Noradrenergic α₁ receptor antagonist treatment attenuates positive subjective effects of cocaine in humans: a randomized trial

Background

Preclinical research implicates dopaminergic and noradrenergic mechanisms in mediating the reinforcing effects of drugs of abuse, including cocaine. The objective of this study was to evaluate the impact of treatment with the noradrenergic α₁ receptor antagonist doxazosin on the positive subjective effects of cocaine.

Methods

Thirteen non-treatment seeking, cocaine-dependent volunteers completed this single-site, randomized, placebo-controlled, within-subjects study. In one study phase volunteers received placebo and in the other they received doxazosin, with the order counterbalanced across participants. Study medication was masked by over-encapsulating doxazosin tablets and matched placebo lactose served as the control. Study medication treatment was initiated at 1 mg doxazosin or equivalent number of placebo capsules PO/day and increased every three days by 1 mg. After receiving 4 mg doxazosin or equivalent number of placebo capsules participants received masked doses of 20 and 40 mg cocaine IV in that order with placebo saline randomly interspersed to maintain the blind.

Results

Doxazosin treatment was well tolerated and doxazosin alone produced minimal changes in heart rate and blood pressure. During treatment with placebo, cocaine produced dose-dependent increases in subjective effect ratings of “high”, “stimulated”, “like cocaine”, “desire cocaine”, “any drug effect”, and “likely to use cocaine if had access” (p<.001). Doxazosin treatment significantly attenuated the effects of 20 mg cocaine on ratings of “stimulated”, “like cocaine”, and “likely to use cocaine if had access” (p<.05). There were trends for doxazosin to reduce ratings of “stimulated”, “desire cocaine”, and “likely to use cocaine if had access” (p<.10).

Conclusions

Medications that block noradrenergic α₁ receptors, such as doxazosin, may be useful as treatments for cocaine dependence, and should be evaluated further.

Trial Registration

Clinicaltrials.gov {"type":"clinical-trial","attrs":{"text":"NCT01062945","term_id":"NCT01062945"}}NCT01062945     

Establishing long-term efficacy in chronic disease: use of recursive partitioning and propensity score adjustment to estimate outcome in MS

Context

Establishing the long-term benefit of therapy in chronic diseases has been challenging. Long-term studies require non-randomized designs and, thus, are often confounded by biases. For example, although disease-modifying therapy in MS has a convincing benefit on several short-term outcome-measures in randomized trials, its impact on long-term function remains uncertain.

Objective

Data from the 16-year Long-Term Follow-up study of interferon-beta-1b is used to assess the relationship between drug-exposure and long-term disability in MS patients.

Design/Setting

To mitigate the bias of outcome-dependent exposure variation in non-randomized long-term studies, drug-exposure was measured as the medication-possession-ratio, adjusted up or down according to multiple different weighting-schemes based on MS severity and MS duration at treatment initiation. A recursive-partitioning algorithm assessed whether exposure (using any weighing scheme) affected long-term outcome. The optimal cut-point that was used to define “high” or “low” exposure-groups was chosen by the algorithm. Subsequent to verification of an exposure-impact that included all predictor variables, the two groups were compared using a weighted propensity-stratified analysis in order to mitigate any treatment-selection bias that may have been present. Finally, multiple sensitivity-analyses were undertaken using different definitions of long-term outcome and different assumptions about the data.

Main Outcome Measure

Long-Term Disability.

Results

In these analyses, the same weighting-scheme was consistently selected by the recursive-partitioning algorithm. This scheme reduced (down-weighted) the effectiveness of drug exposure as either disease duration or disability at treatment-onset increased. Applying this scheme and using propensity-stratification to further mitigate bias, high-exposure had a consistently better clinical outcome compared to low-exposure (Cox proportional hazard ratio = 0.30–0.42; p<0.0001).

Conclusions

Early initiation and sustained use of interferon-beta-1b has a beneficial impact on long-term outcome in MS. Our analysis strategy provides a methodological framework for bias-mitigation in the analysis of non-randomized clinical data.

Trial Registration

Clinicaltrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00206635","term_id":"NCT00206635"}}NCT00206635     

HIV-1 infection and first line ART induced differential responses in mitochondria from blood lymphocytes and monocytes: the ANRS EP45 "Aging" study

Background

The ANRS EP45 “Aging” study investigates the cellular mechanisms involved in the accelerated aging of HIV-1 infected and treated patients. The data reported focus on mitochondria, organelles known to be involved in cell senescence.

