Emanuela Rossi

Atrial Fibrillation and Morbidity and Mortality in a Cohort of Long-term Hemodialysis Patients

BACKGROUND Atrial fibrillation is associated with increased mortality and hospitalization in the general population. Data about mortality, morbidity, and hospitalization in hemodialysis patients with atrial fibrillation are limited. SETTING & PARTICIPANTS All patients (n = 476) in 5 dialysis centers in Lombardia, Italy, as of June 2003 were enrolled and followed up until June 2006 (median age, 69 years; median hemodialysis duration, 45.2 months; and median follow-up, 36 months). 127 patients had atrial fibrillation at enrollment. PREDICTORS & OUTCOME A Cox model was used to relate: (1) atrial fibrillation, age, hemodialysis therapy duration, and comorbid conditions to all-cause and cardiovascular mortality; (2) angiotensin-converting enzyme (ACE)-inhibitor treatment and comorbid conditions to new onset of atrial fibrillation; and (3) atrial fibrillation and comorbid conditions on hospitalization. RESULTS There were 167 deaths (39.5% from cardiovascular disease). In multivariable models, atrial fibrillation was independently associated with increased mortality (hazard ratio [HR], 1.65; 95% confidence interval [CI], 1.18 to 2.31). This was more notable for cardiovascular (HR, 2.15; 95% CI, 1.27 to 3.64) than noncardiovascular mortality (HR, 1.39; 95% CI, 0.89 to 2.15). New-onset atrial fibrillation occurred in 35 of 349 individuals (4.1 events/100 person-years); the risk of incident atrial fibrillation was lower in those using ACE-inhibitor therapy (HR, 0.29; 95% CI, 0.10 to 0.82) and higher in those with left ventricular hypertrophy (HR, 2.55; 95% CI, 1.04 to 6.26). There were 539 hospitalizations during 3 years, with 114 hospitalizations in 162 patients with atrial fibrillation and 155 hospitalizations in 314 patients without atrial fibrillation (HR, 1.54; 95% CI, 1.18 to 2.01). Rates of stroke did not significantly differ by atrial fibrillation status (P = 0.4). LIMITATIONS Because of the observational nature of this study, results for treatment need confirmation in future trials. CONCLUSIONS Atrial fibrillation is associated with greater total and cardiovascular mortality. Patients with atrial fibrillation were hospitalized more frequently than patients without atrial fibrillation. ACE inhibitors may decrease the risk of new-onset atrial fibrillation.

The chemotherapy-induced peripheral neuropathy outcome measures standardization study: from consensus to the first validity and reliability findings

BACKGROUND Chemotherapy-induced peripheral neuropathy (CIPN) is a debilitating and dose-limiting complication of cancer treatment. Thus far, the impact of CIPN has not been studied in a systematic clinimetric manner. The objective of the study was to select outcome measures for CIPN evaluation and to establish their validity and reproducibility in a cross-sectional multicenter study. PATIENTS AND METHODS After literature review and a consensus meeting among experts, face/content validity were obtained for the following selected scales: the National Cancer Institute-Common Toxicity Criteria (NCI-CTC), the Total Neuropathy Score clinical version (TNSc), the modified Inflammatory Neuropathy Cause and Treatment (INCAT) group sensory sumscore (mISS), the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30, and CIPN20 quality-of-life measures. A total of 281 patients with stable CIPN were examined. Validity (correlation) and reliability studies were carried out. RESULTS Good inter-/intra-observer scores were obtained for the TNSc, mISS, and NCI-CTC sensory/motor subscales. Test-retest values were also good for the EORTC QLQ-C30 and CIPN20. Acceptable validity scores were obtained through the correlation among the measures. CONCLUSION Good validity and reliability scores were demonstrated for the set of selected impairment and quality-of-life outcome measures in CIPN. Future studies are planned to investigate the responsiveness aspects of these measures.BACKGROUND Chemotherapy-induced peripheral neuropathy (CIPN) is a debilitating and dose-limiting complication of cancer treatment. Thus far, the impact of CIPN has not been studied in a systematic clinimetric manner. The objective of the study was to select outcome measures for CIPN evaluation and to establish their validity and reproducibility in a cross-sectional multicenter study. PATIENTS AND METHODS After literature review and a consensus meeting among experts, face/content validity were obtained for the following selected scales: the National Cancer Institute-Common Toxicity Criteria (NCI-CTC), the Total Neuropathy Score clinical version (TNSc), the modified Inflammatory Neuropathy Cause and Treatment (INCAT) group sensory sumscore (mISS), the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30, and CIPN20 quality-of-life measures. A total of 281 patients with stable CIPN were examined. Validity (correlation) and reliability studies were carried out. RESULTS Good inter-/intra-observer scores were obtained for the TNSc, mISS, and NCI-CTC sensory/motor subscales. Test-retest values were also good for the EORTC QLQ-C30 and CIPN20. Acceptable validity scores were obtained through the correlation among the measures. CONCLUSION Good validity and reliability scores were demonstrated for the set of selected impairment and quality-of-life outcome measures in CIPN. Future studies are planned to investigate the responsiveness aspects of these measures.

