Effect of atazanavir versus other protease inhibitor-containing antiretroviral therapy on endothelial function in HIV-infected persons: randomised controlled trial

OBJECTIVE: Impaired endothelial function was demonstrated in HIV-infected persons on protease inhibitor (PI)-containing antiretroviral therapy, probably due to altered lipid metabolism. Atazanavir is a PI causing less atherogenic lipoprotein changes. This study determined whether endothelial function improves after switching from other PI to atazanavir. DESIGN: Randomised, observer-blind, treatment-controlled trial. SETTING: Three university-based outpatient clinics. PATIENTS: 39 HIV-infected persons with suppressed viral replication on PI-containing regimens and fasting low-density lipoprotein (LDL)-cholesterol greater than 3 mmol/l. INTERVENTION: Patients were randomly assigned to continue the current PI or change to unboosted atazanavir. MAIN OUTCOME MEASURES: Endpoints at week 24 were endothelial function assessed by flow-mediated dilation (FMD) of the brachial artery, lipid profiles and serum inflammation and oxidative stress parameters. RESULTS: Baseline characteristics and mean FMD values of the two treatment groups were comparable (3.9% (SD 1.8) on atazanavir versus 4.0% (SD 1.5) in controls). After 24 weeks' treatment, FMD decreased to 3.3% (SD 1.4) and 3.4% (SD 1.7), respectively (all p = ns). Total cholesterol improved in both groups (p<0.0001 and p = 0.01, respectively) but changes were more pronounced on atazanavir (p = 0.05, changes between groups). High-density lipoprotein and triglyceride levels improved on atazanavir (p = 0.03 and p = 0.003, respectively) but not in controls. Serum inflammatory and oxidative stress parameters did not change; oxidised LDL improved significantly in the atazanavir group. CONCLUSIONS: The switch from another PI to atazanavir in treatment-experienced patients did not result in improvement of endothelial function despite significantly improved serum lipids. Atherogenic lipid profiles and direct effects of antiretroviral drugs on the endothelium may affect vascular function. Trial registration number: NCT00447070.

Exercise capacity and biventricular function in adult patients with repaired tetralogy of Fallot

BACKGROUND: Adult patients with repaired tetralogy of Fallot (rTOF) often have diminished exercise capacity. The primary objective of this study was to examine whether abnormalities of biventricular function play a role in exercise limitation in patients with rTOF. METHODS: This was a retrospective review of 99 adult patients with rTOF. Right ventricular (RV) and left ventricular (LV) function were assessed echocardiographically using the myocardial performance index (MPI). Maximal oxygen consumption (VO(2) Max) was measured during a level 1 cardiopulmonary exercise test. RESULTS: The mean age of the cohort was 34 +/- 11 years (50% females). Although most of the patients reported good functional capacity, the peak Vo(2)max was decreased at 22 +/- 6 mL/kg per minute (66% +/- 13% predicted Vo(2)max for age and sex). The mean RV and LV MPI were 0.30 +/- 0.07 and 0.42 +/- 0.09, respectively. In the multivariate model, higher RV MPI (P = .04) and LV MPI (P = .005) values, representing impaired ventricular function, were associated with diminished Vo(2)max. There was a significant correlation between the RV and LV MPI (r = 0.54, P = .001). CONCLUSIONS: Impairment of RV and LV function, as measured by MPI, is associated with diminished exercise capacity in patients with repaired tetralogy of Fallot. Furthermore, there is a linear relationship between the RV and LV function suggesting that ventricular interactions are contributing to the limited exercise capacity in this group of patients. Strategies aimed at preserving biventricular function or improving adverse ventricular interactions could help to improve functional capacity in these patients.

