Comparative hydrodynamic evaluation of bioprosthetic heart valves.

BACKGROUND AND AIM OF STUDY: Pressure gradients across cardiac valve prostheses have been identified as one of the most important performance measures in valve replacement surgery. Specifically in aortic valves, these gradients influence reduction of left ventricular hypertrophy and are postulated to influence long-term survival. The correct choice of replacement valve is hampered by a lack of uniform measures of valve performance. The aim of this study was to compare in-vitro hydrodynamic performance of commercially available bioprosthetic valves under identical test conditions. METHODS: In-vitro steady forward flow and pulsatile flow tests were performed on aortic and mitral bioprosthetic valves in accordance with ISO/FDA guidelines at two different institutions to obtain objective hemodynamic performance measures. Measurements were recorded at various flow rates, flow and pressure to obtain mean pressure gradients and effective orifice areas (EOAs). RESULTS: Wide variation in pressure gradients was found among tested valves of each size. For a given size, differences of 200 to 400% were observed; in general, the valve models' relative rankings in pressure drop were independent of size. CONCLUSION: The Carpentier-Edwards Perimount valve showed superior performance at all sizes tested. While the mean pressure gradients and EOAs reported by each institution differed for a given valve, the performance of valve models relative to each other was similar. The testing of valves under identical conditions is a valuable comparative indicator of valve hemodynamic performance.     

In-vitro testing of three totally supra-annular bileaflet mechanical valves: hydrodynamics in the Sheffield pulse duplicator

BACKGROUND AND AIM OF THE STUDY: In-vivo echocardiographic studies are limited by several confounding factors and technical pitfalls, and consequently the hypothetical differential hydraulic behavior between different prosthetic heart valves has not been identified. However, for surgeons it is essential to know the functional and geometric characteristics of the prostheses to be used. Herein, the in-vitro performance of two new supra-annular bileaflet prostheses--the Medtronic Advantage Supra and Sorin Bicarbon Overline--was compared with that of the 21-mm St. Jude Medical (SJM) Regent valve. METHODS: Three high-performance, production-quality prostheses, including the sewing-ring cuffs, were tested in the aortic chamber of a Sheffield pulse duplicator. The sizes of the prostheses which fitted the 21-mm valve holder were: 21 mm Advantage Supra Medtronic; 19 mm SJM Regent, and 18 mm Sorin Bicarbon Overline. The tests were carried out at a fixed pulse rate (70 beats/min), and at increasing cardiac output (CO) of 2, 4, 5, and 7 l/min. Forward-flow pressure drop, total regurgitant volume, closing and leakage volumes, effective orifice area (EOA) and stroke work loss (SWL) were recorded while the valve was operated at each CO. RESULTS: The SJM Regent and Sorin Bicarbon Overline valves each showed, at increasing CO, significantly lower mean and peak gradients. The calculated EOA and SWL were significantly better with the SJM Regent and Sorin Bicarbon Overline prostheses. The Medtronic Advantage Supra valve showed comparable results only while performing at 2 l/min CO. With regards to the regurgitant fraction, lowest values were observed with the Medtronic Advantage Supra valve. CONCLUSION: This hydrodynamic evaluation model allowed a comparison to be made of the efficiency of recently commercialized bileaflet prostheses, among which the older SJM Regent and the newer Sorin Bicarbon Overline valves demonstrated the best performances.     

Statistical methods to improve the precision of the treadmill exercise test

OBJECTIVES: The study systematically compared different measures of ST segment depression from the treadmill exercise test. BACKGROUND: The value of the treadmill exercise test for objectively measuring treatment effects is limited by random error in the measurement of ST depression and may be biased by regression to the mean or by the decision to terminate the test. METHODS: Treadmill exercise was performed in 21 subjects with ischemic heart disease 1 h after isosorbide dinitrate 10 mg or placebo in a double-blind randomized crossover study. A 12-lead electrocardiogram (ECG) was recorded every 30 s during and at peak exercise. The relative sample size needed to detect the nitrate effect was compared for different summary measures of ST depression. RESULTS: The ST depression measured from a single unmatched lead at longest equivalent sub-maximal exercise needed the lowest sample size to detect the nitrate effect in paired comparisons (p = 0.000006). Averaging over multiple leads or times did not improve detection of the nitrate effect. The rate of increase in ST depression (in mm/min) calculated by linear regression needed a similar sample size (x1.32, 95% CI 0.62 to 2.58). A larger sample size was needed for ST depression at peak exercise (x2.9, CI 1.3, 11.1) and exercise duration (x4.5, CI 1.5, 38). Time to 1-mm ST depression was the least efficient measurement (relative sample size x15.5, CI 1.6, >1,000). Comparison of matched leads resulted in >2-fold differences in estimates of the nitrate effect because of bias from regression to the mean. CONCLUSIONS: Maximal ST depression at longest equivalent sub-maximal exercise and the maximal rate of increase in ST depression had less bias and random variation than did other commonly used measures. The rate of increase in ST depression is preferred because it can be calculated in either paired or unpaired studies.     

