Relativistic jet activity from the tidal disruption of a star by a massive black hole.

Supermassive black holes have powerful gravitational fields with strong gradients that can destroy stars that get too close, producing a bright flare in ultraviolet and X-ray spectral regions from stellar debris that forms an accretion disk around the black hole. The aftermath of this process may have been seen several times over the past two decades in the form of sparsely sampled, slowly fading emission from distant galaxies, but the onset of the stellar disruption event has not hitherto been observed. Here we report observations of a bright X-ray flare from the extragalactic transient Swift J164449.3+573451. This source increased in brightness in the X-ray band by a factor of at least 10,000 since 1990 and by a factor of at least 100 since early 2010. We conclude that we have captured the onset of relativistic jet activity from a supermassive black hole. A companion paper comes to similar conclusions on the basis of radio observations. This event is probably due to the tidal disruption of a star falling into a supermassive black hole, but the detailed behaviour differs from current theoretical models of such events.

Antidiabetogenic effects of hydroxychloroquine on insulin sensitivity and beta cell function: a randomised trial.

AIMS/HYPOTHESIS: Hydroxychloroquine (HCQ), an antimalarial drug with anti-inflammatory properties, is employed in rheumatic diseases. In observational studies, patients with rheumatic diseases treated with HCQ have a lower risk of developing diabetes. However, the physiological mechanisms remain unexplained. We hypothesised that HCQ may have favourable effects on insulin sensitivity and/or beta cell function. METHODS: This was a randomised, double-blind, parallel-arm (placebo vs HCQ 400 mg/day) trial at the University of Pittsburgh. Randomisation was conducted by a computer system with concealment by sealed envelopes. Treatment duration was 13 ± 1 weeks. Randomised participants (HCQ n = 17; placebo n = 15) were non-diabetic volunteers, age >18, overweight or obese, with one or more markers of insulin resistance. All participants were included in intention-to-treat analysis. Outcomes were changes in insulin sensitivity and beta cell function measured by intravenous glucose tolerance tests and minimal model analysis. RESULTS: There was a positive change in insulin sensitivity with HCQ but not placebo (mean ± SEM: +20.0% ± 7.1% vs -18.4% ± 7.9%, respectively; p < 0.01; difference: 38.3% ± 10.6%; 95% CI: 17%, 60%). Improvement in beta cell function was also observed with HCQ but not placebo (+45.4% ± 12.3% vs -19.7% ± 13.6%; p < 0.01; difference: 65% ± 19%; 95% CI: 27%, 103%). There were modest treatment effects on fasting plasma glucose and HbA(1c) (p < 0.05) but circulating markers of inflammation (IL-6, IL-1, TNF-α, soluble intercellular adhesion molecule) were not affected in either group. In contrast, adiponectin levels increased after HCQ treatment but not after placebo (+18.7% vs +0.7%, respectively; p < 0.001). Both low- and high-molecular-weight adiponectin forms accounted for the increase. There were no serious or unexpected adverse effects. CONCLUSIONS/INTERPRETATION: HCQ improves both beta cell function and insulin sensitivity in non-diabetic individuals. These metabolic effects may explain why HCQ treatment is associated with a lower risk of type 2 diabetes. An additional novel observation is that HCQ improves adiponectin levels, possibly being a mediator of the favourable effects on glucose metabolism. Our findings suggest that HCQ is a drug with considerable metabolic effects that warrant further exploration in disorders of glucose metabolism. TRIAL REGISTRATION: Clinicaltrials.gov NCT01326533 FUNDING: This study was funded by National Institutes of Health no. 5R21DK082878, UL1-RR024153 and UL-1TR000005.

Patterns of chromosomal variation in natural populations of the neoallotetraploid Tragopogon mirus (Asteraceae).

Cytological studies have shown many newly formed allopolyploids (neoallopolyploids) exhibit chromosomal variation as a result of meiotic irregularities, but few naturally occurring neoallopolyploids have been examined. Little is known about how long chromosomal variation may persist and how it might influence the establishment and evolution of allopolyploids in nature. In this study we assess chromosomal composition in a natural neoallotetraploid, Tragopogon mirus, and compare it with T. miscellus, which is an allotetraploid of similar age (~40 generations old). We also assess whether parental gene losses in T. mirus correlate with entire or partial chromosome losses. Of 37 T. mirus individuals that were karyotyped, 23 (62%) were chromosomally additive of the parents, whereas the remaining 14 individuals (38%) had aneuploid compositions. The proportion of additive versus aneuploid individuals differed from that found previously in T. miscellus, in which aneuploidy was more common (69%; Fisher's exact test, P=0.0033). Deviations from parental chromosome additivity within T. mirus individuals also did not reach the levels observed in T. miscellus, but similar compensated changes were observed. The loss of T. dubius-derived genes in two T. mirus individuals did not correlate with any chromosomal changes, indicating a role for smaller-scale genetic alterations. Overall, these data for T. mirus provide a second example of prolonged chromosomal instability in natural neoallopolyploid populations.

