represent a novel approach to reduce tumor drug resistance, recurrence and metastasis.