Different methylation signatures at diagnosis in patients with high-risk myelodysplastic syndromes and secondary acute myeloid leukemia predict azacitidine response and longer survival.

BACKGROUND: Epigenetic therapy, using hypomethylating agents (HMA), is known to be effective in the treatment of high-risk myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) patients who are not suitable for intensive chemotherapy and/or allogeneic stem cell transplantation. However, response rates to HMA are low and there is an unmet need in finding prognostic and predictive biomarkers of treatment response and overall survival. We performed global methylation analysis of 75 patients with high-risk MDS and secondary AML who were included in CETLAM SMD-09 protocol, in which patients received HMA or intensive treatment according to age, comorbidities and cytogenetic. RESULTS: Unsupervised analysis of global methylation pattern at diagnosis did not allow patients to be differentiated according to the cytological subtype, cytogenetic groups, treatment response or patient outcome. However, after a supervised analysis we found a methylation signature defined by 200 probes, which allowed differentiating between patients responding and non-responding to azacitidine (AZA) treatment and a different methylation pattern also defined by 200 probes that allowed to differentiate patients according to their survival. On studying follow-up samples, we confirmed that AZA decreases global DNA methylation, but in our cohort the degree of methylation decrease did not correlate with the type of response. The methylation signature detected at diagnosis was not useful in treated samples to distinguish patients who were going to relapse or progress. CONCLUSIONS: Our findings suggest that in a subset of specific CpGs, altered DNA methylation patterns at diagnosis may be useful as a biomarker for predicting AZA response and survival.

Right bundle branch block: Prevalence, incidence, and cardiovascular morbidity and mortality in the general population.

Background: Right bundle branch block (RBBB) is among the most common electrocardiographic abnormalities. Objectives: To establish the prevalence and incidence of RBBB in the general population without cardiovascular events (CVE) and whether RBBB increases cardiovascular morbidity and mortality compared with patients with a normal electrocardiogram (ECG). Methods: A historical study of two cohorts including 2981 patients from 29 primary health centres without baseline CVE. Cox (for CVE) and logistic (for cardiovascular factors) regression was used to assess their association with RBBB. Results: Of the patients (58% women; mean age 65.9), 92.2% had a normal ECG, 4.6% incomplete RBBB (iRBBB) and 3.2% complete RBBB (cRBBB). Mean follow-up was five years. Factors associated with appearance of cRBBB were male sex (HR = 3.8; 95%CI: 2.4-6.1) and age (HR = 1.05 per year; 95%CI: 1.03-1.08). In a univariate analysis, cRBBB was associated with an increase in all-cause mortality but only bifascicular block (BFB) was significant after adjusting for confounders. cRBBB tended to increase CVE but the results were not statistically significant. Presence of iRBBB was not associated with adverse outcomes. Patients with iRBBB who progressed to cRBBB showed a higher incidence of heart failure and chronic kidney disease. Conclusion: In this general population cohort with no CV disease, 8% had RBBB, with a higher prevalence among men and elderly patients. Although all-cause mortality and CVE tended to increase in the presence of cRBBB, only BFB showed a statistically significant association with cRBBB. Patients with iRBBB who progressed to cRBBB had a higher incidence of CVE. We detected no effect of iRBBB on morbidity and mortality.

Diagnosis of right bundle branch block: a concordance study.

BACKGROUND: Right bundle branch block is one of the most common electrocardiographic abnormalities. Most cases of right bundle branch block are detected in asymptomatic patients in primary care, so a correct interpretation of electrocardiograms (ECGs) at this level is necessary. The objective of this research is to determine the degree of concordance in the diagnosis of incomplete and complete right bundle branch block between four primary care researchers and a cardiologist. METHODS: The research design is a retrospective cohort study of patients over 18 years of ages of patients over 18 years of ages who underwent an ECG for any reason and were diagnosed with right bundle branch block by their physician. The physicians participating, 4 primary care researchers and a cardiologist were specialized in interpreting electrocardiographic records. The diagnosis of incomplete and complete right bundle branch block was recorded and other secondary variables were analysed. In case of diagnostic discordance between the researchers, the ECGs were reviewed by an expert cardiologist, who interpreted them, established the diagnosis and analysed the possible causes for the discrepancy. RESULTS: We studied 160 patients diagnosed with right bundle branch block by their general practise. The patients had a mean age of 64.8 years and 54% of them were men. The concordance in the diagnosis of incomplete right bundle branch block showed a Fleiss' kappa index (k) of 0.71 among the five researchers and of 0.85 among only the primary care researchers. The k for complete right bundle branch block was 0.93 among the five researchers and 0.96 among only the primary care researchers. CONCLUSION: The interobserver agreement in the diagnosis of right bundle branch block performed by physicians specialized in ECG interpretation (primary care physicians and a cardiologist) was very good. The variability was greater for the diagnosis of incomplete right bundle branch block.