Glucocorticoid use is associated with increase in HDL and no change in other lipids in rheumatoid arthritis patients.

The aim of this article was to examine the association of glucocorticoid use and dose and changes in the lipid profile in rheumatoid arthritis (RA) patients. RA patients between January 1, 2001, and November 30, 2011, who received oral or intravenous glucocorticoids and who had lipid levels within 1 year before and 1 year after ongoing (at least 3 months) glucocorticoids use along with RA patients who did not take glucocorticoids (controls) were included. Glucocorticoid exposure was calculated as a weighted daily dose in prednisone equivalents and analyzed using as cutoff dose prednisone equivalent of 7.5 mg/day. Outcomes were changes in high-density lipoprotein (HDL), low-density lipoprotein (LDL), total cholesterol (TC), triglycerides, and TC/HDL ratio and were calculated in linear regression models adjusting for relevant confounders. In total, 202 subjects on glucocorticoids and 436 controls were included. The glucocorticoid group of ≥7.5 mg/day had the greatest increase in HDL of 6.0 mg/dL (p = 0.003 compared to controls) with lower increases of 3.1 and 2.4 mg/dL in the glucocorticoid group of <7.5 mg/day and controls, respectively. There were no significant differences in other parameters of the lipid profile between the two glucocorticoid groups and controls. In this RA cohort, glucocorticoid dose equivalent of prednisone ≥7.5 mg/day was associated with increased HDL and no change in LDL or TC/HDL ratio compared to no glucocorticoid use These results suggest that this glucocorticoid dose is not associated with an atherogenic lipid profile in RA, a finding that is important in this patient population at high risk for cardiovascular disease.

Propensity-adjusted association of methotrexate with overall survival in rheumatoid arthritis.

OBJECTIVE: While medications used to treat rheumatoid arthritis (RA) may affect survival in RA, few studies take into account the propensity for medication use, which may reflect selection bias in treatment allocation in survival models. We undertook this study to examine the relationship between methotrexate (MTX) use and mortality in RA, after controlling for individual propensity scores for MTX use. METHODS: We studied 5,626 RA patients prospectively for 25 years to determine the risk of death associated with MTX use, modeled in time-varying Cox regression models. We used the random forest method to generate individual propensity scores for MTX use at study entry and during followup in a time-varying manner; these scores were included in the multivariate model. We also investigated whether selective discontinuation of MTX immediately prior to death altered the risk of mortality, and we examined the association of duration of MTX use with survival. RESULTS: During followup, 666 patients (12%) died. MTX use was associated with reduced risk of death (adjusted hazard ratio 0.30 [95% confidence interval 0.09-1.03]). Selective MTX cessation immediately before death did not account for the protective association of MTX use with mortality. Only MTX use for >1 year was associated with lower risks of mortality, but associations were not stronger with longer durations of use. CONCLUSION: MTX use was associated with a 70% reduction in mortality in RA.

A novel B(weak) hybrid allele lacks three enhancer repeats but generates normal ABO transcript levels.

