Paola Rebora

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.

Are Chronic Myeloid Leukemia Patients More at Risk for Second Malignancies? A Population-based Study

The authors used cancer registry data to assess the incidence rate of second primary cancers among chronic myeloid leukemia (CML) patients and the long-term survival of CML patients before the introduction of tyrosine kinase inhibitors. In the Swedish Cancer Registry, the authors identified 2,753 adult CML patients diagnosed between 1970 and 1995 who were followed through December 2007. Standardized incidence ratios (SIRs) and relative survival ratios were computed. With a total of 145 subsequent primary malignancies, an increased incidence rate of second malignancy was found for stomach cancer (SIR = 2.76, 95% confidence interval (CI): 1.33, 5.08), skin cancer (SIR = 5.36, 95% CI: 3.18, 8.47), urogenital tract cancer (SIR = 1.61, 95% CI: 1.15, 2.21), and lymphoid leukemia (SIR = 5.53, 95% CI: 1.79, 12.89). Long-term relative survival figures showed that CML was related, in the era prior to the introduction of imatinib, to a very steep decline in survival (2 years from diagnosis, relative survival = 51%, 95% CI: 49, 53). This was in spite of a marginal improvement after 1985, possibly related to the introduction of interferon-α for treatment. These estimates constitute a relevant reference for future studies and a benchmark for comparisons with prognosis in CML patients after chronic use of tyrosine kinase inhibitors.

Urinary exosomes in the diagnosis of Gitelman and Bartter syndromes

BACKGROUND Gitelman syndrome (GS) and Bartter syndrome (BS) are hereditary salt-losing tubulopathies (SLTs) resulting from defects of renal proteins involved in electrolyte reabsorption, as for sodium-chloride cotransporter (NCC) and furosemide-sensitive sodium-potassium-chloride cotransporter (NKCC2) cotransporters, affected in GS and BS Type 1 patients, respectively. Currently, definitive diagnosis is obtained through expensive and time-consuming genetic testing. Urinary exosomes (UE), nanovesicles released by every epithelial cell facing the urinary space, represent an ideal source of markers for renal dysfunction and injury, because UE molecular composition stands for the cell of origin. On these assumptions, the aim of this work is to evaluate the relevance of UE for the diagnosis of SLTs. METHODS UE were purified from second morning urines collected from 32 patients with genetically proven SLTs (GS, BS1, BS2 and BS3 patients), 4 with unclassified SLTs and 22 control subjects (age and sex matched). The levels of NCC and NKCC2 were evaluated in UE by SDS-PAGE/western blotting with specific antibodies. RESULTS Due to their location on the luminal side of tubular cells, NCC and NKCC2 are well represented in UE proteome. The NCC signal is significantly decreased/absent in UE of Gitelman patients compared with control subjects (Mann-Whitney t-test, P < 0.001) and, similarly, the NKCC2 in those of Bartter type 1 (P < 0.001). The difference in the levels of the two proteins allows recognition of Gitelman and Bartter type 1 patients from controls and, combined with clinical data, from other Bartter patients. Moreover, the receiver operating characteristic curve analysis using UE NCC densitometric values showed a good discriminating power of the test comparing GS patients versus controls and BS patients (area under the curve value = 0.92; sensitivity 84.2% and specificity 88.6%). CONCLUSIONS UE phenotyping may be useful in the diagnosis of GS and BS, thus providing an alternative/complementary, urine-based diagnostic tool for SLT patient recognition and a diagnostic guidance in complex cases.

The role of blood pressure, body weight and fat distribution on left ventricular mass, diastolic function and cardiac geometry in children.

Background: Hypertension and obesity in childhood are related to early cardiac damage, as left ventricular hypertrophy. Few studies have analyzed the independent effects of hypertension and weight excess on diastolic function and left ventricular geometry. Objective: We studied the effects of weight, waist circumference (as an index of fat distribution) and blood pressure on left ventricular mass index, the risk of left ventricular hypertrophy, diastolic function and left ventricular geometry in 526 children (237 girls, age range 6–15 years). Methods: Children were divided into normotensive, prehypertensive and hypertensive (US Nomograms) groups, and into normal-weight, overweight, and obese (International Obesity Task Force classification) groups. Left ventricular mass index, diastolic function and left ventricular geometry were assessed. Results: SBP z-scores and blood pressure categories significantly influenced cardiac mass (P < 0.001 and P = 0.02, respectively) and the prevalence of left ventricular hypertrophy (P < 0.001 and P < 0.05, respectively). Obesity, BMI, and waist circumference z-scores were significantly associated with an increment in E/Em ratio (P < 0.001, P < 0.01, and P < 0.01, respectively). Increasing blood pressure values and the presence of prehypertension (P < 0.05) and hypertension (P < 0.003), but not weight excess, were associated with concentric cardiac remodeling. In contrast, concentric hypertrophy was associated with hypertension (P < 0.01), obesity (P < 0.001), and increasing waist circumference (P < 001). Conclusions: Blood pressure values and hypertension are independently associated with an increase of cardiac mass and the presence of cardiac hypertrophy. Obesity and waist circumference, but not hypertension, are associated with a worsening of diastolic function, whereas only hypertensive children show high prevalence of concentric remodeling. Blood pressure and body weight and fat distribution have an independent and different impact on left ventricular structure and function in children.