Methods

49 HIV-1 infected patients untreated with antiretroviral therapy, together with 49 seronegative age- and sex-matched control subjects and 81 HIV-1 infected and treated patients, were recruited by 3 AIDS centres (Marseille, Montpellier, Nice; France; http://clinicaltrials.gov/, {"type":"clinical-trial","attrs":{"text":"NCT01038999","term_id":"NCT01038999"}}NCT01038999). In more than 88% of treated patients, the viral load was <40 copies/ml and the CD4+ cell count was >500/mm³. ROS (reactive oxygen species) production and ΔΨm (inner membrane potential) were measured by flow cytometry in blood lymphocytes and monocytes (functional parameters). Three mitochondrial network quantitative morphological parameters were computed using confocal microscopy and image analysis. Three PBMC mitochondrial proteins (porin and subunits 2 and 4 of cytochrome C oxidase encoded by mtDNA or nuclear DNA, respectively) were analysed by western blotting.

Results

Quantitative changes in PBMC mitochondrial proteins were not induced by either HIV-1 infection or ART. Discriminant analysis integrating functional (ROS production and ΔΨm) or morphological (network volume density, fragmentation and branching) parameters revealed HIV-1 infection and ART differential effects according to cell type. First line ART tended to rescue lymphocyte mitochondrial parameters altered by viral infection, but induced slight changes in monocytes. No statistical difference was found between the effects of three ART regimens on mitochondrial parameters. Correlations between functional parameters and viral load confirmed the damaging effects of HIV-1 in lymphocyte mitochondria.

Conclusions

In patients considered to be clinically stable, mitochondria exhibited functional and morphological modifications in PBMCs resulting from either direct or indirect effects of HIV-1 infection (lymphocytes), or from first line ART (monocytes). Together with other tissue impairments, these changes may contribute to global aging.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT01038999","term_id":"NCT01038999"}}NCT01038999 {"type":"clinical-trial","attrs":{"text":"NCT01038999","term_id":"NCT01038999"}}NCT01038999     

High-affinity inhibitors of human NAD-dependent 15-hydroxyprostaglandin dehydrogenase: mechanisms of inhibition and structure-activity relationships

Background

15-hydroxyprostaglandin dehydrogenase (15-PGDH, EC 1.1.1.141) is the key enzyme for the inactivation of prostaglandins, regulating processes such as inflammation or proliferation. The anabolic pathways of prostaglandins, especially with respect to regulation of the cyclooxygenase (COX) enzymes have been studied in detail; however, little is known about downstream events including functional interaction of prostaglandin-processing and -metabolizing enzymes. High-affinity probes for 15-PGDH will, therefore, represent important tools for further studies.

Principal Findings

To identify novel high-affinity inhibitors of 15-PGDH we performed a quantitative high-throughput screen (qHTS) by testing >160 thousand compounds in a concentration-response format and identified compounds that act as noncompetitive inhibitors as well as a competitive inhibitor, with nanomolar affinity. Both types of inhibitors caused strong thermal stabilization of the enzyme, with cofactor dependencies correlating with their mechanism of action. We solved the structure of human 15-PGDH and explored the binding modes of the inhibitors to the enzyme in silico. We found binding modes that are consistent with the observed mechanisms of action.

Conclusions

Low cross-reactivity in screens of over 320 targets, including three other human dehydrogenases/reductases, suggest selectivity of the present inhibitors for 15-PGDH. The high potencies and different mechanisms of action of these chemotypes make them a useful set of complementary chemical probes for functional studies of prostaglandin-signaling pathways.

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A bioinformatics classifier and database for heme-copper oxygen reductases

Background

Heme-copper oxygen reductases (HCOs) are the last enzymatic complexes of most aerobic respiratory chains, reducing dioxygen to water and translocating up to four protons across the inner mitochondrial membrane (eukaryotes) or cytoplasmatic membrane (prokaryotes). The number of completely sequenced genomes is expanding exponentially, and concomitantly, the number and taxonomic distribution of HCO sequences. These enzymes were initially classified into three different types being this classification recently challenged.

Methodology

We reanalyzed the classification scheme and developed a new bioinformatics classifier for the HCO and Nitric oxide reductases (NOR), which we benchmark against a manually derived gold standard sequence set. It is able to classify any given sequence of subunit I from HCO and NOR with a global recall and precision both of 99.8%. We use this tool to classify this protein family in 552 completely sequenced genomes.