Randomized controlled trial on single dose steroid before thyroidectomy for benign disease to improve postoperative nausea, pain, and vocal function

OBJECTIVE: To evaluate the effects of a single preoperative dose of steroid on thyroidectomy outcomes. BACKGROUND: Nausea, pain, and voice alteration frequently occur after thyroidectomy. Because steroids effectively reduce nausea and inflammation, a preoperative administration of steroids could improve these thyroidectomy outcomes. METHODS: Seventy-two patients (men = 20, women = 52) undergoing thyroidectomy for benign disease were included in this randomized, controlled, 2 armed (group D: 8 mg dexamethasone, n = 37; group C: 0.9% NaCl, n = 35), double-blinded study (clinical trial number NCT00619086). Anesthesia, surgical procedures, antiemetics, and analgesic treatments were standardized. Nausea (0-3), pain (visual analog scale), antiemetic and analgesic requirements, and digital voice recording were documented before and 4, 8, 16, 24, 36, and 48 hours after surgery. Patients were followed-up 30 days after hospital discharge. RESULTS: Baseline characteristics were similar among the 2 treatment groups. Nausea was pronounced in the first 16 hours postoperatively (scores were <0.3 and 0.8-1.0 for group D and C, respectively (P = 0.005)), and was significantly lower in group D compared with group C during the observation period (P = 0.001). Pain diminished within 48 hours after surgery (visual analog scale 20 and 35 in group D and C, respectively (P = 0.009)). Antiemetic and analgesic requirements were also significantly diminished. Changes in voice mean frequency were less prominent in the dexamethasone group compared with the placebo group (P = 0.015). No steroid-related complications occurred. CONCLUSION: A preoperative single dose of steroid significantly reduced nausea, vomiting, and pain, and improved postoperative voice function within the first 48 hours (most pronounced within 16 hours) after thyroid resection; this strategy should be routinely applied in thyroidectomies.

Sexual and organ function in patients with symptomatic prolapse: are pessaries helpful?

OBJECTIVE: To evaluate quality of life and pelvic organ and sexual function before and during pessary use in patients with symptomatic pelvic organ prolapse and to determine reasons which lead to cessation of pessary use. DESIGN: Prospective observational study. SETTING: Tertiary referral center. PATIENT(S): Patients with symptomatic stage II or more prolapse of the anterior, posterior, or apical vaginal wall with or without uterus were included in this study. INTERVENTION(S): We used the Female Sexual Function Index questionnaire and the Sheffield prolapse questionnaire. For quality of life we used the King's Health Questionnaire. MAIN OUTCOME MEASURE(S): Main outcome measures were quality of life and sexual and pelvic organ function. RESULT(S): A total of 73 women participated in this study; 31 were sexually active. Desire, lubrication, and sexual satisfaction showed statistically significant improvement, and orgasm remained unchanged. Statistically significant improvement in the feeling of bulge occurred during therapy, stool outlet problems were significantly improved, overactive bladder symptoms were significantly better, and pessaries did not significantly alter incontinence. CONCLUSION(S): Pessaries have been shown to be a viable noninvasive treatment for pelvic organ prolapse improving organ and sexual function as well as general wellbeing.

Assessing Decision Making Strategies In Construction Management By Using A Schedule-Based Simulation Framework

During the project, managers encounter numerous contingencies and are faced with the challenging task of making decisions that will effectively keep the project on track. This task is very challenging because construction projects are non-prototypical and the processes are irreversible. Therefore, it is critical to apply a methodological approach to develop a few alternative management decision strategies during the planning phase, which can be deployed to manage alternative scenarios resulting from expected and unexpected disruptions in the as-planned schedule. Such a methodology should have the following features but are missing in the existing research: (1) looking at the effects of local decisions on the global project outcomes, (2) studying how a schedule responds to decisions and disruptive events because the risk in a schedule is a function of the decisions made, (3) establishing a method to assess and improve the management decision strategies, and (4) developing project specific decision strategies because each construction project is unique and the lessons from a particular project cannot be easily applied to projects that have different contexts. The objective of this dissertation is to develop a schedule-based simulation framework to design, assess, and improve sequences of decisions for the execution stage. The contribution of this research is the introduction of applying decision strategies to manage a project and the establishment of iterative methodology to continuously assess and improve decision strategies and schedules. The project managers or schedulers can implement the methodology to develop and identify schedules accompanied by suitable decision strategies to manage a project at the planning stage. The developed methodology also lays the foundation for an algorithm towards continuously automatically generating satisfactory schedule and strategies through the construction life of a project. Different from studying isolated daily decisions, the proposed framework introduces the notion of {em decision strategies} to manage construction process. A decision strategy is a sequence of interdependent decisions determined by resource allocation policies such as labor, material, equipment, and space policies. The schedule-based simulation framework consists of two parts, experiment design and result assessment. The core of the experiment design is the establishment of an iterative method to test and improve decision strategies and schedules, which is based on the introduction of decision strategies and the development of a schedule-based simulation testbed. The simulation testbed used is Interactive Construction Decision Making Aid (ICDMA). ICDMA has an emulator to duplicate the construction process that has been previously developed and a random event generator that allows the decision-maker to respond to disruptions in the emulation. It is used to study how the schedule responds to these disruptions and the corresponding decisions made over the duration of the project while accounting for cascading impacts and dependencies between activities. The dissertation is organized into two parts. The first part presents the existing research, identifies the departure points of this work, and develops a schedule-based simulation framework to design, assess, and improve decision strategies. In the second part, the proposed schedule-based simulation framework is applied to investigate specific research problems.