Increased Serum Uric Acid Levels Blunt the Antihypertensive Efficacy of Lifestyle Modifications in Children at Cardiovascular Risk

Primary hypertension is a growing concern in children because of the obesity epidemic largely attributable to western lifestyles. Serum uric acid is known to be influenced by dietary habits, correlates with obesity, and could represent a risk factor for hypertension. Preliminary studies in children highlighted uric acid as a potentially modifiable risk factor for the prevention and treatment of hypertension. The effect of lifestyle changes (increase of physical activity and dietary modifications) on blood pressure values, weight status, and serum uric acid levels in a cohort of 248 children referred for cardiovascular risk assessment were evaluated over a mean 1.5-year follow-up. At baseline, 48% of children were obese and 50% showed blood pressure values >90th percentile. At follow-up, a significant improvement in weight class (24% obese; P<0.0001) and blood pressure category (22% >90th percentile; P<0.0001) was found. Systolic blood pressure z-score (P<0.0001), uric acid value (P=0.0056), and puberty at baseline (P=0.0048) were independently associated with higher systolic blood pressure z-score at follow-up, whereas a negative association was observed with body mass index z-score decrease during follow-up (P=0.0033). The risk of hypertension at follow-up was associated with body mass index (P=0.0025) and systolic blood pressure (P<0.0001) z-score at baseline and inversely related to delta body mass index (P=0.0002), whereas the risk of showing hypertension ≥99th percentile was more than doubled for each baseline 1 mg/dL increase of serum uric acid (P=0.0130). Uric acid is a powerful determinant of blood pressure over time, independent of lifestyle modifications.

Glutathione S-transferase homozygous deletions and relapse in childhood acute lymphoblastic leukemia: a novel study design in a large Italian AIEOP cohort

AIM In the AIEOP-BFM 2000 trial, 15% of pediatric patients treated according to risk-adapted polychemotherapeutic regimens relapsed. The present study aimed to investigate the influence of GST-M1 and GST-T1 deletions on clinical outcome of children with acute lymphoblastic leukemia treated according to the AIEOP-BFM ALL 2000 study protocol. MATERIALS & METHODS A novel-design, two-phase study was applied to select a subsample of 614 children to be genotyped for the deletions of GST genes. Cumulative incidence of relapse was then estimated by weighted Kaplan-Meier analysis, and the Cox model was applied to evaluate the effect of GST-M1 and GST-T1 isoenzyme deletions on relapse. RESULTS No overall effect was found, but the GST-M1 deletion was associated with better clinical outcome within prednisone poor-responder patients (hazard ratio [HR]: 0.45; 95% CI: 0.23-0.91; p = 0.026), whereas the GST-T1 deletion was associated with worse outcome in the standard-risk group (HR: 4.62; 95% CI: 1.04-20.6; p = 0.045) and within prednisone good responders (HR: 1.62; 95% CI: 1.02-2.58; p = 0.041). CONCLUSION Our results show that GST-M1 and GST-T1 homozygous deletions have opposite correlation with relapse, the former being protective and the latter unfavourable in specific subsets of acute lymphoblastic leukemia patients.

The SIPI for measuring complexity in nursing care: Evaluation study

BACKGROUND The traditional model for nursing staff management widely used in Italian hospitals assumes that diagnosis determines the amount of nursing required, but this has been widely criticized. In order to quantify and monitor the fluctuation of the complexity in nursing care, a questionnaire, called SIPI (Sistema Informativo della Performance Infermieristica), that is based on the care needs expressed by the patients, has been proposed in the Monza Hospital. DESIGN A group of trained nurses were asked to indicate their own perception of the level of nursing day-care complexity provided to each patient and then to complete the SIPI. SETTINGS The Monza Hospital coordinated this multi-centre study that involved 25 Hospitals of North Italy. PARTICIPANTS Each hospital contributed with a minimum of three units, at least one for each area of intensity of clinical care, as defined by health regulators. All adult in-patients being in the units from at least 24h were included in the survey. Psychiatric wards, neonatology, intensive and semi-intensive care wards were non considered. METHODS A group of nurses trained with the use of SIPI completed the questionnaires based on the nursing file of performed activities. Before filling the questionnaire, the nurses were asked to indicate their perception of the level of complexity of the day-care provided to each patient. In order to calculate the SIPI scores that discriminate different nurse complexity levels, a ROC analysis and the multinomial logistic regression model were used, considering the perceived complexity as the standard of reference. RESULTS The nursing day-care complexity was measured in 115 wards, for a total of 17,803 completed questionnaires. Nursing complexity was roughly the same in areas of different intensity of clinical care, both according to perception and as measured by SIPI. A cut-off of 49.2 was identified as optimal to distinguish two classes of complexity with a good performance (80% of specificity, 85% of sensitivity). CONCLUSIONS The SIPI was shown to be a simple and useful tool that may be adopted in the future for an optimal allocation of nursing resources. The results of this study confirmed that elevated intensity of care from the clinical perspective does not necessarily correspond to high nursing complexity.