Characterization of 99mTc-DTPA aerosols for lung permeability studies.

BACKGROUND: The interpretation of 99mTc diethylenetriamine pentaacetate (99mTc DTPA) aerosol clearance is based on the hypothesis that the 99mTc-DTPA complex is not altered by the nebulization process. OBJECTIVES: To characterize (1) the radiochemical purity (RCP) of 99mTc-DTPA and the stability of labeling after jet nebulization, and (2) the particle size distribution of the aerosol. METHODS: RCP and stability--the aerosol was driven by oxygen, captured on filters which were eluted and RCP was checked by thin layer chromatography. Particle size distribution--the aerosol was generated using dry air (50 psi) at three different flow rates, i.e. 3 (1 run), 6 (4 runs) and 9 l x min(-1) (4 runs). The mass median aerodynamic diameter (MMAD) and the geometric standard deviation (sigma(g)) were determined using a cascade impactor from the radioactivity counted on each stage. RESULTS: The RCP was more than 95% in all cases. Mean MMAD (+/-SD) was 0.70 microm (+/-0.07) at 9 l x min(-1), 0.93 microm (+/-0.05) at 6 l x min(-1) (p < 0.05) and 1.50 microm at 3 l x min(-1). Mean sigma(g) (+/-SD) was 2.02 (+/-0.08) at 9 l x min(-1), 2.00 (+/-0.16) at 6 l x min(-1) and 1.90 at 3 l x min(-1). CONCLUSION: This study demonstrates (1) that the high RCP of 99mTc-DTPA is not affected by jet nebulization, even when using oxygen at a high flow rate, and (2) that when using a flow rate between 6 and 9 l x min(-1), the MMAD remains optimal for peripheral lung deposition.     

Prediction of viremia for cases of hepatitis C virus (HCV) infection using a third-generation anti-HCV enzyme immunoassay test

BACKGROUND/AIMS: Positive results for anti-hepatitis C virus (HCV) testing reveal subjects are infected by HCV, with presence of HCV RNA indicating persistent infection. In this study, we attempted to evaluate the validity of the HCV viremia using a commercially available, third-generation anti-HCV test. METHODOLOGY: Sample rate/cut-off rate (S/CO) ratios for 1,907 anti-HCV-positive tests (S/CO >1, AxSYM HCV 3.0; Abbott, IL, USA), which had been performed during the last three years, were retrospectively analyzed. Cases with S/CO values between 1 and 100 were divided into 20 groups according to S/CO range (in increments of 10) and ALT (normal or elevated). Ten random cases were obtained for each of the 20 groups. If cases in any group numbered < or =10, all were recruited. Totally, 193 cases were enrolled for HCV RNA detection (COBAS Amplicor; Roche Diagnostics, NJ, USA). RESULTS: The S/CO distribution was biphasic, with two S/CO peaks in the ranges 1-10 (10.7%) and 81-90 (24.2%). Regardless of the ALT level, all samples with S/COs < or =10 were negative for HCV RNA. Of the samples with S/CO values >10, the optimal cut-off was 40 with sensitivity and specificity for both of 81%. In conclusion, subjects with S/CO values < or =10 (10.7%) were more likely to be cases of past infection or of non-specific reaction. Most (90%, 108/120) of the subjects with S/COs >40 represent current or persistent infection. To predict viremia in subjects with S/COs between 10 and 40, 6.7% of all anti-HCV-positive subjects was invalid by a cross-sectional observation. CONCLUSIONS: Follow-up or further study is recommended. The third-generation EIA test plays a semiquantitative role for the prediction of viremia in HCV infection.     