Conclusions

We concluded that the new and broader data set supports three functional and evolutionary groups of HCOs. Homology between NORs and HCOs is shown and NORs closest relationship with C Type HCOs demonstrated. We established and made available a classification web tool and an integrated Heme-Copper Oxygen reductase and NOR protein database (www.evocell.org/hco).     

Risk factors for preterm birth in an international prospective cohort of nulliparous women

Objectives

To identify risk factors for spontaneous preterm birth (birth <37 weeks gestation) with intact membranes (SPTB-IM) and SPTB after prelabour rupture of the membranes (SPTB-PPROM) for nulliparous pregnant women.

Design

Prospective international multicentre cohort.

Participants

3234 healthy nulliparous women with a singleton pregnancy, follow up was complete in 3184 of participants (98.5%).

Results

Of the 3184 women, 156 (4.9%) had their pregnancy complicated by SPTB; 96 (3.0%) and 60 (1.9%) in the SPTB-IM and SPTB-PPROM categories, respectively. Independent risk factors for SPTB-IM were shorter cervical length, abnormal uterine Doppler flow, use of marijuana pre-pregnancy, lack of overall feeling of well being, being of Caucasian ethnicity, having a mother with diabetes and/or a history of preeclampsia, and a family history of low birth weight babies. Independent risk factors for SPTB-PPROM were shorter cervical length, short stature, participant’s not being the first born in the family, longer time to conceive, not waking up at night, hormonal fertility treatment (excluding clomiphene), mild hypertension, family history of recurrent gestational diabetes, and maternal family history of any miscarriage (risk reduction). Low BMI (<20) nearly doubled the risk for SPTB-PPROM (odds ratio 2.64; 95% CI 1.07–6.51). The area under the receiver operating characteristics curve (AUC), after internal validation, was 0.69 for SPTB-IM and 0.79 for SPTB-PPROM.

Conclusion

The ability to predict PTB in healthy nulliparous women using clinical characteristics is modest. The dissimilarity of risk factors for SPTB-IM compared with SPTB-PPROM indicates different pathophysiological pathways underlie these distinct phenotypes.

Trial Registration

ACTR.org.au ACTRN12607000551493     

Characterization of a large group of individuals with huntington disease and their relatives enrolled in the COHORT study

Background

Careful characterization of the phenotype and genotype of Huntington disease (HD) can foster better understanding of the condition.

Methods

We conducted a cohort study in the United States, Canada, and Australia of members of families affected by HD. We collected demographic and clinical data, conducted the Unified Huntington''s Disease Rating Scale and Mini-Mental State Examination, and determined Huntingtin trinucleotide CAG repeat length. We report primarily on cross-sectional baseline data from this recently completed prospective, longitudinal, observational study.

Results

As of December 31, 2009, 2,318 individuals enrolled; of these, 1,985 (85.6%) were classified into six analysis groups. Three groups had expanded CAG alleles (36 repeats or more): individuals with clinically diagnosed HD [n = 930], and clinically unaffected first-degree relatives who had previously pursued [n = 248] or not pursued [n = 112] predictive DNA testing. Three groups lacked expanded alleles: first-degree relatives who had previously pursued [n = 41] or not pursued [n = 224] genetic testing, and spouses and caregivers [n = 430]. Baseline mean performance differed across groups in all motor, behavioral, cognitive, and functional measures (p<0.001). Clinically unaffected individuals with expanded alleles weighed less (76.0 vs. 79.6 kg; p = 0.01) and had lower cognitive scores (28.5 vs. 29.1 on the Mini Mental State Examination; p = 0.008) than individuals without expanded alleles. The frequency of “high normal” repeat lengths (27 to 35) was 2.5% and repeat lengths associated with reduced penetrance (36 to 39) was 2.7%.

Conclusion

Baseline analysis of COHORT study participants revealed differences that emerge prior to clinical diagnosis. Longitudinal investigation of this cohort will further characterize the natural history of HD and genetic and biological modifiers.

Trial Registration

Clinicaltrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00313495","term_id":"NCT00313495"}}NCT00313495     

Clinical Significance of Soluble Hemoglobin Scavenger Receptor CD163 (sCD163) in Sepsis, a Prospective Study

Objective

We investigated serum soluble CD163 (sCD163) levels for use in the diagnosis, severity assessment, and prognosis of sepsis in the critical ill patients and compared sCD163 with other infection-related variables.