BACKGROUND AND OBJECTIVES: Weak expression of A/B histo-blood group antigens is often explained by single nucleotide substitutions at the ABO locus. However, hybrid alleles containing segments from different ABO alleles can result in unexpected phenotypes and may complicate genotype analysis. We investigated the basis of weak B phenotype in a referred sample. MATERIALS AND METHODS: A healthy young woman was serologically phenotyped as AB(weak) and RBCs were characterized by flow cytometry. All seven ABO exons, five introns plus the 5'-region including the CCAAT-binding factor/Nuclear Factor Y (CBF/NF-Y) binding enhancer were sequenced. ABO transcript levels were measured in fresh peripheral blood samples. Expression of B antigen was semiquantified following transfection of HeLa cells. RESULTS: A new B(weak) allele with 53G>T resulted in a characteristic pattern of moderately weakened B antigen expression on RBCs. Its sequence revealed a novel hybrid between O(2) [O03] and B [B101] alleles with a crossingover region in intron 4 as defined by allele-specific polymorphisms. B transcript levels were similar to normal controls despite the O(2) -related single CBF/NF-Y-binding 43-bp motif in the enhancer region. Expression of the glycosyltransferase including the O(2) -specific Arg18Leu substitution resulted in a slight decrease in B-antigen-positive cells. CONCLUSION: We describe here the first hybrid between an O(2) and a B allele and characterized the associated decrease in B antigen expression. Although it lacks three enhancer repeat units compared to common B alleles, the resulting transcript level was unaltered. This study challenges previous suggestions that the number of 43-bp motifs in the ABO enhancer determines transcription rates in erythroid cells.

An Hsp90 modulator that exhibits a unique mechanistic profile.

Described is the synthesis of two biotinylated derivatives of a cytotoxic macrocycle. Pull-down assays indicate that this macrocycle targets the N-middle domain of Hsp90. Untagged compound can effectively compete away tagged compound-Hsp90 protein complexes, confirming the binding specificity of the macrocycle for Hsp90. The macrocycle is similar in potency to other structurally-related analogs of Sansalvamide A (San A) and induces apoptosis via a caspase 3 mechanism. Unlike other San A derivatives, we show that the macrocycle does not inhibit binding between C-terminal client proteins and co-chaperones and Hsp90, suggesting that it has a unique mechanism of action.

Development and operation of the defence COVID-19 lab as a SARS-CoV-2 diagnostic screening capability for UK military personnel.

BACKGROUND: In the face of the COVID-19 pandemic, the Defence Science and Technology Laboratory (Dstl) and Defence Pathology combined to form the Defence Clinical Lab (DCL), an accredited (ISO/IEC 17025:2017) high-throughput SARS-CoV-2 PCR screening capability for military personnel. LABORATORY STRUCTURE AND RESOURCE: The DCL was modular in organisation, with laboratory modules and supporting functions combining to provide the accredited SARS-CoV-2 (envelope (E)-gene) PCR assay. The DCL was resourced by Dstl scientists and military clinicians and biomedical scientists. LABORATORY RESULTS: Over 12 months of operation, the DCL was open on 289 days and tested over 72 000 samples. Six hundred military SARS-CoV-2-positive results were reported with a median E-gene quantitation cycle (Cq) value of 30.44. The lowest Cq value for a positive result observed was 11.20. Only 64 samples (0.09%) were voided due to assay inhibition after processing started. CONCLUSIONS: Through a sustained effort and despite various operational issues, the collaboration between Dstl scientific expertise and Defence Pathology clinical expertise provided the UK military with an accredited high-throughput SARS-CoV-2 PCR test capability at the height of the COVID-19 pandemic. The DCL helped facilitate military training and operational deployments contributing to the maintenance of UK military capability. In offering a bespoke capability, including features such as testing samples in unit batches and oversight by military consultant microbiologists, the DCL provided additional benefits to the UK Ministry of Defence that were potentially not available from other SARS-CoV-2 PCR laboratories. The links between Dstl and Defence Pathology have also been strengthened, benefitting future research activities and operational responses.

Relationship between nonsustained ventricular tachycardia after non-ST-elevation acute coronary syndrome and sudden cardiac death: observations from the metabolic efficiency with ranolazine for less ischemia in non-ST-elevation acute coronary syndrome-thrombolysis in myocardial infarction 36 (MERLIN-TIMI 36) randomized controlled trial.