Involvement of opioid signaling in food preference and motivation: Studies in laboratory animals.

Motivation is a complex neurobiological process that initiates, directs, and maintains goal-oriented behavior. Although distinct components of motivated behavior are difficult to investigate, appetitive and consummatory phases of motivation are experimentally separable. Different neurotransmitter systems, particularly the mesolimbic dopaminergic system, have been associated with food motivation. Over the last two decades, however, research focusing on the role of opioid signaling has been particularly growing in this area. Opioid receptors seem to be involved, via neuroanatomically distinct mechanisms, in both appetitive and consummatory aspects of food reward. In the present chapter, we review the pharmacology and functional neuroanatomy of opioid receptors and their endogenous ligands, in the context of food reinforcement. We examine literature aimed at the development of laboratory animal techniques to better understand different components of motivated behavior. We present recent data investigating the effect of opioid receptor antagonists on food preference and effort-related decision making in rats, which indicate that opioid signaling blockade selectively affects intake of relatively preferred foods, resulting in reduced willingness to exert effort to obtain them. Finally, we elaborate on the potential role of opioid system manipulations in disorders associated with excessive eating and obesity.

Black hole physics. Black hole lightning due to particle acceleration at subhorizon scales.

Supermassive black holes with masses of millions to billions of solar masses are commonly found in the centers of galaxies. Astronomers seek to image jet formation using radio interferometry but still suffer from insufficient angular resolution. An alternative method to resolve small structures is to measure the time variability of their emission. Here we report on gamma-ray observations of the radio galaxy IC 310 obtained with the MAGIC (Major Atmospheric Gamma-ray Imaging Cherenkov) telescopes, revealing variability with doubling time scales faster than 4.8 min. Causality constrains the size of the emission region to be smaller than 20% of the gravitational radius of its central black hole. We suggest that the emission is associated with pulsar-like particle acceleration by the electric field across a magnetospheric gap at the base of the radio jet.

Bimodal magmatism produced by progressively inhibited crustal assimilation.

The origin of bimodal (mafic-felsic) rock suites is a fundamental question in volcanology. Here we use major and trace elements, high-resolution Sr, Nd and Pb isotope analyses, experimental petrology and thermodynamic modelling to investigate bimodal magmatism at the iconic Carlingford Igneous Centre, Ireland. We show that early microgranites are the result of extensive assimilation of trace element-enriched partial melts of local metasiltstones into mafic parent magmas. Melting experiments reveal the crust is very fusible, but thermodynamic modelling indicates repeated heating events rapidly lower its melt-production capacity. Granite generation ceased once enriched partial melts could no longer form and subsequent magmatism incorporated less fertile restite compositions only, producing mafic intrusions and a pronounced compositional gap. Considering the frequency of bimodal magma suites in the North Atlantic Igneous Province, and the ubiquity of suitable crustal compositions, we propose 'progressively inhibited crustal assimilation' (PICA) as a major cause of bimodality in continental volcanism.

Outcome and predictors of treatment failure in early post-surgical prosthetic joint infections due to Staphylococcus aureus treated with debridement.

