White matter lesions and the risk of incident hip fracture in older persons: results from the progetto veneto anziani study

BACKGROUND: White matter lesions (WMLs) are associated with hypertension, an increased risk of falling, and impaired physical and cognitive performance that may affect the mechanical effect of falls. METHODS: We hypothesized that WMLs are a risk factor for hip fracture (HF). We studied a sample of 820 community-dwelling Italian persons 65 years and older from the cohort of the Progetto Veneto Anziani Study who underwent brain magnetic resonance imaging at baseline. Subjects were classified as having no lesions, focal lesions, or diffuse WMLs. RESULTS: Compared with those with no lesions, participants with diffuse WMLs were older, reported more falls, and had worse physical and cognitive performance, all factors implicated in the causal pathway to HF. During 9 years of follow-up, 51 HFs occurred. Hip fracture risk associated with diffuse WMLs markedly differed between participants younger than 80 years vs those 80 years and older. After adjustment among participants younger than 80 years, diffuse WMLs compared with no lesions were associated with a 2.7-fold (95% confidence interval, 1.1-7.1) increase in the risk of HF. Focal lesions were not statistically significantly associated with an increased risk of HF in the same age group (hazard ratio, 2.0; 95% confidence interval, 0.6-7.6). No associations between diffuse WMLs, focal lesions, and HF were evident among participants 80 years and older, possibly because of the limited sample size. CONCLUSIONS: White matter lesions represent an independent risk factor for HF in persons younger than 80 years. Older persons with diffuse WMLs should be considered candidates for multifactorial interventions aimed at reducing the risk of falling and fractures.     

Clinical evaluation of the use of exemestane as further hormonal therapy after nonsteroidal aromatase inhibitors in postmenopausal metastatic breast cancer patients

OBJECTIVES:The aromatase inhibitors Anastrozole, Letrozole (type 2 nonsteroidal aromatase inhibitors: n-SAI) and Exemestane (type 1 steroidal aromatase inactivator) are used respectively as first- and second-line hormonal therapy in postmenopausal metastatic breast cancer women. Few clinical data are published on the sequential use of different classes of aromatase inhibitors. METHODS: We report an analysis on 30 postmenopausal metastatic breast cancer women treated between January 2000 and May 2002 in 2 Italian Oncology Institutions with the hormonal sequence n-SAI (Anastrozole, Letrozole) --> Exemestane. RESULTS: When receiving n-SAI (Anastrozole 8 patients and Letrozole 22 patients), 1 out of 30 women achieved a partial response, 20 of 30 patients no change (NC) > or =6 months. The analysis of the entire population treated with Exemestane showed an overall clinical benefit (CB) of 46.6 percent (14/30) with a median duration of 12 months (95%CI 6-25) and a median time to progression (TTP) of 4 months (95%CI 1-25). CONCLUSIONS: These data confirm a partial lack of cross-resistance between n-SAI --> Exemestane given in sequence.     

Combined effect of temozolomide and hyperthermia on human melanoma cell growth and O6-methylguanine-DNA methyltransferase activity

Hyperthermic isolated limb perfusion (HILP) with L-phenylalanine mustard (L-PAM) represents an effective treatment for locally advanced melanoma of the limbs. However, regional chemotherapy of melanoma still needs to be improved. Temozolomide (TMZ) is a methylating agent that spontaneously decomposes into the active metabolite of dacarbazine, the most effective agent for the systemic treatment of melanoma. Tumor cells with high levels of O6-methylguanine-DNA methyltransferase (MGMT) and/or with a defective DNA mismatch repair (MMR) are resistant to TMZ. Inhibition of MGMT activity increases TMZ sensitivity of MMR-proficient, but not of MMR-deficient cells, while inhibition of base excision repair (BER) potentiates TMZ cytotoxicity in both cell types. Recent studies, performed in an animal model, have shown that TMZ is more effective than L-PAM when applied regionally and that hyperthermia can increase the antitumor activity of TMZ. In this study, three thermoresistant human melanoma cell lines, endowed with different MGMT activity and functional status of the MMR system, were treated with TMZ at 37 degrees C or 41.5 degrees C for 90 min, and then analyzed for cell growth and MGMT activity. Hyperthermia significantly enhanced TMZ cytotoxicity in MMR-proficient cells, either endowed or not with MGMT activity, and in MMR-deficient cells. Endogenous MGMT activity was not affected by hyperthermia that, however, enhanced the enzyme depletion induced by TMZ treatment. Moreover, MGMT recovery after drug removal was delayed in cells that had been treated at 41.5 degrees C. Taken together, these findings confirm the therapeutic potential of a combined treatment of hyperthermia and TMZ. They also suggest that inhibition of BER and/or increased DNA methylation may be involved in the thermal enhancement of TMZ cytotoxicity. Additional studies are necessary to better clarify the mechanisms underlying hyperthermia-induced potentiation of TMZ activity. However, the present investigation provides further support to the development of clinical trials of HILP with TMZ.     

