Functional impairment of human resident cardiac stem cells by the cardiotoxic antineoplastic agent trastuzumab

Trastuzumab (TZM), a monoclonal antibody against the ERBB2 protein, increases survival in ERBB2-positive breast cancer patients. Its clinical use, however, is limited by cardiotoxicity. We sought to evaluate whether TZM cardiotoxicity involves inhibition of human adult cardiac-derived stem cells, in addition to previously reported direct adverse effects on cardiomyocytes. To test this idea, we exposed human cardiosphere-derived cells (hCDCs), a natural mixture of cardiac stem cells and supporting cells that has been shown to exert potent regenerative effects, to TZM and tested the effects in vitro and in vivo. We found that ERBB2 mRNA and protein are expressed in hCDCs at levels comparable to those in human myocardium. Although clinically relevant concentrations of TZM had no effect on proliferation, apoptosis, or size of the c-kit-positive hCDC subpopulation, in vitro assays demonstrated diminished potential for cardiogenic differentiation and impaired ability to form microvascular networks in TZM-treated cells. The functional benefit of hCDCs injected into the border zone of acutely infarcted mouse hearts was abrogated by TZM: infarcted animals treated with TZM + hCDCs had a lower ejection fraction, thinner infarct scar, and reduced capillary density in the infarct border zone compared with animals that received hCDCs alone (n = 12 per group). Collectively, these results indicate that TZM inhibits the cardiomyogenic and angiogenic capacities of hCDCs in vitro and abrogates the morphological and functional benefits of hCDC transplantation in vivo. Thus, TZM impairs the function of human resident cardiac stem cells, potentially contributing to TZM cardiotoxicity

Toy gun eye injuries - eye protection needed Helsinki ocular trauma study

Purpose We report the epidemiology, findings, treatment, long-term outcome and use of resources for eye injuries caused by toy guns in southern Finland. Methods All new patients injured by toy guns in one year (2011-2012) and treated at Helsinki University Eye Hospital were included. Follow-ups occurred at 3 months and 5 years. Results Toy guns caused 15 eye traumas (1% of all eye traumas). Most patients were male (n = 14) and children aged under 16 years (n = 13). Toy guns involved were airsoft guns (n = 12), pea shooters (n = 2) and paintball (n = 1). Eleven patients did not use protective eyewear, and four patients discontinued their use during the game. Seven patients were not active participants in the game. Blunt ocular trauma was the primary diagnosis in 13 patients and corneal abrasion in two. Seven patients had retinal findings. In the 5-year follow-up, eight of 15 patients had abnormal ocular findings: three had artificial intraocular lens, two iridodialysis, and one each retinal plomb, mydriasis or iris tear. None had glaucoma. Seven patients had permanent subjective impairment due to pain, lowered visual acuity, blur or difficulty in focusing. Four patients needed seven operations. The number of outpatient visits was 90. One patient required hospitalization. Conclusion Toy guns cause serious eye traumas. No glaucoma was found. Proper use of toy guns and protective eyewear during the whole game should be emphasized to both players and bystanders. We recommend that in Finland the selling of airsoft guns be placed under the Firearms Act to make the hazards of airsoft guns known.Peer reviewe

Gadolinium Enhanced MR Coronary Vessel Wall Imaging at 3.0 Tesla

Purpose. We evaluated the influence of the time between low-dose gadolinium (Gd) contrast administration and coronary vessel wall enhancement (LGE) detected by 3T magnetic resonance imaging (MRI) in healthy subjects and patients with coronary artery disease (CAD). Materials and Methods. Four healthy subjects (4 men, mean age 29 ± 3 years and eleven CAD patients (6 women, mean age 61 ± 10 years) were studied on a commercial 3.0 Tesla (T) whole-body MR imaging system (Achieva 3.0 T; Philips, Best, The Netherlands). T1-weighted inversion-recovery coronary magnetic resonance imaging (MRI) was repeated up to 75 minutes after administration of low-dose Gadolinium (Gd) (0.1 mmol/kg Gd-DTPA). Results. LGE was seen in none of the healthy subjects, however in all of the CAD patients. In CAD patients, fifty-six of 62 (90.3%) segments showed LGE of the coronary artery vessel wall at time-interval 1 after contrast. At time-interval 2, 34 of 42 (81.0%) and at time-interval 3, 29 of 39 evaluable segments (74.4%) were enhanced. Conclusion. In this work, we demonstrate LGE of the coronary artery vessel wall using 3.0 T MRI after a single, low-dose Gd contrast injection in CAD patients but not in healthy subjects. In the majority of the evaluated coronary segments in CAD patients, LGE of the coronary vessel wall was already detectable 30–45 minutes after administration of the contrast agent

