Stefano Fumagalli

Reduced Cardiocirculatory Complications With Unrestrictive Visiting Policy in an Intensive Care Unit Results From a Pilot, Randomized Trial

Background— Observational studies suggest that open visiting policies are preferred by most patients and visitors in intensive care units (ICUs), but no randomized trial has compared the safety and health outcomes of unrestrictive (UVP) and restrictive (RVP) visiting policies. The aim of this pilot, randomized trial was to compare the complications associated with UVP (single visitor with frequency and duration chosen by patient) and RVP (single visitor for 30 minutes twice a day). Methods and Results— Two-month sequences of the 2 visiting policies were randomly alternated for 2 years in a 6-bed ICU, with 226 patients enrolled (RVP/UVP, n=115/111). Environmental microbial contamination, septic and cardiovascular complications, emotional profile, and stress hormones response were systematically assessed. Patients admitted during the randomly scheduled periods of UVP received more frequent (3.2±0.2 versus 2.0±0.0 visits per day, mean±SEM) and longer (2.6±0.2 versus 1.0±0.0 h/d) visits (P<0.001 for both comparisons). Despite significantly higher environmental microbial contamination during the UVP periods, septic complications were similar in the 2 periods. The risk of cardiocirculatory complications was 2-fold (odds ratio 2.0; 95% CI, 1.1 to 3.5; P=0.03) in the RVP periods, which were also associated with a nonsignificantly higher mortality rate (5.2% versus 1.8%; P=0.28). The UVP was associated with a greater reduction in anxiety score and a significantly lower increase in thyroid stimulating hormone from admission to discharge. Conclusions— Despite greater environmental microbial contamination, liberalizing visiting hours in ICUs does not increase septic complications, whereas it might reduce cardiovascular complications, possibly through reduced anxiety and more favorable hormonal profile.

Neurosphere-Derived Cells Exert a Neuroprotective Action by Changing the Ischemic Microenvironment

Background Neurosphere-derived cells (NC), containing neural stem cells, various progenitors and more differentiated cells, were obtained from newborn C57/BL6 mice and infused in a murine model of focal ischemia with reperfusion to investigate if: 1) they decreased ischemic injury and restored brain function; 2) they induced changes in the environment in which they are infused; 3) changes in brain environment consequent to transient ischemia were relevant for NC action. Methodology/Principal Findings NC were infused intracerebroventricularly 4 h or 7 d after 30 min middle cerebral artery occlusion. In ischemic mice receiving cells at 4 h, impairment of open field performance was significantly improved and neuronal loss significantly reduced 7–14 d after ischemia compared to controls and to ischemic mice receiving cells at 7 d. Infusion of murine foetal fibroblast in the same experimental conditions was not effective. Assessment of infused cell distribution revealed that they migrated from the ventricle to the parenchyma, progressively decreased in number but they were observable up to 14 d. In mice receiving NC at 7 d and in sham-operated mice, few cells could be observed only at 24 h, indicating that the survival of these cells in brain tissue relates to the ischemic environment. The mRNA expression of trophic factors such as Insulin Growth Factor-1, Vascular Endothelial Growth Factor-A, Transforming Growth Factor-β1, Brain Derived Neurotrophic Factor and Stromal Derived Factor−1α, as well as microglia/macrophage activation, increased 24 h after NC infusion in ischemic mice treated at 4 h compared to sham-operated and to mice receiving cells at 7 d. Conclusions/Significance NC reduce functional impairment and neuronal damage after ischemia/reperfusion injury. Several lines of evidence indicate that the reciprocal interaction between NC and the ischemic environment is crucial for NC protective actions. Based on these results we propose that a bystander control of the ischemic environment may be the mechanism used by NC to rapidly restore acutely injured brain function.