Hallucinatory and rewarding effect of salvinorin A in zebrafish: κ-opioid and CB1-cannabinoid receptor involvement

Rationale The hallucinatory effect and potential abuse of salvinorin A, the major ingredient of Salvia divinorum, has not been documented in animals. Objective The effects of salvinorin A on the zebrafish (Danio rerio) model, through its swimming behavior and conditioned place preference (CPP) task, was studied. Materials and methods Swimming activity was determined in a squared observational chamber after an i.m. treatment of salvinorin A (0.1–10 μg/kg). For the CPP test, zebrafish were given salvinorin A (0.2 and 1 μg/kg) or vehicle and evaluated in a two-compartment chamber. Results Salvinorin A (0.1 and 0.2 μg/kg) induced accelerated swimming behavior in comparison with vehicle, whereas a “trance-like” effect, at doses as 5 and 10 μg/kg, was obtained. Pretreatment with the κ-opioid antagonist, nor-binaltorphimine (nor-BNI; 10 mg/kg) and the cannabinoid type 1 (CB₁) antagonist, rimonabant (1 mg/kg), blocked salvinorin A-induced both stimulating and depressive effects obtained at a dose of 0.2 and 10 μg/kg, respectively. In the CPP test, salvinorin A (0.2 and 0.5 μg/kg) produced an increase in the time spent in the drug-associated compartment. A dose of 1 μg/kg produced no effect, whereas a dose of 80 μg/kg induced aversion. Pretreatment with nor-BNI or rimonabant fully reversed the reinforcing properties of salvinorin A (0.5 μg/kg). Conclusions Taken together, these results indicate that salvinorin A, as is sometimes reported in humans, exhibits rewarding effects, independently from its motor activity, suggesting the usefulness of the zebrafish model to study addictive behavior. These effects appear mediated by activation of both κ-opioid and cannabinoid CB₁ receptors.     

Isolation and characterization of a novel toxin from the venom of the spider Grammostola rosea that blocks sodium channels.

This communication reports the chemical and physiological characterization of a novel peptide (GrTx1) isolated from the venom of the "rosean-tarantula"Grammostola rosea. This component was one among more than 15 distinct components separated from the soluble venom by high-performance liquid chromatography (HPLC). GrTx1 has 29 amino-acid residues, compactly folded by three disulfide bridges with a molecular weight of 3697Da. Here we show that this peptide blocks Na(+) currents of neuroblastoma F-11 cells with an IC(50) of 2.8+/-0.1muM, up to a maximum of about 85% at 10muM. Moreover, the right-shift (+20.1+/-0.4mV) of the fractional voltage-dependent conductance could be also compatible with a putative "gating-modifier" mechanism. No effects were seen on common K(+) channels, such as K(v)1.1 and 1.4, using concentrations of toxin up to 10muM. Sequence analysis reveals that GrTx1 is closely related to other spider toxins reported to affect various distinct ion channel functions. A critical analysis of this study suggests the necessity to search for other potential receptor sites in order to establish the preferred specificity of these kind of peptides.     

Gene expression profiling of childhood adrenocortical tumors

Pediatric adrenocortical tumors (ACT) are rare and often fatal malignancies; little is known regarding their etiology and biology. To provide additional insight into the nature of ACT, we determined the gene expression profiles of 24 pediatric tumors (five adenomas, 18 carcinomas, and one undetermined) and seven normal adrenal glands. Distinct patterns of gene expression, validated by quantitative real-time PCR and Western blot analysis, were identified that distinguish normal adrenal cortex from tumor. Differences in gene expression were also identified between adrenocortical adenomas and carcinomas. In addition, pediatric adrenocortical carcinomas were found to share similar patterns of gene expression when compared with those published for adult ACT. This study represents the first microarray analysis of childhood ACT. Our findings lay the groundwork for establishing gene expression profiles that may aid in the diagnosis and prognosis of pediatric ACT, and in the identification of signaling pathways that contribute to this disease.     