Vertebroplasty: experimental characterization of polymethylmethacrylate bone cement spreading as a function of viscosity, bone porosity, and flow rate

STUDY DESIGN: This is an experimental study on an artificial vertebra model and human cadaveric spine. OBJECTIVE: Characterization of polymethylmethacrylate (PMMA) bone cement distribution in the vertebral body as a function of cement viscosity, bone porosity, and injection speed. Identification of relevant parameters for improved cement flow predictability and leak prevention in vertebroplasty. SUMMARY OF BACKGROUND DATA: Vertebroplasty is an efficient procedure to treat vertebral fractures and stabilize osteoporotic bone in the spine. Severe complications result from bone cement leakage into the spinal canal or the vascular system. Cement viscosity has been identified as an important parameter for leak prevention but the influence of bone structure and injection speed remain obscure. METHODS: An artificial vertebra model based on open porous aluminum foam was used to simulate bone of known porosity. Fifty-six vertebroplasties with 4 different starting viscosity levels and 2 different injection speeds were performed on artificial vertebrae of 3 different porosities. A validation on a human cadaveric spine was executed. The experiments were radiographically monitored and the shape of the cement clouds quantitatively described with the 2 indicators circularity and mean cement spreading distance. RESULTS: An increase in circularity and a decrease in mean cement spreading distance was observed with increasing viscosity, with the most striking change occurring between 50 and 100 Pas. Larger pores resulted in significantly reduced circularity and increased mean cement spreading distance whereas the effect of injection speed on the 2 indicators was not significant. CONCLUSION: Viscosity is the key factor for reducing the risk of PMMA cement leakage and it should be adapted to the degree of osteoporosis encountered in each patient. It may be advisable to opt for a higher starting viscosity but to inject the material at a faster rate.

DENITRIFICATION IN SOILS: FROM GENES TO ENVIRONMENTAL OUTCOMES

Denitrification is an important process of global nitrogen cycle as it removes reactive nitrogen from the biosphere, and acts as the primary source of nitrous oxide (N2O). This thesis seeks to gain better understanding of the biogeochemistry of denitrification by investigating the process from four different aspects: genetic basis, enzymatic kinetics, environmental interactions, and environmental consequences. Laboratory and field experiments were combined with modeling efforts to unravel the complexity of denitrification process under microbiological and environmental controls. Dynamics of denitrification products observed in laboratory experiments revealed an important role of constitutive denitrification enzymes, whose presence were further confirmed with quantitative analysis of functional genes encoding nitrite reductase and nitrous oxide reductase. A metabolic model of denitrification developed with explicit denitrification enzyme kinetics and representation of constitutive enzymes successfully reproduced the dynamics of N2O and N2 accumulation observed in the incubation experiments, revealing important regulatory effect of denitrification enzyme kinetics on the accumulation of denitrification products. Field studies demonstrated complex interaction of belowground N2O production, consumption and transport, resulting in two pulse pattern in the surface flux. Coupled soil gas diffusion/denitrification model showed great potential in simulating the dynamics of N2O below ground, with explicit representation of the activity of constitutive denitrification enzymes. A complete survey of environmental variables showed distinct regulation regimes on the denitrification activity from constitutive enzymes and new synthesized enzymes. Uncertainties in N2O estimation with current biogeochemical models may be reduced as accurate simulation of the dynamics of N2O in soil and surface fluxes is possible with a coupled diffusion/denitrification model that includes explicit representation of denitrification enzyme kinetics. In conclusion, denitrification is a complex ecological function regulated at cellular level. To assess the environmental consequences of denitrification and develop useful tools to mitigate N2O emissions require a comprehensive understanding of the regulatory network of denitrification with respect to microbial physiology and environmental interactions.