Human umbilical cord blood mesenchymal stem cells protect mice brain after trauma

Objective:To investigate whether human umbilical cord blood mesenchymal stem cells, a novel source of progenitors with multilineage potential: 1) decrease traumatic brain injury sequelae and restore brain function; 2) are able to survive and home to the lesioned region; and 3) induce relevant changes in the environment in which they are infused. Design:Prospective experimental study. Setting:Research laboratory. Subjects:Male C57Bl/6 mice. Interventions:Mice were subjected to controlled cortical impact/sham brain injury. At 24 hrs postinjury, human umbilical cord blood mesenchymal stem cells (150,000/5 &mgr;L) or phosphate-buffered saline (control group) were infused intracerebroventricularly contralateral to the injured side. Immunosuppression was achieved by cyclosporine A (10 mg/kg intraperitoneally). Measurements and Main Results:After controlled cortical impact, human umbilical cord blood mesenchymal stem cell transplantation induced an early and long-lasting improvement in sensorimotor functions assessed by neuroscore and beam walk tests. One month postinjury, human umbilical cord blood mesenchymal stem cell mice showed attenuated learning dysfunction at the Morris water maze and reduced contusion volume compared with controls. Hoechst positive human umbilical cord blood mesenchymal stem cells homed to lesioned tissue as early as 1 wk after injury in 67% of mice and survived in the injured brain up to 5 wks. By 3 days postinjury, cell infusion significantly increased brain-derived neurotrophic factor concentration into the lesioned tissue, restoring its expression close to the levels observed in sham operated mice. By 7 days postinjury, controlled cortical impact human umbilical cord blood mesenchymal stem cell mice showed a nonphagocytic activation of microglia/macrophages as shown by a selective rise (260%) in CD11b staining (a marker of microglia/macrophage activation/recruitment) associated with a decrease (58%) in CD68 (a marker of active phagocytosis). Thirty-five days postinjury, controlled cortical impact human umbilical cord blood mesenchymal stem cell mice showed a decrease of glial fibrillary acidic protein positivity in the scar region compared with control mice. Conclusions:These findings indicate that human umbilical cord blood mesenchymal stem cells stimulate the injured brain and evoke trophic events, microglia/macrophage phenotypical switch, and glial scar inhibitory effects that remodel the brain and lead to significant improvement of neurologic outcome.

Prognostic Stratification of Older Persons Based on Simple Administrative Data: Development and Validation of the “Silver Code,” To Be Used in Emergency Department Triage

BACKGROUND Prognostic stratification of older patients with complex medical problems among those who access the emergency department (ED) may improve the effectiveness of geriatric interventions. Whether such targeting can be performed through simple administrative data is unknown. METHODS We examined the discharge records for 10,913 patients aged 75 years or older admitted during 2005 to the ED of all public hospitals in Florence, Italy. Using information on demographics, drug treatment, previous hospital admissions, and discharge diagnoses, we developed a 1-year mortality prognostic index. The predictive validity of this index was tested in a subsample of patients independent of the subsample used for its original development. Finally, we tested whether patients stratified by the prognostic index had different mortality when admitted to a geriatrics compared with an internal medicine ward. RESULTS In the validation subsample, patients with scores of 4-6, 7-10, and 11+ compared with those with scores less than 4 had hazard ratios (95% confidence interval) for 1-year mortality of, respectively, 1.5 (1.3-1.7), 2.2 (1.3-1.7), and 3.0 (2.6-3.4). Patients in the worse prognostic stratum experienced 33% higher mortality when admitted to an internal medicine compared with a geriatrics ward, although mortality was not significantly affected by the type of ward of admission in all other risk strata. CONCLUSIONS Simple administrative data provide prognostic information on long-term mortality in older patients hospitalized via ED. Patients with worse prognostic index scores appear to benefit from admission in a geriatrics compared with an internal medicine ward.

Targeting Mannose-Binding Lectin Confers Long-Lasting Protection With a Surprisingly Wide Therapeutic Window in Cerebral Ischemia

Background— The involvement of the complement system in brain injury has been scarcely investigated. Here, we document the pivotal role of mannose-binding lectin (MBL), one of the recognition molecules of the lectin complement pathway, in brain ischemic injury. Methods and Results— Focal cerebral ischemia was induced in mice (by permanent or transient middle cerebral artery occlusion) and rats (by 3-vessel occlusion). We first observed that MBL is deposited on ischemic vessels up to 48 hours after injury and that functional MBL/MBL-associated serine protease 2 complexes are increased. Next, we demonstrated that (1) MBL−/− mice are protected from both transient and permanent ischemic injury; (2) Polyman2, the newly synthesized mannosylated molecule selected for its binding to MBL, improves neurological deficits and infarct volume when given up to 24 hours after ischemia in mice; (3) anti-MBL-A antibody improves neurological deficits and infarct volume when given up to 18 hours after ischemia, as assessed after 28 days in rats. Conclusions— Our data show an important role for MBL in the pathogenesis of brain ischemic injury and provide a strong support to the concept that MBL inhibition may be a relevant therapeutic target in humans, one with a wide therapeutic window of application.

