Cardiac shockwave therapy in patients with chronic refractory angina pectoris.

BACKGROUND: Cardiac shockwave therapy (CSWT) might improve symptoms and decrease ischaemia burden by stimulating collateral growth in chronic ischaemic myocardium. This prospective study was performed to evaluate the feasibility and safety of CSWT. METHODS: We included 33 patients (mean age 70 ± 7 years, mean left ventricular ejection fraction 55 ± 12 %) with end-stage coronary artery disease, chronic angina pectoris and reversible ischaemia on myocardial scintigraphy. CSWT was applied to the ischaemic zones (3-7 spots/session, 100 impulses/spot, 0.09 mJ/mm(2)) in an echocardiography-guided and ECG-triggered fashion. The protocol included a total of 9 treatment sessions (3 treatment sessions within 1 week at baseline, and after 1 and 2 months). Clinical assessment was performed using exercise testing, angina score (CCS class), nitrate use, myocardial scintigraphy, and cardiac magnetic resonance (CMR) 1 and 4 months after the last treatment session. RESULTS: One and 4 months after CSWT, sublingual nitrate use decreased from 10/week to 2/week (p < 0.01) and the angina symptoms diminished from CCS class III to CCS class II (p < 0.01). This clinical improvement was accompanied by an improved myocardial uptake on stress myocardial scintigraphy (54.2 ± 7.7 % to 56.4 ± 9.4 %, p = 0.016) and by increased exercise tolerance at 4-month follow-up (from 7.4 ± 2.8 to 8.8 ± 3.6 min p = 0.015). No clinically relevant side effects were observed. CONCLUSION: CSWT improved symptoms and reduced ischaemia burden in patients with end-stage coronary artery disease without relevant side effects. The study provides a solid basis for a randomised multicentre trial to establish CSWT as a new treatment option in end-stage coronary artery disease.

A kinase inhibitor screen reveals MEK1/2 as a novel therapeutic target to antagonize IGF1R-mediated antiestrogen resistance in ERα-positive luminal breast cancer.

Antiestrogen resistance of breast cancer has been related to enhanced growth factor receptor expression and activation. We have previously shown that ectopic expression and subsequent activation of the insulin-like growth factor-1 receptor (IGF1R) or the epidermal growth factor receptor (EGFR) in MCF7 or T47D breast cancer cells results in antiestrogen resistance. In order to identify novel therapeutic targets to prevent this antiestrogen resistance, we performed kinase inhibitor screens with 273 different inhibitors in MCF7 cells overexpressing IGF1R or EGFR. Kinase inhibitors that antagonized antiestrogen resistance but are not directly involved in IGF1R or EGFR signaling were prioritized for further analyses. Various ALK (anaplastic lymphoma receptor tyrosine kinase) inhibitors inhibited cell proliferation in IGF1R expressing cells under normal and antiestrogen resistance conditions by preventing IGF1R activation and subsequent downstream signaling; the ALK inhibitors did not affect EGFR signaling. On the other hand, MEK (mitogen-activated protein kinase kinase)1/2 inhibitors, including PD0325901, selumetinib, trametinib and TAK-733, selectively antagonized IGF1R signaling-mediated antiestrogen resistance but did not affect cell proliferation under normal growth conditions. RNAseq analysis revealed that MEK inhibitors PD0325901 and selumetinib drastically altered cell cycle progression and cell migration networks under IGF1R signaling-mediated antiestrogen resistance. In a group of 219 patients with metastasized ER + breast cancer, strong pMEK staining showed a significant correlation with no clinical benefit of first-line tamoxifen treatment. We propose a critical role for MEK activation in IGF1R signaling-mediated antiestrogen resistance and anticipate that dual-targeted therapy with a MEK inhibitor and antiestrogen could improve treatment outcome.

Microsatellite mapping of Ae. speltoides and map-based comparative analysis of the S, G, and B genomes of Triticeae species.