Dibutyltin disrupts glucocorticoid receptor function and impairs glucocorticoid-induced suppression of cytokine production

BACKGROUND: Organotins are highly toxic and widely distributed environmental chemicals. Dibutyltin (DBT) is used as stabilizer in the production of polyvinyl chloride plastics, and it is also the major metabolite formed from tributyltin (TBT) in vivo. DBT is immunotoxic, however, the responsible targets remain to be defined. Due to the importance of glucocorticoids in immune-modulation, we investigated whether DBT could interfere with glucocorticoid receptor (GR) function. METHODOLOGY: We used HEK-293 cells transiently transfected with human GR as well as rat H4IIE hepatoma cells and native human macrophages and human THP-1 macrophages expressing endogenous receptor to study organotin effects on GR function. Docking of organotins was used to investigate the binding mechanism. PRINCIPAL FINDINGS: We found that nanomolar concentrations of DBT, but not other organotins tested, inhibit ligand binding to GR and its transcriptional activity. Docking analysis indicated that DBT inhibits GR activation allosterically by inserting into a site close to the steroid-binding pocket, which disrupts a key interaction between the A-ring of the glucocorticoid and the GR. DBT inhibited glucocorticoid-induced expression of phosphoenolpyruvate carboxykinase (PEPCK) and tyrosine-aminotransferase (TAT) and abolished the glucocorticoid-mediated transrepression of TNF-alpha-induced NF-kappaB activity. Moreover, DBT abrogated the glucocorticoid-mediated suppression of interleukin-6 (IL-6) and TNF-alpha production in lipopolysaccharide (LPS)-stimulated native human macrophages and human THP-1 macrophages. CONCLUSIONS: DBT inhibits ligand binding to GR and subsequent activation of the receptor. By blocking GR activation, DBT may disturb metabolic functions and modulation of the immune system, providing an explanation for some of the toxic effects of this organotin.

Contractile function is preserved in unloaded hearts despite atrophic remodeling

OBJECTIVE: Recent studies have shown that mechanically unloading a failing heart may induce reverse remodeling and functional improvement. However, these benefits may be balanced by an unloading-related remodeling including myocardial atrophy that might lead to decrease in function. Using a model of heterotopic heart transplantation, we aimed to characterize the myocardial changes induced by long-term unloading. MATERIAL AND METHODS: Macroscopic as well as cellular and functional changes were followed in normal hearts unloaded for a 3-month period. Microscopic parameters were evaluated with stereologic methodology. Myocardial contractile function was quantified with a Langendorff isolated, perfused heart technique. RESULTS: Atrophy was macroscopically obvious and accompanied by a 67% reduction of the myocyte volume and a 43% reduction of the interstitial tissue volume, thus accounting for a shift of the myocyte/connective tissue ratio in favor of noncontractile tissue. The absolute number of cardiomyocyte nuclei decreased from 64.7 +/- 5.1 x 10(7) in controls to 22.6 +/- 3.7 x 10(7) (30 days) and 21.6 +/- 3.1 x 10(7) (90 days) after unloading (P < .05). The numeric nucleic density in the unloaded myocardium, as well as the mean cardiomyocyte volume per cardiomyocyte nucleus, remained constant throughout the 90 days of observation. Functional data indicated an increase in ventricular stiffness, although contractile function was preserved, as confirmed by unaltered maximal developed pressure and increased contractility (maximum rate of left ventricular pressure development) and relaxation (minimum rate of left ventricular pressure development). CONCLUSION: Atrophic remodeling involves both the myocyte and interstitial tissue compartment. These data suggest that although there is decreased myocardial volume and increased stiffness, contractile capacity is preserved in the long-term unloaded heart.