Peripheral Treatment with Enoxaparin, a Low Molecular Weight Heparin, Reduces Plaques and β-Amyloid Accumulation in a Mouse Model of Alzheimer's Disease

We investigated the effect of long-term, peripheral treatment with enoxaparin, a low molecular weight heparin, in transgenic mice overexpressing human amyloid precursor protein751. Enoxaparin (6 IU per mouse intraperitoneally, three times a week for 6 months) significantly lowered the number and the area occupied by cortical β-amyloid deposits and the total β-amyloid (1-40) cortical concentration. Immunocytochemical analysis of glial fibrillary acid protein-positive cells showed that enoxaparin markedly reduced the number of activated astrocytes surrounding β-amyloid deposits. In vitro, the drug dose-dependently attenuated the toxic effect of β-amyloid on neuronal cells. Enoxaparin dose-dependently reduced the ability of β-amyloid to activate complement and contact systems, two powerful effectors of inflammatory response in AD brain. By reducing the β-amyloid load and cytotoxicity and proinflammatory activity, enoxaparin offers promise as a tool for slowing the progression of Alzheimers disease.

Neuroprotection by complement (C1) inhibitor in mouse transient brain ischemia.

The authors investigated the effect of the C1 inhibitor (C1-INH), the only known inhibitor of complement C1, in a murine model of transient focal ischemia. Ischemia was induced by intraluminal occlusion of the middle cerebral artery. After 2 hours, reperfusion was produced by removing the nylon monofilament occluding the artery. The effect of 15 U C1-INH (intravenously) was evaluated in terms of general and focal neurologic deficits, ischemic volume, neutral red staining (to identify the brain areas subject to ischemic damage), and glial fibrillary acidic protein immunoreactivity (to show astrocytic response). Forty-eight hours after ischemia, C1-INH significantly improved general and focal deficits by 36% and 54%, respectively, and significantly reduced infarct volume (CI-INH, 6.69% ± 2.93%; saline, 24.24% ± 8.24%) of total brain. Neutral red staining further showed the strong protective effect of C1-INH in cortex, hippocampus, and striatum. Astrocyte activation induced by ischemia was not affected by C1-INH. These findings show that C1-INH displayed a potent neuroprotective action by effectively reducing ischemia—reperfusion injury.

Sudden death and associated factors in a historical cohort of chronic haemodialysis patients