The first microsatellite linkage map of Ae. speltoides Tausch (2n = 2x = 14, SS), which is a wild species with a genome closely related to the B and G genomes of polyploid wheats, was developed based on two F(2) mapping populations using microsatellite (SSR) markers from Ae. speltoides, wheat genomic SSRs (g-SSRs) and EST-derived SSRs. A total of 144 different microsatellite loci were mapped in the Ae. speltoides genome. The transferability of the SSRs markers between the related S, B, and G genomes allowed possible integration of new markers into the T. timopheevii G genome chromosomal maps and map-based comparisons. Thirty-one new microsatellite loci assigned to the genetic framework of the T. timopheevii G genome maps were composed of wheat g-SSR (genomic SSR) markers. Most of the used Ae. speltoides SSRs were mapped onto chromosomes of the G genome supporting a close relationship between the G and S genomes. Comparative microsatellite mapping of the S, B, and G genomes demonstrated colinearity between the chromosomes within homoeologous groups, except for intergenomic T6A(t)S.1G, T4AL.5AL.7BS translocations. A translocation between chromosomes 2 and 6 that is present in the T. aestivum B genome was found in neither Ae. speltoides nor in T. timopheevii. Although the marker order was generally conserved among the B, S, and G genomes, the total length of the Ae. speltoides chromosomal maps and the genetic distances between homoeologous loci located in the proximal regions of the S genome chromosomes were reduced compared with the B, and G genome chromosomes.

Socio-demographic and clinical factors influencing the adherence to treatment in Parkinson's disease: the ADHESON study.

BACKGROUND: Symptoms of Parkinson's disease (PD) are usually controlled by a continuous titration of medication and addition of multiple therapies over the course of the disease. Therapeutic complex schemes, polymedication, comorbidities and the number of medications required contribute to non-adherence. METHODS: This cross-sectional survey was performed in 418 patients with PD on treatment with any antiparkinsonian medication. Patient adherence was assessed through physicians' subjective perception and the Morisky-Green test (MGT). Several social, demographic and clinical features were correlated through bivariate and multivariate analyses. RESULTS: According to the physician's opinion 93.7%, and according to the MGT 60.4% of patients were adherent to parkinsonian therapy. The bivariate analysis showed greater adherence in patients with a high level of knowledge about the disease (62.8%), good clinical control (63.6%), a spouse or life partner (63%) and higher incomes (66%). Negative correlation with psychiatric symptoms was found. In relation to the MGT, the logistic regression model showed a negative correlation between cognitive deterioration and psychiatric pathology and adherence to therapy. CONCLUSIONS: The physician's impression overestimated the compliance of patients when compared with an objective evaluation such as the MGT. Cognitive impairment and psychiatric symptoms are the clinical variables associated with a lower level of adherence.

Corneal endothelial cell density during diabetes mellitus and ocular diabetes complications treatment.

Diabetes mellitus may affect the cornea at various levels. Ocular surface changes and dry eye had been studied. Researchers are concerned that medical treatment of diabetes or retinal complications may result in endothelial damage and cell loss. This report summarizes the possibility of endothelial cell loss in diabetic patients. A decrease in endothelial cell density (ECD) in diabetic patients has been reported. In addition, corneal thickness may increase in diabetic patients. Significant endothelial cell loss has been demonstrated in long-term disease and in cases of poor metabolic control. No association between the use of oral hypoglycemics and ECD has been reported. There is also no evidence of an association between the use of insulin and corneal endothelial damage. No difference in ECD among the various degrees of retinopathy or with a history of photocoagulation has been shown. Regarding the studies comparing diabetic and non-diabetic patients undergoing cataract surgery, in all cases, the decrease in ECD is higher in diabetic patients than that seen in non-diabetic patients. However, there is no evidence of increased endothelial damage in diabetics compared to non-diabetics during vitreo-retinal surgery in phakic eyes. No significant changes in corneal endothelium after intravitreal anti-VEGF injections have been referenced.

Mass carbon monoxide poisoning among television viewers of a football match. / Brote masivo de intoxicación por monóxido de carbono en los telespectadores de un partido de fútbol.