The current state of in-vivo pre-clinical animal models for heart valve evaluation

For over 30 years, animal models have remained a central critical component in the pre-clinical safety evaluation of prosthetic heart valves developed for use in humans. Though many advances have been made in valve design, no ideal replacement prosthesis has yet been developed. As a result, valve manufacturers continue to address issues relating to thrombogenicity, structural integrity, fluid dynamics and calcification in their designs. Many animal models have been developed to examine these issues, including dog, pig, calf and sheep, yet no standard model has been accepted. Recently, the International Standard Organization has provided guidelines in document 5840 to address cardiovascular implants. The aim of this report is to provide a summary of the current state of pre-clinical valve evaluation in animals. Changes in ISO 5840 will be addressed that have occurred between 1998 and the present date, and the role of current available animal models. The aim also is to provide rational guidance in the selection of appropriate animal models to match the purpose of valve implantation studies.     

Normative reference values for lung transfer factor in Isfahan, Iran

OBJECTIVES AND BACKGROUND: Transfer factor or carbon monoxide diffusing capacity (DL(CO)) is a particularly valuable test of the appropriateness of gas exchange across the alveolocapillary membrane. The purpose of this study is to derive predictive equations for DL(CO) and its derivative volume-corrected DL(CO) (DL(CO)/VA) measured by single-breath method in a large non-smoking population sample in Isfahan. METHODOLOGY: We evaluated 1429 randomly selected subjects (732 men, aged 5-85 years). Gender-specific linear prediction equations were developed by multiple regression analysis; with measured DL(CO), and DL(CO)/VA values (mmol/min/kPa), as dependent variables regressed against age (A), height (H) and body surface area (BSA). RESULTS: For both genders, age had negative effects on DL(CO), while height had a positive effect on DL(CO) and DL(CO)/VA (P < 0.01). The prediction equations for DL(CO) and DL(CO)/VA are: '0.152 x height - 0.056 x age - 11.595' and '-0.12 x age + 2.467', for men and: '-0.035 x age - 0.133 x height - 10.707' and '-0.012 x age - 0.02 x height + 2.755', for women, respectively. CONCLUSIONS: Our results therefore provide an original frame of reference for either DL(CO) or DL(CO)/VA in Iranian population, obtained from a standardized single-breath technique.     

Flow-dependent re-endothelialization of tissue-engineered heart valves

BACKGROUND AND AIM OF THE STUDY: The generation of a functional, non-immunogenic, non-thrombogenic construct based on autologous cells seeded onto an acellular extracellular matrix is the major goal in heart valve tissue engineering. The study aim was to identify culturing conditions required to achieve a stable endothelial cell (EC) layer under physiological flow conditions, a prerequisite for the requested characteristics. METHODS: Eleven detergent-decellularized ovine pulmonary valves (PVs) were statically reseeded in special bioreactors with ovine venous ECs (1.2x10(7) cells per valve). The dynamic culture was started with 0.1 l/min in eight bioreactors. In four bioreactors the initial flow rate was slow, and increased by 0.1 l/min twice each day until maximal flow was 0.5 l/min and pulsation rate (PR) was 20 beats/min; in four other bioreactors the flow was increased by 0.7 l/min/day and reached 2.0 l/min with a PR of 50 beats/min. The mean system pressure was maintained at 25 +/- 5 mmHg during the whole dynamic cultivation in both groups. Three statically reseeded valves served as baseline. After achieving maximal appointed flow, the valves were investigated morphologically (hematoxylin and eosin staining, electron microscopy, von Willebrand factor, endothelial nitric oxide synthase immunostaining) and for metabolic activity (MTS assay). RESULTS: After reseeding, the endothelium appeared on the luminal surface of the PV as a non-confluent monolayer. Moderate pulsatile circulation induced complete confluence of EC monolayers on both cusp sides and the pulmonary wall. A high flow rate led to a partial loss of cells on the wall surface with large defects, and to complete cell wash-off from cusps. Cusp and wall metabolic activity was significantly higher after culture under moderate flow (p < 0.001) than in other groups, and was absent from cusps in high-flow bioreactors. CONCLUSION: Moderate pulsatile flow with small increments stimulates EC proliferation on the ovine decellularized valve scaffold. A rapid increase in bioreactor flow to physiological levels leads to significant damage of the reseeded endothelium and complete loss of cusp cellularity. This effect may be responsible for the in-vivo failure of static reseeded tissue-engineered valves exposed to physiological hemodynamic forces.     