Methods

During july 2010 and April 2011, serum was obtained from 102 sepsis patients (days 1, 3, 5, 7, and 10 after admission to an ICU) and 30 systemic inflammatory response syndrome (SIRS) patients with no sepsis diagnosed. Serum levels of sCD163, procalcitonon (PCT), and C reactive protein (CRP) were determined respectively. Sequential organ failure assessment (SOFA) scores for sepsis patients were also recorded. Then evaluated their roles in sepsis.

Results

The sCD163 levels were 0.88(0.78–1.00)ug/mL for SIRS patients, 1.50(0.92–2.00)ug/mL for moderate sepsis patients, and 2.95(2.18–5.57)ug/mL for severe sepsis patients on day1. The areas under the ROC curves for sCD163, CRP, and PCT for the diagnosis of sepsis were, respectively, 0.856(95%CI: 0.791–0.921), 0.696(95%CI: 0.595–0.797), and 0.629(95%CI: 0.495–0.763), At the recommended cut-off 1.49 ug/mL for sCD163, the sensitivity is 74.0% with 93.3% specificity. Based on 28-day survivals, sCD163 levels in the surviving group stay constant, while they tended to gradually increase in the non-surviving group.The area under the ROC curve for sCD163 for sepsis prognosis was 0.706(95%CI 0.558–0.804). Levels of sCD163 with cut-off point >2.84 ug/mL have sensitivity of 55.8.0%, specificity 80.4%.Common risk factors for death and sCD163 were included in multivariate logistic regression analysis; the odds ratios (OR) for sCD163 and SOFA scores for sepsis prognosis were 1.173 and 1.396, respectively (P<0.05). Spearman rank correlation analysis showed that sCD163 was weakly, but positively correlated with CRP, PCT, and SOFA scores (0.2< r <0.4, P<0.0001), but not with leukocyte counts (r <0.2, P = 0.450).

Conclusion

Serum sCD163 is superior to PCT and CRP for the diagnosis of sepsis and differentiate the severity of sepsis. sCD163 levels were more sensitive for dynamic evaluations of sepsis prognosis. Serum sCD163 and SOFA scores are prognostic factors for sepsis.

Trial Registration

www.chictr.org ChiCTR-ONC-10000812      

Surgery versus epilation for the treatment of minor trichiasis in Ethiopia: a randomised controlled noninferiority trial

Background

Trachomatous trichiasis can cause corneal damage and visual impairment. WHO recommends surgery for all cases. However, in many regions surgical provision is inadequate and patients frequently decline. Self-epilation is common and was associated with comparable outcomes to surgery in nonrandomised studies for minor trichiasis (Methods and Findings1,300 individuals with minor trichiasis from Amhara Regional State, Ethiopia were recruited and randomly assigned (1∶1) to receive trichiasis surgery or epilation. The epilation group were given new forceps and epilation training. The surgical group received trichiasis surgery. Participants were examined every 6 months for 2 years by clinicians masked to allocation, with 93.5% follow-up at 24 months. The primary outcome measure (“failure”) was ≥five lashes touching the eye or receiving trichiasis surgery during 24 months of follow-up, and was assessed for noninferiority with a 10% prespecified noninferiority margin. Secondary outcomes included number of lashes touching, time to failure, and changes in visual acuity and corneal opacity.Cumulative risk of failure over 24 months was 13.2% in the epilation group and 2.2% in the surgical group (risk difference = 11%). The 95% confidence interval (8.1%–13.9%) includes the 10% noninferiority margin. Mean number of lashes touching the eye was greater in the epilation group than the surgery group (at 24 months 0.95 versus 0.09, respectively; p<0.001); there was no difference in change in visual acuity or corneal opacity between the two groups.

Conclusions

This trial was inconclusive regarding inferiority of epilation to surgery for the treatment of minor trichiasis, relative to the prespecified margin. Epilation had a comparable effect to surgery on visual acuity and corneal outcomes. We suggest that surgery be performed whenever possible but epilation be used for treatment of minor trichiasis patients without access to or declining surgery.

Trial registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00522912","term_id":"NCT00522912"}}NCT00522912 Please see later in the article for the Editors'' Summary     

FastBLAST: homology relationships for millions of proteins

Background

All-versus-all BLAST, which searches for homologous pairs of sequences in a database of proteins, is used to identify potential orthologs, to find new protein families, and to provide rapid access to these homology relationships. As DNA sequencing accelerates and data sets grow, all-versus-all BLAST has become computationally demanding.

