Adult cardiac stem cells are multipotent and robustly myogenic: c-kit expression is necessary but not sufficient for their identification

Multipotent adult resident cardiac stem cells (CSCs) were first identified by the expression of c-kit, the stem cell factor receptor. However, in the adult myocardium c-kit alone cannot distinguish CSCs from other c-kit-expressing (c-kitpos) cells. The adult heart indeed contains a heterogeneous mixture of c-kitpos cells, mainly composed of mast and endothelial/progenitor cells. This heterogeneity of cardiac c-kitpos cells has generated confusion and controversy about the existence and role of CSCs in the adult heart. Here, to unravel CSC identity within the heterogeneous c-kit-expressing cardiac cell population, c-kitpos cardiac cells were separated through CD45-positive or -negative sorting followed by c-kitpos sorting. The blood/endothelial lineage-committed (Lineagepos) CD45posc-kitpos cardiac cells were compared to CD45neg(Lineageneg/Linneg) c-kitpos cardiac cells for stemness and myogenic properties in vitro and in vivo. The majority (~90%) of the resident c-kitpos cardiac cells are blood/endothelial lineage-committed CD45posCD31posc-kitpos cells. In contrast, the LinnegCD45negc-kitpos cardiac cell cohort, which represents 10% of the total c-kitpos cells, contain all the cardiac cells with the properties of adult multipotent CSCs. These characteristics are absent from the c-kitneg and the blood/endothelial lineage-committed c-kitpos cardiac cells. Single Linnegc-kitpos cell-derived clones, which represent only 1–2% of total c-kitpos myocardial cells, when stimulated with TGF-β/Wnt molecules, acquire full transcriptome and protein expression, sarcomere organisation, spontaneous contraction and electrophysiological properties of differentiated cardiomyocytes (CMs). Genetically tagged cloned progeny of one Linnegc-kitpos cell when injected into the infarcted myocardium, results in significant regeneration of new CMs, arterioles and capillaries, derived from the injected cells. The CSC’s myogenic regenerative capacity is dependent on commitment to the CM lineage through activation of the SMAD2 pathway. Such regeneration was not apparent when blood/endothelial lineage-committed c-kitpos cardiac cells were injected. Thus, among the cardiac c-kitpos cell cohort only a very small fraction has the phenotype and the differentiation/regenerative potential characteristics of true multipotent CSCs

A comparison of location of acute symptomatic vs. 'silent' small vessel lesions

Background: Acute lacunar ischaemic stroke, white matter hyperintensities, and lacunes are all features of cerebral small vessel disease. It is unclear why some small vessel disease lesions present with acute stroke symptoms, whereas others typically do not. Aim: To test if lesion location could be one reason why some small vessel disease lesions present with acute stroke, whereas others accumulate covertly. Methods: We identified prospectively patients who presented with acute lacunar stroke symptoms with a recent small subcortical infarct confirmed on magnetic resonance diffusion imaging. We compared the distribution of the acute infarcts with that of white matter hyperintensity and lacunes using computational image mapping methods. Results: In 188 patients, mean age 67 ± standard deviation 12 years, the lesions that presented with acute lacunar ischaemic stroke were located in or near the main motor and sensory tracts in (descending order): posterior limb of the internal capsule (probability density 0·2/mm3), centrum semiovale (probability density = 0·15/mm3), medial lentiform nucleus/lateral thalamus (probability density = 0·09/mm3), and pons (probability density = 0·02/mm3). Most lacunes were in the lentiform nucleus (probability density = 0·01–0·04/mm3) or external capsule (probability density = 0·05/mm3). Most white matter hyperintensities were in centrum semiovale (except for the area affected by the acute symptomatic infarcts), external capsules, basal ganglia, and brainstem, with little overlap with the acute symptomatic infarcts (analysis of variance, P < 0·01). Conclusions: Lesions that present with acute lacunar ischaemic stroke symptoms may be more likely noticed by the patient through affecting the main motor and sensory tracts, whereas white matter hyperintensity and asymptomatic lacunes mainly affect other areas. Brain location could at least partly explain the symptomatic vs. covert development of small vessel disease

Adherence to growth hormone (GH) therapy in na\uefve to treatment GH-deficient children: data of the Italian Cohort from the Easypod Connect Observational Study (ECOS)