BACKGROUND: Most studies examining the relationship between ventricular tachycardia (VT) after acute coronary syndrome and sudden cardiac death (SCD) were performed before widespread use of reperfusion, revascularization, or contemporary medical therapy and were limited to ST-elevation myocardial infarction. The incidence and prognostic implications of VT in patients with non-ST-elevation acute coronary syndrome receiving contemporary care have not been examined. METHODS AND RESULTS: The Metabolic Efficiency With Ranolazine for Less Ischemia in Non-ST-Elevation Acute Coronary Syndrome-Thrombolysis in Myocardial Infarction 36 (MERLIN-TIMI 36) trial randomized 6560 patients hospitalized with a non-ST-elevation acute coronary syndrome to ranolazine or placebo in addition to standard therapy. Continuous ECG recording was performed for the first 7 days after randomization and evaluated in a blinded core laboratory. SCD (n=121) was assessed over a median follow-up of 1 year. A total of 6345 patients (97%) had continuous ECG recordings evaluable for analysis. Compared with patients with no VT (n=2764), there was no increased risk of SCD in patients with only ventricular triplets (n=1978, 31.2%) (1.4% versus 1.2%); however, the risk of SCD was significantly greater in patients with VT lasting 4 to 7 beats (n=1172, 18.5%) (SCD, 2.9%; adjusted hazard ratio, 2.3; P<0.001) and in patients with VT lasting at least 8 beats (n=431, 6.8%) (SCD, 4.3%; adjusted hazard ratio, 2.8; P=0.001). This effect was independent of baseline characteristics and ejection fraction. VT occurring within the first 48 hours after admission was not associated with SCD. CONCLUSIONS: Nonsustained VT is common after admission for non-ST-elevation acute coronary syndrome, and even short episodes of VT lasting 4 to 7 beats are independently associated with the risk of SCD over the subsequent year. Clinical Trial Registration- URL: http://www.clinicaltrials.gov. Unique identifier: NCT00099788.

A giant gamma-ray flare from the magnetar SGR 1806-20.

Two classes of rotating neutron stars-soft gamma-ray repeaters (SGRs) and anomalous X-ray pulsars-are magnetars, whose X-ray emission is powered by a very strong magnetic field (B approximately 10(15) G). SGRs occasionally become 'active', producing many short X-ray bursts. Extremely rarely, an SGR emits a giant flare with a total energy about a thousand times higher than in a typical burst. Here we report that SGR 1806-20 emitted a giant flare on 27 December 2004. The total (isotropic) flare energy is 2 x 10(46) erg, which is about a hundred times higher than the other two previously observed giant flares. The energy release probably occurred during a catastrophic reconfiguration of the neutron star's magnetic field. If the event had occurred at a larger distance, but within 40 megaparsecs, it would have resembled a short, hard gamma-ray burst, suggesting that flares from extragalactic SGRs may form a subclass of such bursts.

A short gamma-ray burst apparently associated with an elliptical galaxy at redshift z = 0.225.

Gamma-ray bursts (GRBs) come in two classes: long (> 2 s), soft-spectrum bursts and short, hard events. Most progress has been made on understanding the long GRBs, which are typically observed at high redshift (z approximately 1) and found in subluminous star-forming host galaxies. They are likely to be produced in core-collapse explosions of massive stars. In contrast, no short GRB had been accurately (< 10'') and rapidly (minutes) located. Here we report the detection of the X-ray afterglow from--and the localization of--the short burst GRB 050509B. Its position on the sky is near a luminous, non-star-forming elliptical galaxy at a redshift of 0.225, which is the location one would expect if the origin of this GRB is through the merger of neutron-star or black-hole binaries. The X-ray afterglow was weak and faded below the detection limit within a few hours; no optical afterglow was detected to stringent limits, explaining the past difficulty in localizing short GRBs.

Patterns of preventive health services in rheumatoid arthritis patients compared to a primary care patient population.

To determine the proportion of rheumatoid arthritis (RA) patients receiving preventive health care according to US Preventive Services Task Force recommendations compared with a community-based population sample, with emphasis on dyslipidemia testing, given the increased risk of cardiovascular disease (CVD) in RA patients. Patients with RA (ICD-9 code 714.0 at ≥2 office visits with a rheumatologist) and a primary care physician (PCP) at the Geisinger Health System (GHS) were identified through electronic health records. The records were searched back from 3/31/08 for the length of time required to satisfy each outcome measure. Percentages were compared with population testing rates using the Pearson Chi-square test. Eight hundred and thirty-one RA patients were compared to 169,476 subjects with a PCP at GHS, stratified by gender and age. Patients with RA were more likely to have had dyslipidemia and osteoporosis testing compared with the general population (86 vs. 75 and 75 vs. 55%, respectively, P < 0.0001 for both). The proportion of RA patients receiving breast and cervical cancer testing was similar to the general population. The majority (79%) of lipid testing was ordered by PCPs. Those RA patients with recommended lipid testing had more traditional CVD factors (hypertension, diabetes, coronary artery disease). RA patients are screened more than the general population for two RA-related co-morbidities, i.e. dyslipidemia and osteoporosis. The RA patients with traditional cardiovascular risk factors are more likely to be tested for dyslipidemia. Further work is warranted to improve testing for modifiable CVD risk factors in this group with multiple co-morbidities.