Methodology/Principal Findings

We present FastBLAST, a heuristic replacement for all-versus-all BLAST that relies on alignments of proteins to known families, obtained from tools such as PSI-BLAST and HMMer. FastBLAST avoids most of the work of all-versus-all BLAST by taking advantage of these alignments and by clustering similar sequences. FastBLAST runs in two stages: the first stage identifies additional families and aligns them, and the second stage quickly identifies the homologs of a query sequence, based on the alignments of the families, before generating pairwise alignments. On 6.53 million proteins from the non-redundant Genbank database (“NR”), FastBLAST identifies new families 25 times faster than all-versus-all BLAST. Once the first stage is completed, FastBLAST identifies homologs for the average query in less than 5 seconds (8.6 times faster than BLAST) and gives nearly identical results. For hits above 70 bits, FastBLAST identifies 98% of the top 3,250 hits per query.

Conclusions/Significance

FastBLAST enables research groups that do not have supercomputers to analyze large protein sequence data sets. FastBLAST is open source software and is available at http://microbesonline.org/fastblast.     

Returning to Paid Employment after Stroke: The Psychosocial Outcomes In StrokE (POISE) Cohort Study

Objectives

To determine which early modifiable factors are associated with younger stroke survivors'' ability to return to paid work in a cohort study with 12-months of follow-up conducted in 20 stroke units in the Stroke Services NSW clinical network.

Participants

Were aged >17 and <65 years, recent (within 28 days) stroke, able to speak English sufficiently to respond to study questions, and able to provide written informed consent. Participants with language or cognitive impairment were eligible to participate if their proxy provided consent and completed assessments on the participants'' behalf. The main outcome measure was return to paid work during the 12 months following stroke.

Results

Of 441 consented participants (average age 52 years, 68% male, 83% with ischemic stroke), 218 were in paid full-time and 53 in paid part-time work immediately before their stroke, of whom 202 (75%) returned to paid part- or full-time work within 12 months. Being male, female without a prior activity restricting illness, younger, independent in activities of daily living (ADL) at 28 days after stroke, and having private health insurance was associated with return to paid work, following adjustment for other illnesses and a history of depression before stroke (C statistic 0·81). Work stress and post stroke depression showed no such independent association.

Conclusions

Given that independence in ADL is the strongest predictor of return to paid work within 12 months of stroke, these data reinforce the importance of reducing stroke-related disability and increasing independence for younger stroke survivors.

Trial Registration

Australian New Zealand Clinical Trials Registry ANZCTRN 12608000459325     

A randomized controlled phase IIb trial of antigen-antibody immunogenic complex therapeutic vaccine in chronic hepatitis B patients

Background

The safety of the immune complexes composed of yeast-derived hepatitis B surface antigen (HBsAg) and antibodies (abbreviated as YIC) among healthy adults and chronic hepatitis B patients has been proved in phase I and phase IIa trial. A larger number of patients for study of dosage and efficacy are therefore needed.

Methods and Principal Findings

Two hundred forty two HBeAg-positive chronic hepatitis B patients were immunized with six injections of either 30 µg YIC, 60 µg of YIC or alum adjuvant as placebo at four-week intervals under code. HBV markers and HBV DNA were monitored during immunization and 24 weeks after the completion of immunization. The primary endpoint was defined as loss of HBeAg, or presence of anti-HBe antibody or suppression of HBV DNA, while the secondary endpoint was both HBeAg seroconversion and suppression of HBV DNA. Statistical significance was not reached in primary endpoints four weeks after the end of treatment among three groups, however, at the end of follow-up, HBeAg sero-conversion rate was 21.8%(17/78) and 9% (7/78) in the 60 µg YIC and placebo groups respectively (p = 0.03), with 95% confidence intervals at 1.5% to 24.1%. Using generalized estimating equations (GEEs) model, a significant difference of group effects was found between 60 µg YIC and the placebo groups in terms of the primary endpoint. Eleven serious adverse events occurred, which were 5.1%, 3.6%, and 5.0% in the placebo, 30 µg YIC and 60 µg YIC groups respectively (p>0.05).