Cardiopulmonary resuscitation of older, inhospital patients : Immediate efficacy and long-term outcome

Objective To determine the independent effect of advancing age on prognosis after cardiopulmonary resuscitation (CPR). Design and Setting Retrospective analysis of clinical records of patients who received CPR in a geriatric department equipped with an intensive care unit. Patients A total of 245 patients (146 men, 99 women; mean age, 70 ± 11 yrs) received CPR. Of these, 221 had a cardiocirculatory arrest (CA) in the intensive care unit and 24 had a CA in the general ward of the department. Acute myocardial infarction was the most frequent admission diagnosis. Interventions CPR according to standard guidelines in all cases. Measurements and Main Results Immediate, short-term (hospital discharge), and long-term (median follow-up, 31.5 months; range, <1–124 months) survival. Older patients had a lower immediate survival (<70 yrs [72/137] 52.6% vs. ≥70 yrs [43/108] 39.4%;p < .05) and, less frequently, ventricular tachycardia/fibrillation (VT/VF) as a cause of CA. VT/VF bore the lowest immediate mortality rate (19/104; 18.3%) as compared with asystole/complete heart block (66/102; 64.7%) or pulseless electrical activity (40/49; 81.6%;p < .001). Acute myocardial infarction, acute heart failure, hypotension, and occurrence of CA in the intensive care unit were also univariate predictors of unfavorable, immediate prognosis. However, in a multiple logistic analysis model, the mechanism of CA (asystole/complete heart block or pulseless electrical activity vs. VT/VF), acute myocardial infarction, heart failure, and hypotension were independent predictors of unfavorable immediate prognosis, whereas advancing age was not. Similarly, after initially successful CPR, short-term survival was independently associated with acute myocardial infarction, hypotension before CA, initial rhythm at CA, and need for mechanical ventilatory support after CPR, but not with age. Long-term survival (42 patients; 17.2% of the original cohort; median survival, 32 months) was also independent of age, whereas it was negatively associated with heart failure. Conclusion Immediate, short- and long-term prognosis after inhospital CPR is independent of age, at least when possible confounders are simultaneously taken into account.

The Relationship between Heart Rate Variability and Adiposity Differs for Central and Overall Adiposity

While frank obesity is associated with reduced HRV, indicative of poorer autonomic nervous system (ANS) function, the association between body mass index (BMI) and HRV is less clear. We hypothesized that effects of adiposity on ANS are mostly mediated by visceral fat and less by subcutaneous fat; therefore, centrally distributed adipose tissue, that is, waist circumference (WC), should be more strongly associated with HRV than overall adiposity (BMI). To examine this hypothesis, we used data collected in a subset of the Baltimore Longitudinal Study of Aging to compare strength of association between HRV and WC to that of HRV and BMI. Time domain HRV variables SDNN (standard deviation of successive differences in normal-to-normal (N-N) intervals) and RMSSD (root mean square of successive differences in N-N intervals) were calculated from 24-hour Holter recordings in 159 participants (29–96 years). Increasing WC was associated with decreasing SDNN and RMSSD in younger but not older participants (P value for WC-by-age interaction = 0.003). BMI was not associated with either SDNN or RMSSD at any age. In conclusion, central adiposity may contribute to sympathetic and parasympathetic ANS declines early in life.