Haemodynamic responses to physical activity and body posture during everyday life

OBJECTIVE: To determine the relationships between body posture and physical activity and systemic haemodynamics during everyday life. METHODS: Continuous measurements were performed in 34 subjects (16 hypertensive, 12 male), aged 49 +/- 13 (mean +/- standard deviation) years. Blood pressure (BP) was measured in the brachial artery. Physical activity and posture were measured with four accelerometers. Beat-to-beat values of systolic blood pressure (SBP), diastolic blood pressure (DBP), heart rate (HR), stroke volume (SV), cardiac output (CO) and systemic vascular resistance (SVR) were computed from the pressure waveforms. Multiple correlation coefficients (R) between activity and haemodynamic variables were computed and responses to physical activity were estimated with random regression models. RESULTS: The overall percentages of variance in SBP, DBP, HR, SV, CO and SVR explained by activity (R2) were 32, 28, 56, 44, 74, and 45%, respectively. The SBP and HR increased linearly with increasing levels of activity (19 mmHg and 30 beats/min when activity increased 90 percentiles). Other variables showed parabolic relationships. The initial decrease in SV and CO (14 ml and 0.5 l/min) and increase in DBP and SVR (9 mmHg and 2 mmHg min/l) with increasing levels of activity coincided with changes in posture (lying-sitting-standing). The subsequent SV and CO increase (23 ml and 3.7 l/min) and DBP and SVR decrease (8 mmHg and 8 mmHg min/l) coincided with changes in activity (standing-moving generally-walking). CONCLUSIONS: Our findings show that normal daily posture and activity are only moderate determinants of BP, but main determinants of HR and CO variation.     

Accuracy of pulmonary function tests in predicted exercise capacity in COPD patients

PURPOSE: The purpose of this study was to examine exercise tolerance in patients with COPD from measurements of resting pulmonary function parameters. METHODS: A total of 57 COPD patients were administered the pulmonary function test (PFT) and cardiopulmonary exercise test. The results were analyzed and essentially linear relationships emerged when each subject's VO2 peak was plotted against his individual PFT parameters. Those significant contributors were then introduced in a stepwise multiple regression analysis to determine the best predictor of the VO2 peak. RESULTS: Stepwise multiple regressions in variables revealed that peak oxygen consumption (VO2 peak) was predicted best by the following equation: VO2 peak=(maximum voluntary ventilation x 0.024)+(forced mid-expiratory flow x 0.47)+(body surface area x 0.988)-0.913 (r=0.90; r2=0.81 SE=0.29 L/min). CONCLUSION: We conclude that exercise capacity was predicted from measurements of resting pulmonary function parameters with excellent accuracy in the COPD patient.     

Development and validation of a noninvasive method to estimate cardiac output using cuff sphygmomanometry

BACKGROUND: Obtaining cardiac output (CO) measurements noninvasively during routine blood pressure recording can improve hypertension management. A new method has been developed that estimates cardiac output using pulse-waveform analysis (PWA) from a brachial cuff sphygmomanometer. This study evaluates the ability of PWA to track changes in CO as derived by Doppler ultrasound during dobutamine stimulation. HYPOTHESIS: This study aims to validate the PWA CO estimation over a wide CO range as would be obtained by dobutamine stimulation during Doppler ultrasound evaluation. METHOD: A total of 48 patients undergoing standard dobutamine stress echocardiography testing for accepted clinical indications were enrolled. Among them, 44 patients (age 36-83, 18 females, 26 males) with good waveform data for analyses provided estimates of CO in this study. Noninvasive measurements of CO were performed using both Doppler ultrasound recordings and PWA techniques simultaneously at each stage of dobutamine infusion. RESULTS: A total of 207 simultaneous pulse-waveform analyses and Doppler measurements were taken during dobutamine stress on 44 cardiac patients. Linear regression analysis revealed good intra-patient correlation between pulse-waveform analysis and Doppler at different dobutamine-induced CO with coefficients from r = 0.69 to 0.98 (p < 0.05). Analysis of all patients yielded an overall correlation of r = 0.82 (p < 0.001, bias = 0.4 L/min, standard deviation = 1.8 L/min). CONCLUSION: The CO measured noninvasively from a sphygmomanometer using this PWA method correlates well with those of Doppler through a range of dobutamine-stimulated levels. The CO by PWA should be useful for monitoring hemodynamic changes in hypertensive and cardiac patients during routine blood pressure measurement.     