Acute nifedipine withdrawal: Consequences of preoperative and late cessation of therapy in patients with prior unstable angina

Reports of acute ischemic events after withdrawal of calcium antagonist therapy in outpatients and during bypass surgery in patients with prior angina at rest prompted the examination of the effect of nifedipine withdrawal in 81 patients who had completed a prospective, double-blind randomized trial of nifedipine versus placebo for rest angina. Thirty-nine patients underwent bypass surgery for uncontrolled angina or left main coronary artery disease. No significant difference between patients withdrawn from nifedipine or placebo was seen in the incidence of perioperative myocardial infarction, hypotension requiring intraaortic balloon counterpulsation, vasopressor or vasodilator requirements or incidence of significant arrhythmias.An additional 42 patients had completed 2 years on a protocol consisting of nitrates and propranolol in addition to nifedipine or placebo. During a mean of 66 hours of continuous monitoring after withdrawal of nifedipine or placebo, heart rate and blood pressure were unchanged. A worsening of previously present angina at rest occurred in five patients who had continued to experience rest angina before drug withdrawal, four of whom were withdrawn from nifedipine. No patient with class I to III angina experienced new onset of rest angina during drug withdrawal. No patient experienced myocardial infarction. There was no significant difference between patients withdrawn from nifedipine or placebo in the duration or frequency of ischemic ST changes on continuous electrocardiographic monitoring, or in duration or positive results of serial exercise treadmill testing.Thus, no early adverse effects of acute nifedipine withdrawal were found in patients with prior rest angina at the time of bypass surgery or in stable patients receiving long-term medical therapy. Patients with continued symptoms of rest angina, however, may experience adverse ischemic events with nifedipine withdrawal

Prevalence of variations in melanoma susceptibility genes among Slovenian melanoma families

<p>Abstract</p> <p>Background</p> <p>Two high-risk genes have been implicated in the development of CM (cutaneous melanoma). Germline mutations of the CDKN2A gene are found in < 25% of melanoma-prone families and there are only seven families with mutation of the <it>CDK4 </it>gene reported to date. Beside those high penetrance genes, certain allelic variants of the <it>MC1R </it>gene modify the risk of developing the disease.</p> <p>The aims of our study were: to determine the prevalence of germline <it>CDKN2A </it>mutations and variants in members of families with familial CM and in patients with multiple primary CM; to search for possible <it>CDK4 </it>mutations, and to determine the frequency of variations in the <it>MC1R </it>gene.</p> <p>Methods</p> <p>From January 2001 until January 2007, 64 individuals were included in the study. The group included 28 patients and 7 healthy relatives belonging to 25 families, 26 patients with multiple primary tumors and 3 children with CM. Additionally 54 healthy individuals were included as a control group. Mutations and variants of the melanoma susceptibility genes were identified by direct sequencing.</p> <p>Results</p> <p>Seven families with CDKN2A mutations were discovered (7/25 or 28.0%). The L94Q mutation found in one family had not been previously reported in other populations. The D84N variant, with possible biological impact, was discovered in the case of patient without family history but with multiple primary CM. Only one mutation carrier was found in the control group. Further analysis revealed that c.540C>T heterozygous carriers were more common in the group of CM patients and their healthy relatives (11/64 vs. 2/54). One p14ARF variant was discovered in the control group and no mutations of the <it>CDK4 </it>gene were found.</p> <p>Most frequently found variants of the <it>MC1R </it>gene were T314T, V60L, V92M, R151C, R160W and R163Q with frequencies slightly higher in the group of patients and their relatives than in the group of controls, but the difference was statistically insignificant.</p> <p>Conclusion</p> <p>The present study has shown high prevalence of p16INK4A mutations in Slovenian population of familial melanoma patients (37%) and an absence of p14ARF or <it>CDK4 </it>mutations.</p