Conclusions

Though statistical differences in the preset primary and secondary endpoints among the three groups were not reached, a late and promising HBeAg seroconversion effect was shown in the 60 µg YIC immunized regimen. By increasing the number of patients and injections, the therapeutic efficacy of YIC in chronic hepatitis B patients will be further evaluated.

Trial Registration

ChiCTR.org ChiCTR-TRC-00000022     

Lack of adherence to isoniazid chemoprophylaxis in children in contact with adults with tuberculosis in Southern Ethiopia

Setting

Hawassa, Southern Region of Ethiopia.

Objectives

To determine compliance to isoniazid (INH) preventive therapy (IPT) and its effectiveness in preventing (TB) disease in children in contact with adults with pulmonary TB (PTB).

Design

This was a prospective cohort study of children <15 years old in contact with adults with smear-positive PTB. Asymptomatic children ≤5 years were provided IPT independently of their Tuberculin Skin Test (TST) status and children >5 years old were given advice but did not receive IPT, as recommended by the National TB control programme. Compliance to IPT and incidence of clinical TB were determined monthly for six months and then quarterly for up to 30 months.

Results

One hundred and eighty four children in contact with 83 smear-positive PTB cases were identified. Eighty two were ≤5 and 102>5 years old. Only 27 (33%) of 82 children given IPT took it for >4 months and 10 (12%) completed the 6-month course. The main reason for non-compliance was the perception that drugs were not necessary when the child was healthy. Eleven children (all except one >5 years old) developed symptoms of TB disease and initiated treatment, resulting in an incidence of 28.6 cases for all and 53.5 for children >5 years old per 1000 children-year.

Conclusion

Compliance to IPT in children is poor in Southern Region of Ethiopia and this was associated with the parents'' perception of the low importance of chemoprophylaxis in asymptomatic children. Poor compliance might be an important barrier for the wider implementation of IPT.

Trial Registration

Clinicaltrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00456469","term_id":"NCT00456469"}}NCT00456469     

Feasibility of bispectral index-guided propofol infusion for flexible bronchoscopy sedation: a randomized controlled trial

Objectives

There are safety issues associated with propofol use for flexible bronchoscopy (FB). The bispectral index (BIS) correlates well with the level of consciousness. The aim of this study was to show that BIS-guided propofol infusion is safe and may provide better sedation, benefiting the patients and bronchoscopists.

Methods

After administering alfentanil bolus, 500 patients were randomized to either propofol infusion titrated to a BIS level of 65-75 (study group) or incremental midazolam bolus based on clinical judgment to achieve moderate sedation. The primary endpoint was safety, while the secondary endpoints were recovery time, patient tolerance, and cooperation.

Results

The proportion of patients with hypoxemia or hypotensive events were not different in the 2 groups (study vs. control groups: 39.9% vs. 35.7%, p = 0.340; 7.4% vs. 4.4%, p = 0.159, respectively). The mean lowest blood pressure was lower in the study group. Logistic regression revealed male gender, higher American Society of Anesthesiologists physical status, and electrocautery were associated with hypoxemia, whereas lower propofol dose for induction was associated with hypotension in the study group. The study group had better global tolerance (p<0.001), less procedural interference by movement or cough (13.6% vs. 36.1%, p<0.001; 30.0% vs. 44.2%, p = 0.001, respectively), and shorter time to orientation and ambulation (11.7±10.2 min vs. 29.7±26.8 min, p<0.001; 30.0±18.2 min vs. 55.7±40.6 min, p<0.001, respectively) compared to the control group.

Conclusions

BIS-guided propofol infusion combined with alfentanil for FB sedation provides excellent patient tolerance, with fast recovery and less procedure interference.

Trial Registration

ClinicalTrials. gov {"type":"clinical-trial","attrs":{"text":"NCT00789815","term_id":"NCT00789815"}}NCT00789815     

Psyllium supplementation in adolescents improves fat distribution & lipid profile: a randomized, participant-blinded, placebo-controlled, crossover trial

Aims

We aimed to assess the effects of psyllium supplementation on insulin sensitivity and other parameters of the metabolic syndrome in an at risk adolescent population.

Methods

This study encompassed a participant-blinded, randomized, placebo-controlled, crossover trial. Subjects were 47 healthy adolescent males aged 15–16 years, recruited from secondary schools in lower socio-economic areas with high rates of obesity. Participants received 6 g/day of psyllium or placebo for 6 weeks, with a two-week washout before crossing over. Fasting lipid profiles, ambulatory blood pressure, auxological data, body composition, activity levels, and three-day food records were collected at baseline and after each 6-week intervention. Insulin sensitivity was measured by the Matsuda method using glucose and insulin values from an oral glucose tolerance test.