Publication bias and heterogeneity in the relationship between systolic blood pressure,birth weight,and catch-up growth--a meta analysis

OBJECTIVE: To use meta-analytic techniques to formally examine (1) publication bias, and (2) between-study heterogeneity in the reported regression coefficient of systolic blood pressure (SBP) on birth weight, adjusting for current weight. DATA IDENTIFICATION: A total of 55 separate analyses reporting on 382 514 male and female subjects ranging from 0 to 75 years, summarized in a recent systematic review. RESULTS: Some 52 of 55 analyses reported a negative regression coefficient (beta) of SBP on birth weight, adjusting for current size, and in 27 of 55 (49%) the 95% confidence interval (CI) did not include zero. A pooled estimate of the regression coefficient across studies under a random-effects model was -1.38 mmHg/kg (95% CI: -1.66 to -1.10). The magnitude of the regression coefficient was negatively correlated with the age of the study population (r = -0.44, P = 0.0007). However, there was strong evidence of publication bias with smaller studies tending to report more negative betas - the Pearson correlation between beta and its standard error (SE(beta)) was -0.55 (P < 0.0001). To examine independent effects, meta analysis regressions of beta on age and SE(beta) were run. After controlling for age, there remained strong evidence of publication bias (P = 0.002), whereas after controlling for publication bias as measured by SE(beta), the relationship between beta and age was not significant (P = 0.08). CONCLUSIONS: This analysis strongly suggests, but does not prove, that publication bias is present when systematically examining the relationship between blood pressure and birth weight. Controlling for publication bias lessens the apparent relationship between the regression coefficient and age of the study population.     

Opening and closure characteristics of different types of stented biological valves

BACKGROUND: In an increasingly senescent population stented biological valves have regained renewed popularity because of the absence of anticoagulation, while the stented design allows for safe and easier implantation. Constructed bovine pericardial valves as well as valves with porcine cusps are used, both of which exhibit good clinical results although degeneration still appears. While clinical hemodynamic studies did not show particular differences between both valves types, the opening and closure behavior of native cusps and artificially constructed pericardial leaflets is different. It is unclear whether these phenomena account for differences in load and stress which may influence onset and course of degeneration. MATERIAL AND METHODS: Edwards Perimount (EP) and Medtronic Mosaic (MM) heart valves with diameters of 21 mm, 23 mm, and 25 mm were investigated in a pulse duplicator. Movements of the valves were visualized with a high-speed camera (1000 frames/sec). Mean transvalvular gradient (mm Hg), dissipated power (mW), and power transfer by stretching (mW), mean orifice area (mm2), opening time (ms), and closure time (ms) were analyzed in a range of cardiac outputs from 1.4 l/min to 6.3 l/min and 70 beats per minute. RESULTS: Closure times were generally longer than opening times for both valve types. Opening time of EP valves was longer than opening time of the MM valves of the same size (EP23: 31.2 +/- 2.5 ms; MM23: 12.7 +/- 0.1 ms). With respect to closure times, however, there were no marked differences between all valves (EP23: 69.3 +/- 2.0 ms; MM23: 63.2 +/- 6.3 ms). Smaller sized Perimount valves exhibited lower mean transvalvular gradients than Mosaic valves of the same size (EP23: 7.21 +/- 0.07 mm Hg; MM23: 10.5 +/- 0.15 mm Hg). In larger sizes these differences diminished. Power transfer to the valve's structures was significantly enhanced in EP valves (EP23: 134 +/- 1.3 mW; MM23: 64 +/- 0.9 mW). CONCLUSIONS: While valves with constructed pericardium showed lower mean transvalvular gradients, particularly in the smaller sizes, this valve type exhibited alterations of movement performance in contrast to porcine valves. It can be speculated that constant power transfer to the valve's structures may result in an earlier degeneration because of the impact of the increased load and stress on the suspension apparatus of the constructed pericardial leaflets.     

Substrate utilization and thermogenic responses to beta-adrenergic stimulation in obese subjects with NIDDM.