Pathway Analysis for Genome-Wide Association Study of Basal Cell Carcinoma of the Skin

Recently, a pathway-based approach has been developed to evaluate the cumulative contribution of the functionally related genes for genome-wide association studies (GWASs), which may help utilize GWAS data to a greater extent.In this study, we applied this approach for the GWAS of basal cell carcinoma (BCC) of the skin. We first conducted the BCC GWAS among 1,797 BCC cases and 5,197 controls in Caucasians with 740,760 genotyped SNPs. 115,688 SNPs were grouped into gene transcripts within 20 kb in distance and then into 174 Kyoto Encyclopedia of Genes and Genomes pathways, 205 BioCarta pathways, as well as two positive control gene sets (pigmentation gene set and BCC risk gene set). The association of each pathway with BCC risk was evaluated using the weighted Kolmogorov-Smirnov test. One thousand permutations were conducted to assess the significance.Both of the positive control gene sets reached pathway p-values<0.05. Four other pathways were also significantly associated with BCC risk: the heparan sulfate biosynthesis pathway (p  =  0.007, false discovery rate, FDR  =  0.35), the mCalpain pathway (p  =  0.002, FDR  =  0.12), the Rho cell motility signaling pathway (p  =  0.011, FDR  =  0.30), and the nitric oxide pathway (p  =  0.022, FDR  =  0.42).We identified four pathways associated with BCC risk, which may offer new insights into the etiology of BCC upon further validation, and this approach may help identify potential biological pathways that might be missed by the standard GWAS approach

Geriatric patients' expectations of their physicians: findings from a tertiary care hospital in Pakistan

<p>Abstract</p> <p>Background</p> <p>Geriatric health is a neglected and under-explored area internationally and in Pakistan. We aimed to ascertain the expectations of the geriatric patients from their physicians and the factors associated with patient satisfaction in this particular age bracket.</p> <p>Methods</p> <p>A cross-sectional survey was carried out at a tertiary care teaching hospital in Karachi, Pakistan. Data collection was carried out via face-to-face interviews based on structured, pre-tested questionnaires. All consenting individuals aged 65 years or above were recruited into the study. Convenience sampling was used to draw the sample. The data was analyzed using SPSS version 16. Geriatric patient's expectations from physicians were elicited using a set of 11 questions that were graded on a scale of 1-3 where 1 = not important, 2 = important, 3 = very important.</p> <p>Results</p> <p>Three hundred and eighty geriatric patients were interviewed. The response rate of this study was 89.8%. The mean age of the respondents was 73.4 ± 6.8 years. Two hundred and forty eight respondents (65.3%) were female. Diabetes mellitus (53.7%), hypertension (59.5%), arthritis (40.5%) and renal disease (32.1%) were common ailments among geriatric patients. More than 50% of the patients were visiting their physicians once every two to three months. Discussing treatment options and letting patients make the final decision (79.2%), prescribing minimum possible medications (84.5%), physician's holistic knowledge about the spectrum of care issues for geriatric patients (79.2%), being given a realistic but optimistic picture of future health by physicians (85.5%) were ranked as very important expectations by patients from their physicians. Cumulative household income (p = 0.005), most important health complaint (p = 0.01) and frequency of experiencing health complaint (p < 0.001) emerged as independent predictors of the satisfaction of geriatric patients from care provided by physicians.</p> <p>Conclusion</p> <p>We have documented the expectations of the geriatric patients from their physicians in a developing country. Physicians belonging to all disciplines should keep these expectations in mind during clinical encounters with geriatric patients.</p