Experience with debridement and prosthesis retention in early prosthetic joint infections (PJI) due to Staphylococcus aureus is scarce. The present study aimed to evaluate the outcome and predictors of failure. Patients prospectively registered with an early PJI due to S. aureus and 2 years of follow-up were reviewed. Demographics, co-morbidity, type of implant, clinical manifestations, surgical treatment, antimicrobial therapy and outcome were recorded. Remission was defined when the patient had no symptoms of infection, the prosthesis was retained and C-reactive protein (CRP) was ≤ 1 mg/dL. Univariate and multivariate analysis were performed. Fifty-three patients with a mean ± SD age of 70 ± 10.8 years were reviewed. Thirty-five infections were on knee prosthesis and 18 were on hip prosthesis. The mean ± SD duration of intravenous and oral antibiotics was 10.6 ± 6.7 and 88 ± 45.9 days, respectively. After 2 years of follow-up, 40 (75.5%) patients were in remission. Variables independently associated with failure were the need for a second debridement (OR 20.4, 95% CI 2.3-166.6, p 0.006) and a CRP > 22 mg/dL (OR 9.8, 95% CI 1.5-62.5, p 0.01). The onset of the infection within the 25 days after joint arthroplasty was at the limit of significance (OR 8.3, 95% CI 0.8-85.6, p 0.07). Debridement followed by a short period of antibiotics is a reasonable treatment option in early PJI due to S. aureus. Predictors of failure were the need for a second debridement to control the infection a CRP > 22 mg/dL and the infection onset within the first 25 days after joint arthroplasty.

Effects of the adenosine A 2A antagonist KW 6002 (istradefylline) on pimozide-induced oral tremor and striatal c-Fos expression: comparisons with the muscarinic antagonist tropicamide.

Typical antipsychotic drugs, including haloperidol and pimozide, have been shown to produce parkinsonian motor effects such as akinesia and tremor. Furthermore, there is an antagonistic interaction between adenosine A(2A) and dopamine D(2) receptors in the basal ganglia, which is important for motor functions related to the production of parkinsonian symptoms. Several experiments were conducted to assess the effects of the selective adenosine A(2A) antagonist KW 6002 on both the motor and cellular effects of subchronic administration of pimozide. The motor test employed was tremulous jaw movements, which is used as a model of parkinsonian tremor. In addition, c-Fos expression in the ventrolateral neostriatum, which is the striatal area most associated with tremulous jaw movements, was used as a marker of striatal cell activity in animals that were tested in the behavioral experiments. Repeated administration of 1.0 mg/kg pimozide induced tremulous jaw movements and increased ventrolateral striatal c-Fos expression, while administration of 20.0 mg/kg of the atypical antipsychotic quetiapine did not. The tremulous jaw movements induced by pimozide were significantly reduced by co-administration of either the adenosine A(2A) antagonist KW 6002 or the muscarinic antagonist tropicamide. Pimozide-induced increases in ventrolateral striatal c-Fos expression were reduced by a behaviorally effective dose of KW 6002, but c-Fos expression in pimozide-treated rats was actually increased by tropicamide. These results indicate that two different drug manipulations that act to reduce tremulous jaw movements can have different effects on DA antagonist-induced c-Fos expression, suggesting that adenosine A(2A) antagonism and muscarinic receptor antagonism exert their motor effects by acting on different striatal circuits.

Results of treatment of subtrochanteric femoral fractures with the AO/ASIF Long Trochanteric Fixation Nail (LTFN).

PURPOSE OF THE STUDY: This retrospective study reports on the clinical results of a group of 23 patients with subtrochanteric femoral fractures using the Long Trochanteric Fixation Nail (LTFN). MATERIAL: Between January 2005 and January 2008, 23 patients (20 women, 3 men; average age: 64.8 years old) with subtrochanteric femoral fractures were treated surgically. According to the AO/ASIF Classification, the most frequent fracture type was an 32-A1. They were also classified regarding the Seinsheimer Classification, in which the commonest type was the IIB. Of the 23 fractures, 14 of them had been the result of an unexpected fall, 2 were the result of a high-energy trauma and 7 consisted of pathologic fractures. METHODS: All the patients were treated using the LTFN device and they all received clinical and radiological follow-ups at least until their fractures were consolidated. The average surgery time, average decrease in haemoglobin in the first 24 hours post- surgery, average need for red blood cell transfusion, postoperative mortality at a 6th month follow-up, time to autonomous deambulation, most frequent destination at the time of discharge, average time for consolidation of the fracture and average follow-up time were reported. Intraoperative and postoperative complications were also recorded. RESULTS: The average surgery time from cut to stitch was 97.45 minutes with the decrease in haemoglobin averaging 26.45 g/L and, on average, the need for red blood cell transfusion was 1.12 concentrates. In the first postoperative week, 57.1% of the total number patients were capable of deambulation. The time to hospital discharge was 12.9 days. After an average follow-up of 13.9 months, total weightbearing was achieved in the 64.7% of the patients. The average consolidation time was 21.6 weeks and none of the patients developed pseudoarthrosis. Technical failures were seen in 4.3% of the cases: 1 patient suffered a migration of the distal locking screw. There were no cases of deep infection, cut-out, bending/breaking of the implant, malrotation or fracture of the femoral shaft at the tip of the implant. DISCUSSION: From a mechanical point of view the use of a long intramedullary nail in combination with a blade or a screw seems to be the most appropriate treatment for subtrochanteric fractures of the femur. Despite the improvement of implants and surgical techniques, failures due to complications are still considerable. The low distal shaft diameter of the LTFN, in combination with an extremely precise positioning of the blade in the middle of the femoral head, can prevent mechanical complications. Open reduction and cerclage cabling may be required so as to obtain a correct alignment of the fracture. CONCLUSION: We conclude that the LTFN is a safe and reliable intramedullary device for the treatment of subtrochanteric fractures of the femur. Deambulation within the first postoperative surgery is possible when positioned properly. Its implantation requires more surgical time than the standard nails.