OBJECTIVE: This study intended to investigate disturbances in beta-adrenergically-mediated substrate utilization and thermogenesis in obese subjects with mild non insulin-dependent diabetes mellitus (NIDDM). DESIGN: Following a baseline period of 30 min, the beta-agonist isoproterenol (ISO) was administered in increasing doses of 6, 12, and 24 ng/kgFFM x min, each dose for 30 min. SUBJECTS: Nine healthy lean males (CON, 50.6+/-2.4 y, % body fat: 16.0+/-1.8) and 10 obese subjects with NIDDM (51.8+/-2.4 y, % body fat 34.1+/-1.9). RESULTS: Basal non esterified fatty acid concentrations (NEFA) and basal fat oxidation (absolute or expressed per unit fat free mass, FFM) were significantly higher in NIDDM as compared to CON, whereas basal carbohydrate (CHO) oxidation was significantly lower. The ISO-induced increase in NEFA-concentrations was blunted in NIDDM (delta at 24 ng/kgFFM x min: CON: 717+/-59 micromol/l vs NIDDM: 358+/-97 micromol/l, P< 0.01). The non-protein respiratory exchange ratio (RER) did not change in NIDDM and significantly decreased in CON during ISO-infusion (P < 0.05), reflecting the tendency towards a blunted increase in fat oxidation in NIDDM (delta fat ox at 24 ng; CON: 0.025+/-0.005 g/min vs NIDDM 0.016+/-0.007 g/min). The ISO-induced thermogenic response was comparable in NIDDM and CON (at 24 ng %increase above baseline: CON: 16.8+/-2.2% vs NIDDM: 14.7+/-0.9%). At all time points, there were no significant differences in circulating ISO and noradrenaline concentrations. Basal adrenaline (A) concentrations and A concentrations during ISO-infusion were significantly lower in NIDDM (basal A; CON: 64+/-15 pg/ml vs NIDDM: 25+/-2 pg/ml, P < 0.001). CONCLUSION: There appear to be deviations in beta-adrenoceptor mediated fat utilization and adrenal medulla function in obesity-associated NIDDM. The impairments in sympathetically mediated fat utilization have previously been observed in 'simple' obese subjects, indicating that these disturbances are confined to the obese state per se.     

Onset of action of formoterol/budesonide in single inhaler vs. formoterol in patients with COPD

Formoterol is a beta(2)-agonist bronchodilator that combines a fast onset of action with a long duration of broncholytic effect. An increasing documentation is showing that the combination of a long acting beta(2)-adrenoceptor agonist bronchodilator and an inhaled corticosteroid targets the airways obstruction in patients with COPD. In this study, we have explored whether the acute addition of an inhaled corticosteroid influences the fast bronchodilator response to formoterol. A total of 20 patients with stable COPD were randomized. Single doses of formoterol/budesonide 2 x (4.5/160)microg or formoterol 2 x 4.5 microg were given via Turbuhaler. Serial measurements of FEV(1) were performed over 60 min. Formoterol/budesonide elicited a significantly larger mean FEV(1)-AUC(0-15 min) than formoterol alone. Also the change in FEV(1) 15 min after inhalation of formoterol/budesonide combination (0.197 l; 95% CI: to 0.142-0.252) was greater than that induced by formoterol alone (0.147 l; 95% CI: to 0.092-0.201). The mean increases in FEV(1) were always higher after budesonide/formoterol than formoterol alone, although both treatments induced a significant improvement over baseline at each explored time point. Even the FEV(1)-AUC(0-60 min) after formoterol/budesonide was significantly larger than that after formoterol. Both treatments induced a significant reduction in VAS score but did not modify heart rate in a statistically significant manner. This study indicates that the addition of budesonide influences the fast onset of action of formoterol, but does not induce systemic effects, in patients with stable COPD.     

急性缺血性卒中患者肾功能下降的危险因素——基于医院的回顾性病例系列研究

目的 探讨缺血性卒中患者肾功能下降的危险因素.方法 回顾性分析缺血性卒中患者的病历资料,按估计肾小球滤过率(estimated glomenlar filtration rate,eGFR)水平分为肾功能正常组[ eGFR≥60 ml/(min·1.73 m2)]和肾功能下降组[ eGFR＜ 60 ml/(min·1....     