Renal, but not systemic, hemodynamic effects of dopamine are influenced by the severity of congestive heart failure*

Objective:To determine whether the short-term systemic and renal hemodynamic response to dopamine is influenced by clinical severity of congestive heart failure. Design:Effects of increasing doses of dopamine were assessed in patients consecutively admitted for acutely decompensated congestive heart failure. Setting:Intensive care unit. Patients:We enrolled 16 congestive heart failure patients stratified by clinical severity (New York Heart Association [NYHA] class III, n = 8; NYHA class IV, n = 8) and two additional NYHA class III patients as controls. Interventions:Measurements were carried out throughout five 20-min experimental periods: baseline, dopamine infusion at 2, 4, and 6 μg·kg−1·min−1, and recovery. Controls received a similar amount of saline. Measurements and Main Results:Systemic and renal hemodynamics were determined respectively by right cardiac catheterization and radioisotopes (iodine 131-labeled hippuran and iodine 125-labeled iothalamate clearance). The peak increase in heart rate and cardiac index occurred at a dopamine dose of 4–6 μg·kg−1·min−1. The dose-response relation was similar in NYHA classes III and IV. Improvement in effective renal plasma flow and glomerular filtration rate, peaking at 4 μg·kg−1·min−1, was more rapid and marked in NYHA class III than class IV patients, in whom the renal fraction of cardiac output failed to increase. The systemic and renal effects of dopamine were independent of age. No change occurred in controls. Conclusions:The dose of dopamine producing an optimal improvement of systemic and renal hemodynamics in congestive heart failure is higher than usually reported. A greater clinical severity of congestive heart failure impairs the renal effects of dopamine, probably through a selective loss in renal vasodilating capacity.

S100A13 is a new angiogenic marker in human melanoma

Angiogenesis is critical in melanoma progression and metastasis and relies on the synthesis and release of proangiogenic molecules such as vascular endothelial growth factor (VEGF)-A and fibroblast growth factors (FGFs). S100A13 is a small calcium-binding protein that facilitates the release of FGF-1, the prototype of the FGF family. S100A13 is upregulated in astrocytic gliomas, in which it correlates with VEGF-A expression, microvessel density and tumor grading, and promotes a more aggressive, invasive phenotype in lung cancer-derived cell lines. To investigate the involvement of S100A13 in human cutaneous melanoma, we analyzed a series of 87 cutaneous melanocytic lesions: 14 common acquired melanocytic nevi, 14 atypical, so-called ‘dysplastic’ nevi, 45 melanomas (17 radial growth phase and 28 vertical growth phase) and 14 melanoma metastases. Main clinical and pathological features, including histotype, Breslow thickness, Clarks level and outcome were recorded. Microvessel density was determined with CD105/endoglin staining. Semiquantitative determination of S100A13, FGF-1 and VEGF-A protein expression was obtained by immunostaining. Quantification of S100A13 mRNA was achieved by real-time PCR. We found that S100A13 was expressed in melanocytic lesions; compared with benign nevi, S100A13 protein expression was significantly upregulated in melanomas (P=0.024), in which it correlated positively with the intensity of VEGF-A staining (P=0.041) and microvessel density (P=0.007). The level of expression of S100A13 mRNA also significantly increased with progression of disease, from radial growth phase (0.7±0.7) to vertical growth phase (3.6±3.1) to metastases (7.0±7.0) (P<0.001). Furthermore, S100A13 mRNA correlated positively with VEGF-A (P=0.023), TNM stage (P=0.05), risk of relapse (P=0.014) and status at follow-up (P=0.024). In conclusion, S100A13 is expressed in melanocytic lesions when the angiogenic switch occurs and it may cooperate with VEGF-A in supporting the formation of new blood vessels, favoring the shift from radial to vertical tumor growth. Therefore, S100A13 may represent a new angiogenic and prognostic marker in melanoma.

Heart Failure in Community-Dwelling Older Persons: Aims, Design and Adherence Rate of the ICARe Dicomano Project: An Epidemiologic Study

BACKGROUND: The prevalence of heart failure (HF) increases with age, and HF is a major cause of disability and mortality in older persons. Detection of HF in epidemiological studies has relied on criteria validated only in young and middle‐age adults, and, therefore, may prove inadequate in older subjects, because they do not take into account the pathophysiologic and clinical peculiarities of HF in old age. Thus, the true prevalence of HF in the older general population remains uncertain and has probably been underestimated in previous studies. Moreover, the mechanism and the extent by which HF hinders physical functioning in older people has not been fully elucidated.