Risk of severe asthma episodes predicted from fluctuation analysis of airway function

Asthma is an increasing health problem worldwide, but the long-term temporal pattern of clinical symptoms is not understood and predicting asthma episodes is not generally possible. We analyse the time series of peak expiratory flows, a standard measurement of airway function that has been assessed twice daily in a large asthmatic population during a long-term crossover clinical trial. Here we introduce an approach to predict the risk of worsening airflow obstruction by calculating the conditional probability that, given the current airway condition, a severe obstruction will occur within 30 days. We find that, compared with a placebo, a regular long-acting bronchodilator (salmeterol) that is widely used to improve asthma control decreases the risk of airway obstruction. Unexpectedly, however, a regular short-acting beta2-agonist bronchodilator (albuterol) increases this risk. Furthermore, we find that the time series of peak expiratory flows show long-range correlations that change significantly with disease severity, approaching a random process with increased variability in the most severe cases. Using a nonlinear stochastic model, we show that both the increased variability and the loss of correlations augment the risk of unstable airway function. The characterization of fluctuations in airway function provides a quantitative basis for objective risk prediction of asthma episodes and for evaluating the effectiveness of therapy.

Prognostic clinical and radiological parameters for immediate facial nerve function following vestibular schwannoma surgery

OBJECTIVE: The paper aims to define the parameters available before surgery which could predict immediate facial nerve function after excision of a vestibular schwannoma (VS). METHODS: Ninety-nine patients with VS operated consecutively by a single surgeon using an identical surgical technique have been evaluated retrospectively. Data were collected regarding patients' sex, age at onset of symptoms and at surgery, initial symptoms, neurological status at presentation, early post-operative neurological status and complications. The main radiological parameters included in the study were tumour extension pattern, diameters, shape, and volume, as well as extent of bony changes of the internal auditory canal. RESULTS: As the tumour stage and volume increase, facial nerve function is worse after surgery (p < 0.001 and p < 0.05, respectively). Concomitantly, larger extra-meatal tumour diameters in three dimensions (sagittal, coronal and axial) led to worse function (p < 0.01). Anterior and/or caudal tumour extension (p = 0.001 and p = 0.004, respectively) had more significant correlation than posterior and/or cranial extension (p = 0.022 and p = 0.353, respectively). Polycyclic VS had the worst prognosis, followed by the tumours with oval shape. The extent of intra-meatal tumour growth does not correlate with immediate facial nerve outcome. The different angles, lengths and diameters of the internal auditory channel showed no significant correlation with facial nerve outcome. Patients with headache as an initial symptom and those with gait instability and/or pre-operative poor facial nerve function had significantly worse immediate facial nerve outcome. CONCLUSION: Our data suggests that the analysis of the radiological and neurological patient data prior to surgery could give reliable clues regarding the immediate post-operative facial nerve function.

Effect of urinary tract infection on reservoir function in patients with ileal bladder substitute

PURPOSE: We determined the functional consequences of urinary tract infection in patients with an ileal bladder substitute in terms of urinary continence, post-void residual and urinary retention. MATERIALS AND METHODS: A total of 48 patients with culture documented urinary tract infection (single organism, 10(5) or greater cfu) were retrospectively evaluated before, during and after the infection for changes in continence, post-void residual and urinary retention as well as for resolution of symptomatology after appropriate antibiotic therapy. RESULTS: Of the 48 patients 40 had a single infection while the remaining 8 had multiple urinary tract infection episodes. During daytime 27 of the 44 patients with previously good daytime continence experienced deterioration in their baseline voiding status while infected. Of the 40 patients who were previously continent at night 20 had incontinence while infected. There were 15 patients with documented post-void residual and urinary retention developed in 4 during the urinary tract infection. All patients returned to baseline continence status and reservoir function after appropriate antibiotic treatment based on objective and subjective assessments. CONCLUSIONS: Urinary tract infection may cause urinary incontinence in patients with ileal bladder substitutes. Therefore, when there are complaints of de novo urinary incontinence, a finding of post-void residual or an acute presentation of urinary retention, a urinary tract infection should be excluded. When the urinary tract infection is appropriately treated urinary continence and reservoir function return to their baseline status.