[Complications after regional anesthesia]. / Complicaciones tras técnicas de anestesia regional.

In recent years, there has been a considerable increase in the number of procedures carried out under regional anesthesia. The techniques used can be associated with a number of complications, which should be understood so that they can be recognized and managed appropriately. The overall incidence of reported complications associated with these techniques is low and therefore, with currently available data, we can only have an approximate idea of their incidence. The objective of this study is to systematically describe the complications that may arise from the use of neuraxial and peripheral regional anesthesia techniques.

Observation of pulsed gamma-rays above 25 GeV from the Crab pulsar with MAGIC.

One fundamental question about pulsars concerns the mechanism of their pulsed electromagnetic emission. Measuring the high-end region of a pulsar's spectrum would shed light on this question. By developing a new electronic trigger, we lowered the threshold of the Major Atmospheric gamma-ray Imaging Cherenkov (MAGIC) telescope to 25 giga-electron volts. In this configuration, we detected pulsed gamma-rays from the Crab pulsar that were greater than 25 giga-electron volts, revealing a relatively high cutoff energy in the phase-averaged spectrum. This indicates that the emission occurs far out in the magnetosphere, hence excluding the polar-cap scenario as a possible explanation of our measurement. The high cutoff energy also challenges the slot-gap scenario.

Reduction in the anxiolytic effects of ethanol by centrally formed acetaldehyde: the role of catalase inhibitors and acetaldehyde-sequestering agents.

RATIONALE: Considerable evidence indicates that brain ethanol metabolism mediated by catalase is involved in modulating some of the behavioral and physiological effects of this drug, which suggests that the first metabolite of ethanol, acetaldehyde, may have central actions. Previous results have shown that acetaldehyde administered into the lateral ventricles produced anxiolysis in a novel open arena in rats. OBJECTIVES: The present studies investigate the effects of centrally formed acetaldehyde on ethanol-induced anxiolysis. MATERIALS AND METHODS: The effects of the catalase inhibitor sodium azide (SA; 0 or 10 mg/kg, IP) on ethanol-induced anxiolysis (0.0, 0.5, or 1.0 g/kg, IP) were evaluated in CD1 mice in two anxiety paradigms, the elevated plus maze and the dark/light box. Additional studies assessed the effect of the noncompetitive catalase inhibitor 3-amino-1,2,4-triazole (AT; 0.5 g/kg, IP) and the acetaldehyde inactivation agent D: -penicillamine (50 mg/kg, IP) on the plus maze. RESULTS: SA reduced the anxiolytic effects of ethanol on several parameters evaluated in the elevated plus maze and in the dark/light box. In the plus maze, AT completely blocked and D-penicillamine significantly reduced the anxiolytic properties of ethanol. CONCLUSIONS: Thus, when cerebral metabolism of ethanol into acetaldehyde is blocked by catalase inhibitors, or acetaldehyde is inactivated, there is a suppressive effect on the anxiolytic actions of ethanol. These data provide further support for the idea that centrally formed or administered acetaldehyde can contribute to some of the psychopharmacological actions of ethanol, including its anxiolytic properties.