Hydroxychloroquine use and decreased risk of diabetes in rheumatoid arthritis patients.

BACKGROUND/OBJECTIVES: Several studies have associated hydroxychloroquine use with decreased risk of diabetes mellitus (diabetes) or improved glycemic control in rheumatoid arthritis patients, but the studies were small or used data from self-report. The present study sought to replicate this protective relationship in a health system using electronic health records with laboratory data and physician diagnoses. METHODS: This study is a retrospective cohort of 1127 adults with newly diagnosed rheumatoid arthritis and no diabetes within the Geisinger Health System between January 1, 2003, and March 31, 2008. Patients were classified as ever users (n = 333) or never users (n = 794) of hydroxychloroquine. Incident diabetes cases were defined using 2010 American Diabetes Association criteria. RESULTS: The median follow-up times for the ever and never hydroxychloroquine users were 26.0 and 23.0 months, respectively (P = 0.28). The median duration of hydroxychloroquine exposure was 14.0 months. Of the 48 cases developing diabetes during observation, 3 were exposed to hydroxychloroquine at time of development and 45 were nonexposed, yielding incidence rates of 6.2 and 22.0 per 1000 per year (P = 0.03), respectively. In time-varying Cox proportional hazards regression models adjusting for sex, age, body mass index, positive rheumatoid factor and anti-cyclic citrullinated peptide antibodies, erythrocyte sedimentation rate, and nonsteroidal anti-inflammatory drug, glucocorticoid, methotrexate, and tumor necrosis factor α inhibitor use, the hazard ratio for incident diabetes among hydroxychloroquine users was 0.29 (95% confidence interval, 0.09-0.95; P = 0.04) compared with nonusers. CONCLUSIONS: Our findings support the potential benefit of hydroxychloroquine in attenuating the risk of diabetes in rheumatoid arthritis patients. Further work is needed to determine its potential preventive role in other groups at high risk for diabetes.

Single integration and spread of a Copia-like sequence nested in rDNA intergenic spacers of Allium cernuum (Alliaceae).

The 35S ribosomal DNA (rDNA) intergenic spacer (IGS) of Allium cernuum is examined. Initial sequencing of IGS clones revealed that some rDNA units contain a truncated retrotransposon sequence most similar to members of the Copia superfamily. Fluorescence in situ hybridisation (FISH) to metaphase chromosomes indicates that this element is dispersed along both pairs of major rDNA arrays. Southern hybridisation confirmed the presence of this 'relic' Copia-like element in more than 10% of 35S rDNA units, in the same position within the IGS. To measure the intragenomic divergence of the relic retroelement and its flanking sequences amongst different rDNA units, a 1.1-kb region was amplified and cloned. These data collectively point to a single origin for units containing the putative retrotransposon fragment. It is likely that units containing the putative retroelement increased in copy number and dispersed via rDNA homogenisation mechanisms, rather than by multiple retrotransposition events.

A magnetic emergency release system for halo traction.

A magnetic emergency release system was developed for use in halo traction systems. Commercially available rare earth mounting magnets, with selected weight-carrying capacities, along with ferromagnetic receptacles, were used in line between halos and overhead pulleys to both carry the prescribed traction force and provide an emergency release in the event of excessive applied force due to a transportation accident and/or sudden application of full body weight when using overhead walkers equipped with traction systems. The magnet-receptacle pairs were calibrated with an in-line digital scale. Load rate dependencies were noted, indicating that prescribed magnet-receptacle pairs should be chosen to carry at least 110% body weight. This weight capacity is reduced to approximately 88% of body weight during higher loading rates, such as transportation accidents and accidental falls.

The relationship between animal and plant protein intake and overall diet quality in young adults.

BACKGROUND & AIMS: Overall diet quality is a key predictor of disease risk and mortality. Diets higher in animal protein have been associated with increased disease risk and all-cause mortality. However, the source of protein consumed will inevitably influence the intake of other macronutrients and micronutrients which can also play a role in the onset of disease. The aim of the present study was to assess the relationship between animal and plant protein intake and overall diet quality in young adult females and males. METHODS: Dietary intake was assessed via 3-day food log (n = 150; 53% females) and data were analyzed using the Nutrition Data Systems for Research (NDSR). RESULTS: Females and males consuming <70% of their protein from animal sources had higher scores on a modified Healthy Eating Index (HEI) compared those consuming >70% of their protein from animal sources. Males scored lower than females on the modified HEI regardless of protein source intake variation. CONCLUSIONS: Our findings suggest that overall diet quality differs with varying protein source consumption and eating <70% of protein from animal sources might lead to a better score on the HEI. Future research investigating protein source and disease risk should examine overall dietary quality as a potential effect modifier.