Results

45 subjects completed the study, and compliance was very high: 87% of participants took >80% of prescribed capsules. At baseline, 44% of subjects were overweight or obese. 28% had decreased insulin sensitivity, but none had impaired glucose tolerance. Fibre supplementation led to a 4% reduction in android fat to gynoid fat ratio (p = 0.019), as well as a 0.12 mmol/l (6%) reduction in LDL cholesterol (p = 0.042). No associated adverse events were recorded.

Conclusions

Dietary supplementation with 6 g/day of psyllium over 6 weeks improves fat distribution and lipid profile (parameters of the metabolic syndrome) in an at risk population of adolescent males.

Trial Registration

Australian New Zealand Clinical Trials Registry ACTRN12609000888268     

Activity of the neuroendocrine axes in patients with polymyalgia rheumatica before and after TNF-α blocking etanercept treatment

Introduction

In this study, we evaluated the activity of the neuroendocrine axes in patients with polymyalgia rheumatica (PMR) before and after tumor necrosis factor (TNF)-α-blocking etanercept treatment, which previously has been shown to reduce interleukin 6 (IL-6) and C-reactive protein (CRP) markedly in PMR.

Methods

Plasma samples were collected from 10 glucocorticoid-naïve patients with PMR and 10 matched controls before and after etanercept treatment (25 mg biweekly for 2 weeks). The primary end points were pre- and posttreatment levels of adrenocorticotropic hormone (ACTH), cortisol, adrenaline, thyroid-stimulating hormone (TSH), follicle-stimulating hormone (FSH), prolactin, and insulin-like growth factor 1 (IGF-1).

Results

Before TNF-α-blocking treatment, plasma TNF-α, ACTH, and cortisol levels were higher in patients versus controls (P < 0.05 and P < 0.001, respectively); during TNF-α blockade in patients, levels of both hormones decreased (P < 0.05 and P < 0.01, respectively), whereas levels in controls increased (P < 0.05), abolishing the pretreatment differences. Pretreatment adrenaline levels were more than twice as high in patients than in controls (P < 0.01); after treatment in patients, levels had decreased (P < 0.05) but remained higher versus controls (P < 0.05). Levels of the other hormones never differed significantly between groups (P > 0.05).

Conclusions

In PMR, TNF-α may increase the activities of the hypothalamic-pituitary-adrenal and the hypothalamic-sympthoadrenomedullary axes. Secretion of TSH, FSH, prolactin, and IGF-1 is not clearly changed in PMR.

Trial registration

ClinicalTrials.gov ({"type":"clinical-trial","attrs":{"text":"NCT00524381","term_id":"NCT00524381"}}NCT00524381).     

Randomized trial of time-limited interruptions of protease inhibitor-based antiretroviral therapy (ART) vs. continuous therapy for HIV-1 infection

Background

The clinical outcomes of short interruptions of PI-based ART regimens remains undefined.

Methods

A 2-arm non-inferiority trial was conducted on 53 HIV-1 infected South African participants with viral load <50 copies/ml and CD4 T cell count >450 cells/µl on stavudine (or zidovudine), lamivudine and lopinavir/ritonavir. Subjects were randomized to a) sequential 2, 4 and 8-week ART interruptions or b) continuous ART (cART). Primary analysis was based on the proportion of CD4 count >350 cells(c)/ml over 72 weeks. Adherence, HIV-1 drug resistance, and CD4 count rise over time were analyzed as secondary endpoints.

Results

The proportions of CD4 counts >350 cells/µl were 82.12% for the intermittent arm and 93.73 for the cART arm; the difference of 11.95% was above the defined 10% threshold for non-inferiority (upper limit of 97.5% CI, 24.1%; 2-sided CI: −0.16, 23.1). No clinically significant differences in opportunistic infections, adverse events, adherence or viral resistance were noted; after randomization, long-term CD4 rise was observed only in the cART arm.

Conclusion

We are unable to conclude that short PI-based ART interruptions are non-inferior to cART in retention of immune reconstitution; however, short interruptions did not lead to a greater rate of resistance mutations or adverse events than cART suggesting that this regimen may be more forgiving than NNRTIs if interruptions in therapy occur.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00100646","term_id":"NCT00100646"}}NCT00100646