Regulation of interference-sensitive crossover distribution ensures crossover assurance in Arabidopsis

During meiosis, crossovers (COs) are typically required to ensure faithful chromosomal segregation. Despite the requirement for at least one CO between each pair of chromosomes, closely spaced double COs are usually underrepresented due to a phenomenon called CO interference. Like Mus musculus and Saccharomyces cerevisiae, Arabidopsis thaliana has both interference-sensitive (Class I) and interference-insensitive (Class II) COs. However, the underlying mechanism controlling CO distribution remains largely elusive. Both AtMUS81 and AtFANCD2 promote the formation of Class II CO. Using both AtHEI10 and AtMLH1 immunostaining, two markers of Class I COs, we show that AtFANCD2 but not AtMUS81 is required for normal Class I CO distribution among chromosomes. Depleting AtFANCD2 leads to a CO distribution pattern that is intermediate between that of wild-type and a Poisson distribution. Moreover, in Atfancm, Atfigl1, and Atrmi1 mutants where increased Class II CO frequency has been reported previously, we observe Class I CO distribution patterns that are strikingly similar to Atfancd2. Surprisingly, we found that AtFANCD2 plays opposite roles in regulating CO frequency in Atfancm compared with either in Atfigl1 or Atrmi1. Together, these results reveal that although AtFANCD2, AtFANCM, AtFIGL1, and AtRMI1 regulate Class II CO frequency by distinct mechanisms, they have similar roles in controlling the distribution of Class I COs among chromosomes.

Meiosis is a specialized cell division process that includes two rounds of chromosome segregation following a single round of premeiotic DNA replication and is essential for sexual reproduction in most eukaryotes. During meiosis, homologous recombination (HR) is employed to repair double strand breaks (DSBs) catalyzed by the SPO11 transesterase, yielding crossovers (COs) or noncrossovers (1). In most eukaryotes, meiotic COs are required to ensure the faithful segregation of homologous chromosomes (homologs). COs create new haplotypes, which in turn generate phenotypic diversity among offspring (2). Numerous studies in multiple species have shown that the number and distribution of COs are tightly regulated (3, 4). For instance, the model plant Arabidopsis thaliana has about 10 COs during each meiosis (5) that are nonrandomly distributed along and among chromosomes. Despite the small number of COs, each of the five pairs of Arabidopsis homologs experiences at least one CO—a phenomenon known as CO assurance (6). A second regulatory mechanism, CO interference, inhibits closely spaced double COs (7). However, the molecular mechanisms controlling CO distribution are elusive.Most eukaryotes have two kinds of COs (1): Class I COs that are sensitive to interference and Class II COs which are interference insensitive. In wild-type (WT) Arabidopsis, 85 to 90% of COs belong to Class I and are mediated by the ZMM group of proteins (Zip1-4, Mer3, and Msh4-5) and MLH1/3 (8–13). Class II COs can be generated by at least two parallel pathways in Arabidopsis (14–16), which depend on either the structure-specific endonuclease AtMUS81 (15, 16) or a homolog of Fanconi Anemia Complementation Group D2 (AtFANCD2) (14). The homolog of the Holliday junction resolvase GEN1 is required for the formation of Class II CO in rice (17) but not in Arabidopsis (18), suggesting that Class II CO pathways have diverged between monocots and dicots. In addition to pro–Class II CO factors, Arabidopsis has at least three anti–Class II CO mechanisms: the AtFANCM helicase and its cofactors AtMHF1 and AtMHF2 (19, 20); members of BLM-TOP3-RMI1 (BTR) complex AtRECQ4A, AtRECQ4B, AtTOP3α, and AtRMI1 (21, 22); and AtFIGL1 AAA-ATPase and its interacting protein AtFLIP1 (23, 24). Interestingly, although total CO frequency increases and Class I CO numbers remain unchanged when these anti–Class II CO pathways are perturbed, univalents are still occasionally observed, suggesting that CO assurance has also been weakened (22, 23).In this study, we investigated the influence of AtFANCD2, AtFANCM, AtFIGL1, and AtRMI1 on the distribution of Class I COs among chromosomes. We demonstrate that these factors have a role in promoting a non-Poisson distribution of Class I COs among chromosomes.     