Long-term survival and stroke-free survival after eversion carotid endarterectomy for asymptomatic severe carotid stenosis

BACKGROUND: Level 1 evidence supports carotid endarterectomy (CEA) as the standard treatment for severe (>70% lumen reduction) carotid stenosis in asymptomatic patients, though its safety and efficacy in high-risk patients remain controversial. Long-term survival and stroke-free survival after CEA may guide decisions concerning this procedure for asymptomatic patients, but this outcome has only been considered in few reports outside the large randomized trial setting. This study analyzed long-term survival and stroke-free survival after CEA and the impact of risk factors in a consecutive series of asymptomatic patients, including those with medical comorbidities and particular anatomical features believed to increase the perioperative morbidity and mortality of CEA. METHODS: For over 10 years, data were prospectively collected for all patients who underwent CEA for asymptomatic severe carotid disease at our institution. All CEAs performed by the same surgeon involved eversion technique, with patients under deep general anesthesia and continuous perioperative electroencephalographic (EEG) monitoring for selective shunting. All patients had neurological follow-up and duplex ultrasound at 1, 6, and 12 months, and yearly thereafter. A complete follow-up (mean, 6.1 years; range, 0.1 to 10.6 years) was obtained in 348 patients (93%) with an overall 365 CEAs (93%). Survival analyses were performed using Kaplan-Meier life tables. RESULTS: Among 374 patients undergoing 391 CEAs, there were no perioperative deaths or strokes. There were 17 (4.8%) late deaths, mainly cardiac-related (70%), and 2 (0.5%) non-fatal strokes. At 5 and 10 years, survival was 96.3% and 85.7%, and stroke-free survival was 95.6% and 84.8%, respectively. At multivariate analysis, diabetes mellitus (P = .002) and cardiac disease (P = .005) were independent predictors of a shorter long-term survival. CONCLUSIONS: Eversion CEA proved safe and effective in a series of patients with asymptomatic severe carotid disease representing the typical population of daily clinical practice. Although long-term results were extremely favorable, excellent stroke-free survival was not translated into a longer patient survival.     

Progression of atherosclerosis in asymptomatic carotid arteries after contralateral endarterectomy: a 10-year prospective study

OBJECTIVE: The best way to manage both symptomatic and asymptomatic severe carotid stenoses has been thoroughly demonstrated by large randomized clinical trials, but less is known about the natural history and management of the contralateral asymptomatic internal carotid artery (ICA). This prospective study was undertaken to determine whether disease progressed in the contralateral ICA of patients who had undergone carotid endarterectomy (CEA) and were followed up clinically and by duplex ultrasound (US) scan. METHODS: The contralateral asymptomatic ICAs of 599 patients who had undergone CEA for severe carotid disease over a 10-year period were followed up clinically and with duplex US scan at 1 month and then every 6 months. ICA stenosis was classified as mild (30%-49%), moderate (50%-69%), severe (70%-99%), or occlusion. Progression was defined as an increase in ICA stenosis of 50% or more for ICAs with a less than 50% baseline lesion or as an increase to a higher category if the baseline stenosis was 50% or more. End points of the study were the incidence of contralateral disease progression and late neurologic events. Kaplan-Meier analysis was used to estimate freedom from disease progression and from neurologic events. The relationship between progression and risk factors was also analyzed. RESULTS: Overall, disease progressed in 25.2% of patients (151/599) after a mean follow-up of 4.1 years. Disease progressed in 34.3% of patients (101/294) with mild stenosis vs 47.9% of patients with moderate stenosis (47/98; P = .016). Three additional patients with mild lesions at baseline progressed to severe lesions. The median time to progression was 29.8 months for mild and 18.5 months for moderate stenoses (P = .033). The rate of late neurologic events referable to the contralateral ICA was 3.2% (19/599) for the entire series and 4.8% (19/392) for patients with a 30% or greater ICA stenosis: these included 4 (0.7%) strokes and 15 (2.5%) transient ischemic attacks. All but 3 events (16.3%; 16/98) occurred in patients with disease progression from moderate to severe stenosis. Overall, 53 late CEAs were performed. CONCLUSIONS: This prospective analysis has shown that disease progression in contralateral asymptomatic ICAs after CEA is relatively common in patients with a diseased ICA at the baseline and strongly supports duplex US surveillance, approximately every 6 months, in patients with more than mild disease. A baseline lesion is significantly predictive of progression to severe stenosis, and progression from moderate to severe stenosis is strongly associated with neurologic clinical events. No demographic or clinical factor proved useful in identifying patients likely to experience disease progression.