BACKGROUND In haemodialysis patients, deaths due to cardiovascular causes constitute a large proportion of total mortality and sudden cardiac deaths account for approximately 22% of all deaths. The aim of this study was to evaluate the incidence of sudden cardiac death and associated risk factors in a cohort of haemodialysis patients. METHODS AND RESULTS The 3-year cumulative incidence of death in a cohort of 476 patients on chronic haemodialysis treatment was 34.3% (SE 2.3). Sudden death had a 6.9% (SE 1.2) cumulative incidence, with 32 events representing 19.2% of all deaths, while cardiovascular not sudden death and noncardiovascular death accounted for a 3-year cumulative incidence of 7.3% (SE 1.2) and 20.1% (SE 1.9), respectively. According to Cox multivariate analysis, significant risk factors for sudden death were the presence of atrial fibrillation, diabetes mellitus, predialytic hyperkalaemia, haemodialysis mode and C-reactive protein level, which were associated with a 2.9 (CI(95%) 1.3-6.4), 3.0 (CI(95%) 1.3-7.2), 2.7 (CI(95%) 1.3-5.8), 4.5 (CI(95%) 1.3-15.5) and 3.3 (CI(95%) 1.2-8.8)-fold increase in the risk of sudden death, respectively. Sudden death was significantly more frequent during the first 24 h of the first short interdialytic interval and during the last 24 h of the long interval, i.e. immediately before and immediately after the first weekly haemodialysis session (P = 0.02). CONCLUSIONS Our data show that the incidence of sudden death in haemodialysis patients is high and that atrial fibrillation, diabetes, hyperkalaemia, haemodialysis mode and C-reactive protein play an important role in developing fatal arrhythmia. Further studies will be necessary to define which interventions could be helpful in reducing this cause of mortality.

The Powerful Neuroprotective Action of C1-Inhibitor on Brain Ischemia-Reperfusion Injury Does Not Require C1q

C1-inhibitor (C1-INH) is a major regulator of the complement classical pathway. Besides this action, it may also inhibit other related inflammatory systems. We have studied the effect of C1-INH in C57BL/6 mice with focal transient brain ischemia induced by 30 minutes of occlusion of the middle cerebral artery. C1-INH induced a dose-dependent reduction of ischemic volume that, with the dose of 15 U/mouse, reached 10.8% of the volume of saline-treated mice. Four days after ischemia the treated mice had significantly lower general and focal neurological deficit scores. Fluoro-Jade staining, a marker for neuronal degeneration, showed that C1-INH-treated mice had a lower number of degenerating cells. Leukocyte infiltration, as assessed by CD45 immunostaining, was also markedly decreased. We then investigated the response to ischemia in C1q(-/-) mice. There was a slight, nonsignificant decrease in infarct volume in C1q(-/-) mice (reduction to 72.3%) compared to wild types. Administration of C1-INH to these mice was still able to reduce the ischemic volume to 31.4%. The study shows that C1-INH has a strong neuroprotective effect on brain ischemia/reperfusion injury and that its action is independent from C1q-mediated activation of classical pathway.

C1-inhibitor protects against brain ischemia-reperfusion injury via inhibition of cell recruitment and inflammation.

Previous studies demonstrated that C1-inhibitor (C1-INH), a complement and contact-kinin systems inhibitor, is neuroprotective in cerebral ischemia. To investigate the mechanism of this action, we evaluated the expression of neurodegeneration and inflammation-related factors in mice subjected to 2-h ischemia and 2 or 46 h reperfusion. C1-INH significantly dampened the mRNA expression of the adhesion molecules P-selectin and ICAM-1 induced by the ischemic insult. It significantly decreased the pro-inflammatory cytokine (TNF alpha, IL-18) and increased the protective cytokine (IL-6, IL-10) gene expression. C1-INH treatment prevented the decrease of NFH gene, a marker of cellular integrity and counteracted the increase of pro-caspase 3, an apoptosis index. Furthermore, C1-INH markedly inhibited the activation and/or recruitment of microglia/macrophage, as shown by immunohistochemistry. In conclusion, C1-INH exerts an anti-inflammatory and anti-apoptotic action on ischemia-reperfusion injury. Our present and past data support a major effect of C1-INH on cell recruitment from the vasculature to the ischemic site.