Sex-Specific Muscular Mediation of the Relationship Between Physical Activity and Cortical Bone in Young Adults.

Muscle mass is a commonly cited mediator of the relationship between physical activity (PA) and bone, representing the mechanical forces generated during PA. However, neuromuscular properties (eg, peak force) also account for unique portions of variance in skeletal outcomes. We used serial multiple mediation to explore the intermediary role of muscle mass and force in the relationships between cortical bone and moderate-to-vigorous intensity PA (MVPA). In a cross-sectional sample of young adults (n = 147, 19.7 ± 0.7 years old, 52.4% female) cortical diaphyseal bone was assessed via peripheral quantitative computed tomography at the mid-tibia. Peak isokinetic torque in knee extension was assessed via Biodex dynamometer. Thigh fat-free soft tissue (FFST) mass, assessed via dual-energy X-ray absorptiometry, represented the muscular aspect of tibial mechanical forces. Habitual MVPA was assessed objectively over 7 days using Actigraph GT3X+ accelerometers. Participants exceeded MVPA guidelines (89.14 ± 27.29 min/day), with males performing 44.5% more vigorous-intensity activity relative to females (p < 0.05). Males had greater knee extension torque and thigh FFST mass compared to females (55.3%, and 34.2%, respectively, all p < 0.05). In combined-sex models, controlling for tibia length and age, MVPA was associated with strength strain index (pSSI) through two indirect pathways: (i) thigh FFST mass (b = 1.11 ± 0.37; 95% CI, 0.47 to 1.93), and (i) thigh FFST mass and knee extensor torque in sequence (b = 0.30 ± 0.16; 95% CI, 0.09 to 0.73). However, in sex-specific models MVPA was associated with pSSI indirectly through its relationship with knee extensor torque in males (b = 0.78 ± 0.48; 95% CI, 0.04 to 2.02) and thigh FFST mass in females (b = 1.12 ± 0.50; 95% CI, 0.37 to 2.46). Bootstrapped CIs confirmed these mediation pathways. The relationship between MVPA and cortical structure appears to be mediated by muscle in young adults, with potential sex-differences in the muscular pathway. If confirmed, these findings may highlight novel avenues for the promotion of bone strength in young adults. © 2019 American Society for Bone and Mineral Research.

Outcomes of gastrocnemius-soleus complex lengthening for isolated equinus contracture in children with cerebral palsy.

BACKGROUND: The goal of the gastrocnemius-soleus complex (GSC) lengthenings in children with cerebral palsy (CP) is to achieve a plantigrade foot and normalize kinematics during gait. The study purpose was to evaluate the results of GSC lengthening for isolated equinus contracture in individuals with CP. It was hypothesized that GSC lengthenings would normalize passive ankle range of motion, kinematic, kinetic, and temporal spatial parameters. METHODS: Gait data from 15 able-bodied participants from the laboratory normal database and passive range of motion, kinematic, kinetic, and temporal spatial gait parameters, and oxygen cost were collected and analyzed for 27 individuals with CP (36 limbs) with isolated equinus contracture who received GSC lengthenings. Data were compared between preoperative and postoperative assessments. RESULTS: Mean age at baseline was 11.4 years (+/-3.2 y). Mean time between surgery and postoperative gait analysis was 1.3 years (+/-0.3 y). Passive range of motion measurements were obtained. Kinematic and kinetic data for the hip, knee and ankle, and temporal spatial parameters were obtained from a representative gait trial preoperatively and postoperatively. Paired t tests (P<0.05) determined whether preoperative data differed from postoperative data or from able-bodied data. The passive range of motion at the ankle was improved and normalized postoperatively. Ankle kinematics normalized without compensatory changes occurring at the knee or hip kinematics. Ankle moments and powers become more normal but did not completely normalize. Kinematics and kinetics of the hip and knee were not adversely affected. No changes in the temporal spatial data or oxygen cost occurred postoperatively. CONCLUSIONS: These data support the finding that with appropriate patient selection isolated GSC lengthening does not result in overcorrection. LEVEL OF EVIDENCE: Retrospective comparative study; level 3.