Background: With the use of non-objective measurement, adherence to growth hormone (GH) therapy has been reported suboptimal in a large proportion of patients, and poor adherence has been shown to affect short-term growth response in patients receiving GH treatment. Objective: The Easypod\u2122 electronic device allows objective measurement of adherence. In this study, we report 3-year prospective adherence data of the Italian cohort of na\uefve GH deficient (GHD) children extrapolated from the Easypod Connect Observational Study (ECOS) database. Patients and methods: Seventy-three GHD children na\uefve to GH treatment were included in the analysis. 22 Italian centers participated in the study. Results: Mean adherence rate was consistently above 85% across the 3-year observation period. Particularly, mean adherence was 88.5%, 86.6%, and 85.7% after 1, 2 and 3\ua0years, respectively. Mean (\ub1 SD) height-SDS increase after the first year was 0.41 (\ub1 0.38). Conclusions: The majority of na\uefve GHD children starting GH treatment with Easypod maintained an adherence rate > 85% up to 3\ua0years. Easypod is a useful tool to follow-up patients\u2019 adherence allowing timely intervention to improve optimal treatment for these patients

Adherence to growth hormone (GH) therapy in naïve to treatment GH-deficient children: data of the Italian Cohort from the Easypod Connect Observational Study (ECOS)

Background: With the use of non-objective measurement, adherence to growth hormone (GH) therapy has been reported suboptimal in a large proportion of patients, and poor adherence has been shown to affect short-term growth response in patients receiving GH treatment. Objective: The Easypod™ electronic device allows objective measurement of adherence. In this study, we report 3-year prospective adherence data of the Italian cohort of naïve GH deficient (GHD) children extrapolated from the Easypod Connect Observational Study (ECOS) database. Patients and methods: Seventy-three GHD children naïve to GH treatment were included in the analysis. 22 Italian centers participated in the study. Results: Mean adherence rate was consistently above 85% across the 3-year observation period. Particularly, mean adherence was 88.5%, 86.6%, and 85.7% after 1, 2 and 3 years, respectively. Mean (± SD) height-SDS increase after the first year was 0.41 (± 0.38). Conclusions: The majority of naïve GHD children starting GH treatment with Easypod maintained an adherence rate > 85% up to 3 years. Easypod is a useful tool to follow-up patients’ adherence allowing timely intervention to improve optimal treatment for these patients

Adherence with tobramycin inhaled solution and health care utilization

<p>Abstract</p> <p>Background</p> <p>Adherence with tobramycin inhalation solution (TIS) during routine cystic fibrosis (CF) care may differ from recommended guidelines and affect health care utilization.</p> <p>Methods</p> <p>We analyzed 2001-2006 healthcare claims data from 45 large employers. Study subjects had diagnoses of CF and at least 1 prescription for TIS. We measured adherence as the number of TIS therapy cycles completed during the year and categorized overall adherence as: low ≤ 2 cycles, medium >2 to <4 cycles, and high ≥ 4 cycles per year. Interquartile ranges (IQR) were created for health care utilization and logistic regression analysis of hospitalization risk was conducted by TIS adherence categories.</p> <p>Results</p> <p>Among 804 individuals identified with CF and a prescription for TIS, only 7% (n = 54) received ≥ 4 cycles of TIS per year. High adherence with TIS was associated with a decreased risk of hospitalization when compared to individuals receiving ≤ 2 cycles (adjusted odds ratio 0.40; 95% confidence interval 0.19-0.84). High adherence with TIS was also associated with lower outpatient service costs (IQR: $2,159-$8444 vs. $2,410-$14,423) and higher outpatient prescription drug costs (IQR: $35,125-$60,969 vs. $10,353-$46,768).</p> <p>Conclusions</p> <p>Use of TIS did not reflect recommended guidelines and may impact other health care utilization.</p

Clinical outcomes in patients treated for coronary in-stent restenosis with drug-eluting balloons: Impact of high platelet reactivity.