Three-year cost analysis of function-centred versus pain-centred inpatient rehabilitation in patients with chronic non-specific low back pain

OBJECTIVE: To compare costs of function- and pain-centred inpatient treatment in patients with chronic low back pain over 3 years of follow-up. DESIGN: Cost analysis of a randomized controlled trial. PATIENTS: A total of 174 patients with chronic low back pain were randomized to function- or pain-centred inpatient treatment. METHODS: Data on direct and indirect costs were gathered by questionnaires sent to patients, health insurance providers, employers, and the Swiss Disability Insurance Company. RESULTS: There was a non-significant difference in total medical costs after 3 years' follow-up. Total costs were 77,305 Euros in the function-centred inpatient treatment group and 83,085 Euros in the pain-centred inpatient treatment group. Likewise, indirect costs after 3 years from lost work days were non-significantly lower in the function-centred in-patient treatment group (6354 Euros; 95% confidence interval -20,892, 8392) and direct medical costs were non-significantly higher in the function-centred inpatient treatment group (574 Euros; 95% confidence interval -862, 2011). CONCLUSION: The total costs of function-centred and pain-centred inpatient treatment were similar over the whole 3-year follow-up.

Adjuvant breast cancer treatment and cognitive function: current knowledge and research directions

Evidence is mounting that potentially curative systemic adjuvant therapy for early-stage breast cancer may result in cognitive impairment. Five published studies have investigated cognitive function in this setting, and the consistent results of all five studies suggest an adverse effect of adjuvant chemotherapy. These studies are reviewed with particular attention to their methodologic limitations. For example, all five studies used cross-sectional designs, none controlled for possible confounding hormonal factors, and three examined patients who had not received a uniform chemotherapy regimen. The potential roles of chemotherapy-induced menopause and of adjuvant hormonal therapy in cognitive impairment are also discussed. Priorities for future research include confirmation of an effect of adjuvant chemotherapy in a study with a longitudinal design, closer examination of the potential contribution of hormonal factors, and similar studies on the effect of adjuvant therapy on cognitive function in other cancer types. If an effect of systemic adjuvant therapy on cognitive function is confirmed, such an effect will have implications for informed consent. It may also result in incorporation of objective measures of cognition in clinical trials of adjuvant therapy and in the investigation of preventive interventions that might minimize the impact of cognitive dysfunction after cancer treatment.

Effects of coronary sinus occlusion on myocardial ischaemia in humans: role of coronary collateral function

OBJECTIVE This study tested the hypotheses that intermittent coronary sinus occlusion (iCSO) reduces myocardial ischaemia, and that the amount of ischaemia reduction is related to coronary collateral function. DESIGN Prospective case-control study with intraindividual comparison of myocardial ischaemia during two 2-min coronary artery balloon occlusions with and without simultaneous iCSO by a balloon-tipped catheter. SETTING University Hospital. PATIENTS 35 patients with chronic stable coronary artery disease. INTERVENTION 2-min iCSO. MAIN OUTCOME MEASURES Myocardial ischaemia as assessed by intracoronary (i.c.) ECG ST shift at 2 min of coronary artery balloon occlusion. Collateral flow index (CFI) without iCSO, that is, the ratio between mean distal coronary occlusive (Poccl) and mean aortic pressure (Pao) both minus central venous pressure. RESULTS I.c. ECG ST segment shift (elevation in all) at the end of the procedure with iCSO versus without iCSO was 1.33±1.25 mV versus 1.85±1.45 mV, p<0.0001. Regression analysis showed that the degree of i.c. ECG ST shift reduction during iCSO was related to CFI, best fitting a Lorentzian function (r(2)=0.61). Ischaemia reduction with iCSO was greatest at a CFI of 0.05-0.20, whereas in the low and high CFI range the effect of iCSO was absent. CONCLUSIONS ICSO reduces myocardial ischaemia in patients with chronic coronary artery disease. Ischaemia reduction by iCSO depends on coronary collateral function. A minimal degree of collateral function is necessary to render iCSO effective. ICSO cannot manifest an effect when collateral function prevents ischaemia in the first place.