Very-high-energy gamma rays from a distant quasar: how transparent is the universe?

The atmospheric Cherenkov gamma-ray telescope MAGIC, designed for a low-energy threshold, has detected very-high-energy gamma rays from a giant flare of the distant Quasi-Stellar Radio Source (in short: radio quasar) 3C 279, at a distance of more than 5 billion light-years (a redshift of 0.536). No quasar has been observed previously in very-high-energy gamma radiation, and this is also the most distant object detected emitting gamma rays above 50 gigaelectron volts. Because high-energy gamma rays may be stopped by interacting with the diffuse background light in the universe, the observations by MAGIC imply a low amount for such light, consistent with that known from galaxy counts.

Forebrain circuitry involved in effort-related choice: Injections of the GABAA agonist muscimol into ventral pallidum alter response allocation in food-seeking behavior.

Organisms often make effort-related choices based upon assessments of motivational value and work requirements. Nucleus accumbens dopamine is a critical component of the brain circuitry regulating work output in reinforcement-seeking behavior. Rats with accumbens dopamine depletions reallocate their instrumental behavior away from food-reinforced tasks that have high response requirements, and instead they select a less-effortful type of food-seeking behavior. The ventral pallidum is a brain area that receives substantial GABAergic input from nucleus accumbens. It was hypothesized that stimulation of GABA(A) receptors in the ventral pallidum would result in behavioral effects that resemble those produced by interference with accumbens dopamine transmission. The present studies employed a concurrent choice lever pressing/chow intake procedure; with this task, interference with accumbens dopamine transmission shifts choice behavior such that lever pressing for food is decreased but chow intake is increased. In the present experiments, infusions of the GABA(A) agonist muscimol (5.0-10.0 ng) into the ventral pallidum decreased lever pressing for preferred food, but increased consumption of the less preferred chow. In contrast, ventral pallidal infusions of muscimol (10.0 ng) had no significant effect on preference for the palatable food in free-feeding choice tests. Furthermore, injections of muscimol into a control site dorsal to the ventral pallidum produced no significant effects on lever pressing and chow intake. These data indicate that stimulation of GABA receptors in ventral pallidum produces behavioral effects similar to those produced by accumbens dopamine depletions. Ventral pallidum appears to be a component of the brain circuitry regulating response allocation and effort-related choice behavior, and may act to convey information from nucleus accumbens to other parts of this circuitry. This research may have implications for understanding the brain mechanisms involved in energy-related psychiatric dysfunctions such as psychomotor retardation in depression, anergia, and apathy.

Incidence of congenital hypothyroidism and congenital adrenal hyperplasia at Flushing Hospital Medical Center

BACKGROUND: Newborn screening (NBS) program is a simple and inexpensive method for early detection and treatment of over forty conditions as of 2005. Most cases of congenital hypothyroidism (CH) are sporadic and occurs in 1 in 3500 live births. Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive disorders that occurs in 1 in 1600 live births. The detection of CH is determined by either low T4 and/or elevated TSH and the detection of CAH is determined by elevated 17OH progesterone on Guthrie filter paper. Infants who meet the above criteria on NBS for either condition must undergo confirmatory testing. OBJECTIVE: Is the incidence of CH and CAH at FHMC, a community hospital in northern Queens, New York serving a multiethnic population different from theincidence of CH and CAH in New York State (NYS)? DESIGN/METHODS: We reviewed records of the infants recalled and confirmed to have CH and CAH for 2000, 2001 and 2004 and compared with reported incidence of the same conditions in NYS. RESULTS: The total number of live births in NYS was 760,112 and in FHMC 6348 for the three years studied, accounting for 0.7 to 0.8of total NYS live births. The population served by FHMC included 43White, 35Asian, 16Hispanic, 3Afro-American and 3other. A total of 5 patients were identified to have CH in the three years studied, accounting for an incidence of 0.12 (p > 0.05). Three patients were identified to have CAH in 2004 or an incidence of 1.4 (p < 0.05). [Table 1]. CONCLUSIONS: The incidence rate of CH was similar to that of NYS. However, the incidence rate of CAH at FHMC was greater than that reported by NYS. This difference in incidence rate for CAH may be related to the ethnic composition of the population that FHMC serves. Pediatricians and pediatric endocrinologists must be cognizant of the signs and symptoms of CAH in certain populations known to have higher incidence for this condition. Further follow up of incidence rate for CAH at FHMC is indicated since CAH was added to the NBS in 2003.