BACKGROUND: The impact of high platelet reactivity (HPR) on clinical outcomes after elective percutaneous coronary interventions (PCI) with drug-eluting balloons (DEB) due to in-stent restenosis (ISR) is unknown. OBJECTIVE: We sought to evaluate the prognostic importance of HPR together with conventional risk factors in patients treated with DEB. METHODS: Patients treated with DEB due to ISR were enrolled in a single-centre, prospective registry between October 2009 and March 2015. Only patients with recent myocardial infarction (MI) received prasugrel, others were treated with clopidogrel. HPR was defined as an ADP-test >46U with the Multiplate assay and no adjustments were done based on results. The primary endpoint of the study was a composite of cardiovascular mortality, MI, any revascularization or stroke during one-year follow-up. RESULTS: 194 stable angina patients were recruited of whom 90% were treated with clopidogrel. Clinical characteristics and procedural data were available for all patients; while platelet function testing was performed in 152 subjects of whom 32 (21%) had HPR. Patients with HPR had a higher risk for the primary endpoint (HR: 2.45; CI: 1.01-5.92; p = 0.03). The difference was primarily driven by a higher risk for revascularization and MI. According to the multivariate analysis, HPR remained a significant, independent predictor of the primary endpoint (HR: 2.88; CI: 1.02-8.14; p = 0.04), while total DEB length and statin treatment were other independent correlates of the primary outcome. CONCLUSION: HPR was found to be an independent predictor of repeat revascularization and MI among elective patients with ISR undergoing PCI with DEB

Complete response for advanced liver cancer during sorafenib therapy: Case Report

<p>Abstract</p> <p>Background</p> <p>Hepatocellular carcinoma (HCC) is the fifth most common neoplasia in the world. In the past, treatment of advanced HCC with conventional antineoplastic drugs did not result in satisfactory outcomes: recently, in this patient population the oral multikinase inhibitor sorafenib has been able to induce a statistically significant improvement of overall survival. Similarly to other anti-angiogenic drugs employed in other tumour types, also sorafenib seldom induces the dimensional tumour shrinking usually observed with conventional cytotoxic drugs: data gathered from studies carried out with sorafenib and other competitors under development do not report any complete response in HCV-induced HCC.</p> <p>Case presentation</p> <p>An 84-year old man with a long-lasting history of chronic HCV hepatitis was referred to our Institution for an ultrasonography investigation of a focal hepatic lesion. To better characterize the liver disease and clearly define the diagnosis of the focal hepatic lesion, the patient was hospitalized in our department. Laboratory and instrumental investigations confirmed the clinical picture of HCV-related liver cirrhosis and identified a hepatic lesion of about 6 cm featuring infiltrating HCC with thrombosis of the portal trunk. Due to the advanced stage of the disease, therapy with sorafenib 400 mg bid was started. Right from one month after the treatment was started, a reduction of alpha-fetoprotein level was observed which, by the third month, turned down within the normal limits. In addition the CT scan showed 50% reduction of the neoplastic lesion along with canalization of the portal trunk. At the sixth month the normalization of the alpha-fetoprotein level at the lower limit of normality was confirmed and the MRI showed complete disappearance of the neoplasia. In addition a reduction of a metallo-proteinase serum level was obserdved. At the twelfth month a further MRI confirmed complete response had been maintained. At present the patient is in a follow-up program to evaluate the duration of the complete response.</p> <p>Conclusions</p> <p>This case is worth mentioning since, to the best of our knowledge, it represents the first evidence of complete response to sorafenib in an elderly patient with advanced HCV-related HCC.</p

Population-Attributable Risks for Ischemic Stroke in a Community in South Brazil: A Case-Control Study

Background: Risk factors for ischemic stroke are mostly known, but it is still unclear in most countries, what are their combined population-attributable risk percent (PAR%). In a case-control study the individual odds ratios (ORs) and the individual and combined PAR%, including risk factors not addressed in previous studies were estimated. Methods: Cases and controls were selected from patients attending to an emergency department. Cases were patients aged with 45 years or more with the first episode of ischemic stroke, characterized by a focal neurological deficit or change in the mental status occurring during the previous 24 hours. Controls, matched to cases by age and gender, were selected from patients without neurological complaints. Results: 133 cases and 272 controls were studied. Odds ratios for ischemic stroke were: atrial fibrillation (27.3; CI 95 % 7.5

A search for the decay modes B+/- to h+/- tau l

We present a search for the lepton flavor violating decay modes B+/- to h+/- tau l (h= K,pi; l= e,mu) using the BaBar data sample, which corresponds to 472 million BBbar pairs. The search uses events where one B meson is fully reconstructed in one of several hadronic final states. Using the momenta of the reconstructed B, h, and l candidates, we are able to fully determine the tau four-momentum. The resulting tau candidate mass is our main discriminant against combinatorial background. We see no evidence for B+/- to h+/- tau l decays and set a 90% confidence level upper limit on each branching fraction at the level of a few times 10^-5.Comment: 15 pages, 7 figures, submitted to Phys. Rev.