BACKGROUND: The objective was to study a mass carbon monoxide (CO) poisoning and the characteristics of the asymptomatic cases. METHODS: On the 2nd of February, 2015, a group of more than 30 television viewers of a football match contacted the emergency department due to suspected CO poisoning from a butane stove. A visual inspection of the location of the exposure and a descriptive epidemiological study were conducted. Based on the type of variable, the presence of a statistical association was studied with Fisher's exact test or the Kruskal-Wallis test. RESULTS: Thirty-four of the 39 individuals were affected (87.2%). The exposed individuals had a mean age of 43.8 years (SD, 22.1), and 28.2% (11/39) were women. The time of exposure was 52.4min (SD, 21.0), and the mean distance from the oven was 4.2m (SD, 2.5). The most common symptoms were headache (50%), nausea (20.6%), weakness (20.6%) and dizziness (14.7%). The carboxyhaemoglobin (COHb) levels were very high (13.8% ±5.8%). Some 97.1% of the individuals required oxygen therapy, and 39.4% required hyperbaric chamber treatment. Some 29.5% of the cases had no symptoms but showed COHb levels similar to those that did have symptoms (13.6% vs. 15.3%, nonsignificant difference). The asymptomatic cases had a shorter exposure time (38.3min vs. 53.3min; P<.036). CONCLUSIONS: Almost a third of the exposed individuals were asymptomatic, even with COHb levels similar to those of the symptomatic patients, and the majority of these asymptomatic patients even required oxygen treatment in a hyperbaric chamber.

[Dietetic and pharmacologic treatment of hypercholesterolemia. Study of 32 patients over 14 months]. / Trattamento dietetico e farmacologico delle ipercolesterolemie. Studio su 32 pazienti della durata di 14 mesi.

The aim of the study was to evaluate the effectiveness of dietetic-behavioural and pharmacological treatment on 32 patients with high level hypercholesterolemia (LDL-c greater than 160 mg/dl) over 14 months. Clinical and laboratory tests were performed at time 0 (enrollment), at time 1 (after 2 months dietetic-behavioural treatment only), at time 2 and time 3 (after 6 and 12 months respectively of combined dietetic-behavioural and pharmacological treatment). The dietetic-behavioural treatment consist of reduced intake of saturated fatty acids, cholesterol and rapidly absorbed glycid; increased intake of omega-3 fatty acids and fiber; reduced overall calorie intake. The patients were also advised to take light daily exercise. The pharmacological treatment (sinivastatin 20 mg/die) was given to patients whose total cholesterol levels were over 250 mg/dl after 60 days of dietetic-behavioural only treatment and then continued for the whole study. The result showed an average reduction of 20% (p less than 0.01) in LDL-c in all patients after dietetic-behavioural only treatment and a further 20% (p less than 0.01) reduction after 12 months of combined treatment. There was therefore confirmation of the validity of dietetic-behavioural and pharmacological treatment during our study.

CUSUM analysis of brachial artery access for peripheral endovascular interventions.

AIM: Evaluate efficacy and safety of diagnostic and therapeutic endovascular interventions performed through transbrachial approach. Transbrachial artery catheterization has long been considered a secondary access site due to its related complication rate (7-11%). Low-profile and long-delivery endovascular systems, however, are reviving the interest in this approach. METHODS: We retrospectively analysed all endovascular interventions attempted through a brachial artery access from 2003 to 2010. Two hundredth thirty seven consecutive patients (mean age 68.5 years, 89.5% male) underwent 168 transbrachial diagnostic (70.9%) and 69 therapeutic procedures (29.1%), characterised by micropuncture access (100%), 4-to-7 Fr sheath delivery systems and final digital compression (100%). CUSUM curves were created to evaluate learning effects and quality of care. RESULTS: All but one procedure were completed according to their scheduled intention. The overall complication rate was 5.5% (5 pseudoaneurysms (2.1%), 4 transient ischemic attack (1.7%), 3 brachial artery thromboses (1.3%) and 1 cardiac tamponade (0.4%). Surgical intervention was required in four of these patients (30.8%). No significant differences were observed according to age or sex. CUSUM curves created at a 2% theoretical risk showed two statistically significant upward inflections: one early in the series associated with diagnostic procedures (P=0.043) and another at the end of the study related to therapeutic interventions (P=0.018). CONCLUSION: Transbrachial catheterization is an effective and relatively safe access site for endovascular procedures. Its complication rate, although lower than before, still deserve it as a secondary access site. CUSUM curves let identify learning effects in diagnostic and interventional procedures.