Exposure to non-arsenic pesticides is associated with lymphoma among farmers in Spain.

OBJECTIVES: To estimate the risk of lymphoma among farmers in Spain. METHODS: This is a multicentre case control study conducted in Spain. Cases were subjects diagnosed with lymphoma according to the World Health Organization (WHO) classification in four hospitals between 1998-2002. Hospital controls were frequency matched to the cases by sex, age, and centre. All subjects were interviewed about jobs ever held in lifetime for at least one year and the exposures in those jobs were recorded. The risk of lymphomas among subjects ever having had a job as a farmer was compared with all other occupations. Farmers were analysed according to the type of farming job performed: crop farming, animal farming, and general farming. Occupational exposure was summarised into 15 main categories: organic dust, radiation, contact with animals, PAH, non-arsenic pesticides (carbamates, organophosphates, chlorinated hydrocarbons, triazines and triazoles, phenoxy herbicides, chlorophenols, dibenzodioxin, and dibenzofuran), arsenic pesticides, contact with meat, contact with children, solvents, asbestos, soldering fumes, organic colourants, polychlorinated biphenyls, ethylene oxide, and hair dyes. RESULTS: Although farmers were not at an increased risk of lymphoma as compared with all other occupations, farmers exposed to non-arsenic pesticides were found to be at increased risk of lymphoma (OR = 1.8, 95% CI 1.1 to 2). This increased risk was observed among farmers working exclusively either as crop farmers or as animal farmers (OR = 2.8, 95% CI 1.3 to 5.8). Risk was highest for exposure to non-arsenic pesticides for over nine years (OR = 2.4, 95% CI 1.2 to 2.8). CONCLUSIONS: Long term exposure to non-arsenic pesticides may induce lymphomagenesis among farmers.

Variable very-high-energy gamma-ray emission from the microquasar LS I +61 303.

Microquasars are binary star systems with relativistic radio-emitting jets. They are potential sources of cosmic rays and can be used to elucidate the physics of relativistic jets. We report the detection of variable gamma-ray emission above 100 gigaelectron volts from the microquasar LS I 61 + 303. Six orbital cycles were recorded. Several detections occur at a similar orbital phase, which suggests that the emission is periodic. The strongest gamma-ray emission is not observed when the two stars are closest to one another, implying a strong orbital modulation of the emission or absorption processes.

Prognostic value of minimal residual disease (MRD) in acute myeloid leukemia (AML) with favorable cytogenetics [t(8;21) and inv(16)].

Most patients with acute myeloid leukemia (AML) and t(8;21) or inv(16) have a good prognosis with current anthracycline- and cytarabine-based protocols. Tandem analysis with flow cytometry (FC) and real-time RT-PCR (RQ-PCR) was applied to 55 patients, 28 harboring a t(8;21) and 27 an inv(16), including one case with a novel CBFbeta/MYH11 transcript. A total of 31% (n=17) of CR patients relapsed: seven with t(8;21) and 10 with inv(16). The mean amount of minimal residual disease (MRD) detected by FC in relapsed and nonrelapsed patients was markedly different: 0.3 vs 0.08% (P=0.002) at the end of treatment. The mean number of fusion transcript copies/ ABL x 10(4) also differed between relapsed and non-relapsed patients: 2385 vs 122 (P=0.001) after induction, 56 vs 7.6 after intensification (P=0.0001) and 75 vs 3.3 (P=0.0001) at the end of chemotherapy. Relapses were more common in patients with FC MRD level >0.1% at the end of treatment than in patients with < or = 0.1%: cumulative incidence of relapse (CIR) was 67 and 21% (P=0.03), respectively. Likewise, using RQ-PCR, a cutoff level of >10 copies at the end of treatment correlated with a high risk of relapse: CIR was 75% for patients with RQ-PCR >10 compared to 21% for patients with RQ-PCR levels < or = 10 (P=0.04). Combined use of FC and RQ-PCR may improve MRD detection, and provide useful clinical information on relapse kinetics in AML patients.