Glutamine-Enriched Nutrition Does Not Reduce Mucosal Morbidity or Complications After Stem-Cell Transplantation for Childhood Malignancies: A Prospective Randomized Study

Background. Intravenous glutamine-enriched solution seems to be effective in posttransplant period in decreasing the severity and duration of mucositis. The aim of this randomized study was to determine the benefit of glutamine supplementation both on mucosal morbidity and in posttransplant associated complications. Methods. Children undergoing allogeneic hematopoietic stem-cell transplantation (HSCT) for malignant hematological diseases were randomly assigned to standard total parenteral nutrition (S-TPN) or glutamine-enriched (GE)-TPN solution consisting of 0.4 g/kg/day of l-alanine-glutamine dipeptide. This treatment started on the day of HSCT and ended when the patients could orally cover more than 50% of their daily energy requirements. The severity and the rate of post-HSCT mucositis were based on World Health Organization criteria. All the analyses were conducted on intention-to-treat principle. Results. One hundred twenty consecutive patients (83 men; median age, 8.1 years) were enrolled. The mean duration of treatment was 23.5 and 23 days in the two treatment arms. The mean calorie intake was 1538 kcal/d in the S-TPN group and 1512 kcal/d in GE-TPN group. All patients were well nourished before and after HSCT. Mucositis occurred in 91.4% and 91.7% of patients in S-TPN and GE-TPN arm, respectively (P=0.98). Odds ratio adjusted by type of HSCT was 0.98 (95% confidence interval, 0.26–2.63). Type and duration of analgesic treatment, clinical outcome (engraftment, graft versus host disease, early morbidity, and mortality, relapse rate up to 180 days post-HSCT) were not significantly different in the two treatment arms. Conclusion. GE-TPN solution does not affect mucositis and outcome in well-nourished HSCT allogeneic patients.

A randomized and controlled study of noninvasive hemodynamic monitoring as a guide to drug treatment of uncontrolled hypertensive patients.

Background: In the BEtter control of BP in hypertensive pAtients monitored Using the HOTMAN sYstem study, we investigated whether utilizing noninvasive monitoring of hemodynamic parameters combined with a drug selection algorithm (integrated hemodynamic management – IHM) compared with conventional drug selection may improve uncontrolled hypertension in European Hypertension Excellence centers. Method: Uncontrolled (office SBP >140 mmHg and ambulatory daytime SBP >135 mmHg while taking ≥2 antihypertensive drugs) essential hypertensive patients were referred to five European Hypertension Excellence centers and, if eligible, were randomized to IHM-guided (n = 83) vs. conventional (control, n = 84) treatment adjustment in an investigator-initiated multicenter prospective randomized parallel groups controlled study. Results: The average number of antihypertensive drugs increased from 3.1 to 4.1 in both groups and differed only in a rise of the use of diuretics in the IHM groups (from 13 to 31%). Daytime SBP, defined as the primary endpoint, decreased markedly and to the same extent from baseline to 6 months in IHM (–15.8 ± 14.8 mmHg) and control (–15.4 ± 14.5 mmHg) groups (P = 0.87), with a similar behavior of office SBP (no between group differences, P = 0.18). Average number of adverse events was significantly lower in IHM than in controls (P = 0.008) but of the more general type and not necessarily related to drug treatment. Conclusion: Thus, noninvasive hemodynamic monitoring associated with a drug selection algorithm induced similar reductions in ambulatory daytime and office SBP compared with conventional drug selection in uncontrolled hypertensive patients referred to European Hypertension Excellence centers. Clinical Trial Registration – URL: http://www.clinicaltrials.gov. Unique identifier: NCT01482364

High risks of familial chronic lymphatic leukemia for specific relatives: signposts for genetic discovery?

High risks of familial chronic lymphatic leukemia for specific relatives: signposts for genetic discovery?