Nutritional status at diagnosis is related to clinical outcomes in children and adolescents with cancer: A perspective from Central America

BACKGROUND The prevalence of malnutrition in children may exceed 50% in countries with limited resources. The aims of this study were to assess nutritional status at diagnosis in children and adolescents with cancer, and to correlate it with clinical outcomes in the Spanish speaking countries of Central America that formed the AHOPCA (Asociacion de Hemato-Oncologia Pediatrica de Centro America) consortium. METHODS Patients aged 1-18 years, diagnosed with cancer between 1st October 2004 and 30th September 2007, were eligible for study. Weight (kg) and height or length (m), mid upper arm circumference--MUAC and triceps skin fold thickness--TSFT were measured and their Z-scores or percentiles were calculated. Three categories of nutritional status were defined according to these parameters. RESULTS A total of 2954 new patients were enrolled; 1787 had all anthropometric measurements performed and 1513 also had measurements of serum albumin. By arm anthropometry 322/1787 patients (18%) had moderate nutritional depletion and 813/1787 patients (45%) were severely depleted. Adding serum albumin, the proportion classified as severely depleted rose to 59%. Malnourished children more often abandoned therapy and their event free survival was inferior to that of other children. CONCLUSIONS Arm anthropometry in children with cancer is a sensitive measure of nutritional status. Since malnutrition at diagnosis was related to important clinical outcomes, an opportunity exists to devise simple, cost-effective nutritional interventions in such children that may enhance their prospects for survival.

Warfarin use, mortality, bleeding and stroke in haemodialysis patients with atrial fibrillation

BACKGROUND Oral anticoagulation therapy (OAT) is the choice treatment for thromboembolism prevention in atrial fibrillation (AF), although data about OAT use in haemodialysis (HD) patients with AF are contradictory. METHODS The effect of OAT on the risk of mortality, stroke and bleeding was prospectively evaluated in a population of HD patients with AF. All the patients of 10 HD Italian centres alive on 31 October 2010 with documented AF episode(s) were recruited and followed-up for 2 years. OAT and antiplatelet intake, age, dialytic age, comorbidities and percentage time in the target international normalized ratio (INR) range (target therapeutic range; TTR) were considered as predictors of hazard of death, thromboembolic and bleeding events. RESULTS At recruitment, 134 patients out of 290 were taking OAT. During the follow-up, 115 patients died (4 strokes, 3 haemorrhagic and 1 thromboembolic). Antiplatelet therapy, but not OAT, was associated with increased mortality (HR 1.71, CI 1.10-2.64, P = 0.02). The estimated survival of patients always taking OAT tended to be higher than that of patients who stopped taking (68.6 versus 49.6%, P = 0.07). OAT was not correlated to a significant decreased risk of thromboembolic events (HR 0.12, CI 0.00-3.59, P = 0.20), while it was associated with an increased risk of bleeding (HR 3.96, CI 1.15-13.68, P = 0.03). Higher TTR was associated with a reduced bleeding risk (HR 0.09, CI 0.01-0.76, P = 0.03), while previous haemorrhagic events were associated with higher haemorrhagic risk (HR 2.17, CI 1.09-4.35, P = 0.03). CONCLUSIONS In our population of HD patients with AF, the mortality is very high. OAT is not associated with increased mortality, while antiplatelet drugs are. OAT seems, on the contrary, associated with a better survival; however, it does not decrease the incidence of ischaemic stroke, whereas it increases the incidence of bleeding. Bleeding risk is lower in subjects in whom the INR is kept within the therapeutic range.

Heparin attenuates cytotoxic and inflammatory activity of Alzheimer amyloid-β in vitro

Amyloid-beta protein (Abeta) is implicated in the pathogenesis of Alzheimers disease because of its neurotoxicity and the ability to trigger local inflammation. Compounds that interact with the amino acids of the N-terminal region or interfere with aggregation can reduce the Abeta biologic activity. We evaluated the effect of heparin on Abeta (1-42) neurotoxicity and on its ability to activate complement and contact system. On differentiated PC12 cells, a reliable model of neuronal cells, heparin at the doses of 10 and 20 microg/ml significantly counteracted Abeta cytotoxicity as assessed by measuring MTT conversion. We then explored the effect of heparin on Abeta (1-42)-induced complement and contact system activation. Abeta (1-42) was incubated with heparin in presence of normal plasma as the source of complement and contact system factors. Heparin reduced, in a dose-dependent manner, complement and contact system activation, assessed by measuring the degree of C4 and high molecular weight kininogen cleavage. The present data show that heparin can attenuate neurotoxic and pro-inflammatory activity of Abeta and suggest that this drug could represent a new strategy to reduce the progressive neurodegeneration in AD.