Comparison of two budesonide powder inhalers,Easyhaler and Turbuhaler,in steroid-naïve asthmatic patients

The objective of this multicenter study was to compare the clinical efficacy, safety, and acceptability of Easyhaler and Turbuhaler for the delivery of budesonide 200 micrograms/dose twice daily in steroid-na?ve asthmatic patients. Three hundred and twenty-six newly diagnosed, steroid-na?ve adult patients with mild-to-moderate asthma were recruited into this randomized, double-blind, double-dummy, parallel-group study, comprising a 2-week run-in period and 8 weeks of treatment. Patients received budesonide inhalation powder 400 micrograms/day either via Easyhaler (n = 159) or via Turbuhaler (n = 167), plus salbutamol inhalation powder (100 micrograms/dose) via Easyhaler as rescue therapy. The study was completed by 292 patients: 143 in the Easyhaler group and 149 in the Turbuhaler group. The primary outcome variable, mean morning peak expiratory flow (PEF), improved significantly and almost similarly by 36.3 and 30.6 l/min, respectively, from run-in to weeks 7-8. At weeks 7-8, the mean (SE) difference in morning PEF between the two treatments was 7.1 (9.4) l/min (90% CI from -8.4 to 22.6) on per protocol analysis, which was within the defined limits for therapeutic equivalence. There were no significant differences between treatments in terms of secondary efficacy variables or adverse events. However, patients found Easyhaler more acceptable than Turbuhaler. The results show that budesonide via Easyhaler is clinically as effective as Pulmicort Turbuhaler when equal daily doses of budesonide are delivered to steroid-na?ve asthmatic patients. Moreover, patients found Easyhaler more acceptable than Turbuhaler, and a majority would prefer Easyhaler if given a choice.     

Efficacy of major general surgery performed by non-physician clinicians at a central hospital in Malawi

In some sub-Saharan African countries non-physician clinicians have to perform major general surgery without medical officers and surgeons. The safety of this practice has not been established. The aim of this study was to evaluate the contribution of clinical officers (COs) to major general surgery at Zomba Central Hospital. We performed a retrospective five-year period study during 2003-2007. The perioperative outcome for three procedures was analysed. During the study 2931 major general surgical procedures were performed: 1437 (49%) by surgeons; 366 (12.5%) by COs assisted by surgeons; and 1128 (38.5%) by COs alone. COs performed 50% of prostatectomies, ventriculo-peritoneal-shuntings and strangulated hernia repairs with bowel resection alone. Baseline parameters and perioperative outcomes of the patients who underwent operations with surgeons present (as operator or assistant, 'surgeon group') or patients operated by COs alone ('CO group') were similar. COs can safely perform major general surgery when adequate training and supervision are provided.     

Outlet strut fracture of Björk-Shiley convexo concave heart valves: the UK cohort study

OBJECTIVE—To investigate the risk of outlet strut fracture (OSF) in Björk-Shiley convexo concave (BSCC) valves in relation to patients' clinical and valve characteristics.
DESIGN—A cohort of 2977 patients with 3325 valves with a follow up of 18 years.
SETTING—38 cardiac implantation centres in the UK.
RESULTS—56 OSF events were reported with 43 occurring in mitral and 13 in aortic valves. The overall OSF rate was 0.17%/year. No dominant clinical factor of risk was found, but multiple regression analysis identified age, body surface area, valve size, shop order fracture rate, and manufacturing period as risk factors for OSF. A 4% (95% confidence interval (CI) 2% to 6%) decrease in the risk of OSF was observed for each advancing year of age and a fivefold (95% CI 2 to 13) increase in risk for a 0.5 m² increase in body surface area. The association between the risk of OSF and valve size was not constant over time. Excess risks among 31 mm and 33 mm sizes (mainly mitral valves) decreased over time while that for 23 mm (almost all aortic valves) increased. The risk of OSF increased by 40% (95% CI 20% to 50%) for a unit increase in the fracture rate of other valves in the same batch. For valves manufactured during 1981 to 1984 the risk of OSF was 4 (95% CI 2 to 12) times greater than for valves manufactured before 1981.
CONCLUSIONS—The OSF rates for 60° BSCC valves observed in the UK are the highest among all monitored populations. The changing patterns of mitral and aortic valve OSF rates over time observed in this study have not been identified previously and highlight the need for continued monitoring of patients with the BSCC valve.


Keywords: cohort studies; heart valves; outlet strut fracture