Exploring the Lipid Paradox Theory in Rheumatoid Arthritis: Associations of Low Circulating Low-Density Lipoprotein Concentration With Subclinical Coronary Atherosclerosis.

OBJECTIVE: Rheumatoid arthritis (RA) patients with the lowest circulating low-density lipoprotein (LDL) concentrations are at heightened risk of cardiovascular events. However, the atherosclerosis burden within this subgroup is unknown. METHODS: RA patients pooled from 4 cohort studies of cardiovascular disease (CVD; n = 546) were compared with non-RA controls from the Multi-Ethnic Study of Atherosclerosis (n = 5,279). Those taking lipid-lowering medications were excluded. Differences in cardiac computed tomography-derived Agatston coronary artery calcium (CAC) scores between the RA and control groups were compared across strata of LDL concentration. RESULTS: Among those with low LDL concentrations (<70 mg/dl), mean adjusted CAC scores were >4-fold higher for RA patients than for controls (18.6 versus 4.6 Agatston units, respectively; P < 0.001), a difference significantly greater than that in any other LDL concentration stratum except LDL concentration ≥160 mg/dl. Similarly, 32% of the RA patients with low LDL concentration had a CAC score of ≥100 Agatston units compared with only 7% of controls in the same LDL concentration stratum (odds ratio 5.97; P < 0.001), a difference significantly greater than that in all of the other LDL concentration strata. Low LDL concentration was most strongly associated with higher CAC score among RA patients who were white, had ever smoked, or were not obese. Other than a higher frequency of current smokers, RA patients with low LDL concentrations did not have more CVD risk factors or higher measures of RA disease activity or severity than RA patients with higher LDL concentrations. CONCLUSION: RA patients with low LDL concentration may represent a group for whom heightened screening and prevention of atherosclerotic CVD is appropriate.

Effect of ranolazine, an antianginal agent with novel electrophysiological properties, on the incidence of arrhythmias in patients with non ST-segment elevation acute coronary syndrome: results from the Metabolic Efficiency With Ranolazine for Less Ischemia in Non ST-Elevation Acute Coronary Syndrome Thrombolysis in Myocardial Infarction 36 (MERLIN-TIMI 36) randomized controlled trial.

BACKGROUND: Ranolazine, a piperazine derivative, reduces ischemia via inhibition of the late phase of the inward sodium current (late I(Na)) during cardiac repolarization, with a consequent reduction in intracellular sodium and calcium overload. Increased intracellular calcium leads to both mechanical dysfunction and electric instability. Ranolazine reduces proarrhythmic substrate and triggers such as early afterdepolarization in experimental models. However, the potential antiarrhythmic actions of ranolazine have yet to be demonstrated in humans. METHODS AND RESULTS: The Metabolic Efficiency With Ranolazine for Less Ischemia in Non-ST-Elevation Acute Coronary Syndrome (MERLIN)-Thrombolysis in Myocardial Infarction (TIMI) 36 (MERLIN-TIMI 36) trial randomized 6560 patients hospitalized with a non-ST-elevation acute coronary syndrome to ranolazine or placebo in addition to standard therapy. Continuous ECG (Holter) recording was performed for the first 7 days after randomization. A prespecified set of arrhythmias were evaluated by a core laboratory blinded to treatment and outcomes. Of the 6560 patients in MERLIN-TIMI 36, 6351 (97%) had continuous ECG recordings that could be evaluated for arrhythmia analysis. Treatment with ranolazine resulted in significantly lower incidences of arrhythmias. Specifically, fewer patients had an episode of ventricular tachycardia lasting > or = 8 beats (166 [5.3%] versus 265 [8.3%]; P<0.001), supraventricular tachycardia (1413 [44.7%] versus 1752 [55.0%]; P<0.001), or new-onset atrial fibrillation (55 [1.7%] versus 75 [2.4%]; P=0.08). In addition, pauses > or = 3 seconds were less frequent with ranolazine (97 [3.1%] versus 136 [4.3%]; P=0.01). CONCLUSIONS: Ranolazine, an inhibitor of late I(Na), appears to have antiarrhythmic effects as assessed by continuous ECG monitoring of patients in the first week after admission for acute coronary syndrome. Studies specifically designed to evaluate the potential role of ranolazine as an antiarrhythmic agent are warranted.