Annexin A2 depletion delays EGFR endocytic trafficking via cofilin activation and enhances EGFR signaling and metastasis formation.

Enhanced epidermal growth factor receptor (EGFR) activity has been strongly linked to breast cancer progression and mediators of EGFR endocytosis may well be involved. We developed a semi-automated high-content fluorescence microscopy-based EGFR endocytosis screen to identify proteins that mediate EGFR endocytosis in human HBL100 breast cancer cells. Knockdown of 172 individual endocytosis and actin-regulatory genes with small interfering RNAs led to the identification of 14 genes of which the contribution to EGFR endocytosis in breast cancer is until now poorly defined, including DNAJC6, GDI2, FGD6, HAX1, NECAP2 and AnxA2. We show that depletion of the actin and endocytosis regulatory protein annexin A2 (AnxA2) in a panel of four triple negative breast cancer (TNBC) cell lines affected EGFR endocytosis. Depletion of AnxA2 in the aggressive and highly metastatic MDA-MB-231 TNBC cell line resulted in the inhibition of EGFR transport beyond the early endosomes. This inhibition coincided with enhanced epidermal growth factor (EGF)-induced cell migration and downstream signaling via c-Jun N-terminal kinase (JNK) and Akt. Moreover, AnxA2 knockdown increased lung metastasis formation in mice. The effect of AnxA2 knockdown on EGFR endocytosis in MDA-MB-231 was related to dephosphorylation/activation of the actin-severing protein cofilin, as re-expression of an inactive S3E-cofilin mutant, but not an active S3A-cofilin mutant, re-established EGFR endocytosis to control levels. Together, our data provide evidence for AnxA2 as a mediator of EGFR endocytosis and signaling in breast cancer via regulation of cofilin activation.

Identification of glycosyltransferases involved in cell wall synthesis of wheat endosperm.

Plant cell walls are complex structures critical for plant fitness and valuable for human nutrition as dietary fiber and for industrial uses such as biofuel production. The cell wall polysaccharides in wheat endosperm consist of two major polymers, arabinoxylans and beta-glucans, as well as other minor components. Most of these polysaccharides are synthesized in the Golgi apparatus but the mechanisms underlying their synthesis have yet to be fully elucidated and only a few of the enzymes involved have been characterized. To identify actors involved in the wheat endosperm cell wall formation, we used a subcellular fractionation strategy to isolate Golgi-enriched fractions from endosperm harvested during active cell wall deposition. The proteins extracted from these Golgi-enriched fractions were analyzed by LC-MS/MS. We report the identification of 1135 proteins among which 64 glycosyltransferases distributed in 17 families. Their potential function in cell wall synthesis is discussed. In addition, we identified 63 glycosylhydrolases, some of which may be involved in cell wall remodeling. Several glycosyltransferases were validated by showing that when expressed as fusion proteins with a fluorescent reporter, they indeed accumulate in the Golgi apparatus. Our results provide new candidates potentially involved in cell wall biogenesis in wheat endosperm.

Young children with Velo-Cardio-Facial syndrome (CATCH-22). Psychological and language phenotypes.

This is the first clinical description of a detailed psychological, speech, and language phenotype of four young children (< 5 years) with Velo-Cardio-Facial syndrome (VCFS) due to a deletion on chromosome 22 (22q11.2). The reported elevated risk of developing schizophrenia or bipolar disorder in adolescence for individuals with this chromosomal deletion led us to examine the psychiatric and cognitive status of young children with VCFS. Our observations suggest a phenotype comprised of a borderline to mildly retarded level of intellectual functioning, a language delay, a general deficit in social initiation, difficulties with attention/concentration, and a perturbed train of thought.