Nanopore sequencing of DNA-barcoded probes for highly multiplexed detection of microRNA, proteins and small biomarkers.

There is an unmet need to develop low-cost, rapid and highly multiplexed diagnostic technology platforms for quantitatively detecting blood biomarkers to advance clinical diagnostics beyond the single biomarker model. Here we perform nanopore sequencing of DNA-barcoded molecular probes engineered to recognize a panel of analytes. This allows for highly multiplexed and simultaneous quantitative detection of at least 40 targets, such as microRNAs, proteins and neurotransmitters, on the basis of the translocation dynamics of each probe as it passes through a nanopore. Our workflow is built around a commercially available MinION sequencing device, offering a one-hour turnaround time from sample preparation to results. We also demonstrate that the strategy can directly detect cardiovascular disease-associated microRNA from human serum without extraction or amplification. Due to the modularity of barcoded probes, the number and type of targets detected can be significantly expanded.

Vegetarian or vegan diets and blood lipids: a meta-analysis of randomized trials.

AIMS: Due to growing environmental focus, plant-based diets are increasing steadily in popularity. Uncovering the effect on well-established risk factors for cardiovascular diseases, the leading cause of death worldwide, is thus highly relevant. Therefore, a systematic review and meta-analysis were conducted to estimate the effect of vegetarian and vegan diets on blood levels of total cholesterol, low-density lipoprotein cholesterol, triglycerides, and apolipoprotein B. METHODS AND RESULTS: Studies published between 1980 and October 2022 were searched for using PubMed, Embase, and references of previous reviews. Included studies were randomized controlled trials that quantified the effect of vegetarian or vegan diets vs. an omnivorous diet on blood lipids and lipoprotein levels in adults over 18 years. Estimates were calculated using a random-effects model. Thirty trials were included in the study. Compared with the omnivorous group, the plant-based diets reduced total cholesterol, low-density lipoprotein cholesterol, and apolipoprotein B levels with mean differences of -0.34 mmol/L (95% confidence interval, -0.44, -0.23; P = 1 × 10-9), -0.30 mmol/L (-0.40, -0.19; P = 4 × 10-8), and -12.92 mg/dL (-22.63, -3.20; P = 0.01), respectively. The effect sizes were similar across age, continent, duration of study, health status, intervention diet, intervention program, and study design. No significant difference was observed for triglyceride levels. CONCLUSION: Vegetarian and vegan diets were associated with reduced concentrations of total cholesterol, low-density lipoprotein cholesterol, and apolipoprotein B-effects that were consistent across various study and participant characteristics. Plant-based diets have the potential to lessen the atherosclerotic burden from atherogenic lipoproteins and thereby reduce the risk of cardiovascular disease.

Microfluidic T Cell Selection by Cellular Avidity.

No T cell receptor (TCR) T cell therapies have obtained clinical approval. The lack of strategies capable of selecting and recovering potent T cell candidates may be a contributor to this. Existing protocols for selecting TCR T cell clones for cell therapies such as peptide multimer methods have provided effective measurements on TCR affinities. However, these methods lack the ability to measure the collective strength of intercellular interactions (i.e., cellular avidity) and markers of T cell activation such as immunological synapse formation. This study describes a novel microfluidic fluid shear stress-based approach to identify and recover highly potent T cell clones based on the cellular avidity between living T cells and tumor cells. This approach is capable of probing approximately up to 10 000 T cell-tumor cell interactions per run and can recover potent T cells with up to 100% purity from mixed populations of T cells within 30 min. Markers of cytotoxicity, activation, and avidity persist when recovered high cellular avidity T cells are subsequently exposed to fresh tumor cells. These results demonstrate how microfluidic probing of cellular avidity may fast track the therapeutic T cell selection process and move the authors closer to precision cancer immunotherapy.

DSP missense variant in a Scottish Highland calf with congenital ichthyosis, alopecia, acantholysis of the tongue and corneal defects.

BACKGROUND: Ichthyosis describes a localized or generalized hereditary cornification disorder caused by an impaired terminal keratinocyte differentiation resulting in excessive stratum corneum with the formation of more or less adherent scales. Ichthyosis affects humans and animals. Two rare bovine forms are reported, the severe harlequin ichthyosis and the less severe congenital ichthyosis, both characterized by a severe orthokeratotic lamellar hyperkeratosis. RESULTS: A 2-weeks-old purebred Scottish Highland calf was referred because of a syndrome resembling congenital ichthyosis. The clinical phenotype included diffuse alopecia and a markedly lichenified skin covered with large and excessive scales. Additionally, conjunctivitis and ulceration of the cornea were noted. Post-mortem examination revealed deep fissures in the diffusely thickened tongue and histopathological findings in the skin confirmed the clinical diagnosis. Whole-genome sequencing of the affected calf and comparison of the data with control genomes was performed. A search for private variants in known candidate genes for skin phenotypes including genes related with erosive and hyperkeratotic lesions revealed a single homozygous protein-changing variant, DSP: c.6893 C>A, or p.Ala2298Asp. The variant is predicted to change a highly conserved residue in the C-terminal plakin domain of the desmoplakin protein, which represents a main intracellular component of desmosomes, important intercellular adhesion molecules in various tissues including epidermis. Sanger sequencing confirmed the variant was homozygous in the affected calf and heterozygous in both parents. Further genotyping of 257 Scottish Highland animals from Switzerland revealed an estimated allele frequency of 1.2%. The mutant allele was absent in more than 4800 controls from various other cattle breeds. CONCLUSIONS: This study represents the first report of combined lesions compatible with congenital ichthyosis, alopecia, acantholysis of the tongue and corneal defects associated with a DSP missense variant as the most likely underlying cause. To the best of our knowledge, this study is also the first report of a DSP-related syndromic form of congenital ichthyosis in domestic animals. The results of our study enable genetic testing to avoid the unintentional occurrence of further affected cattle. The findings were added to the Online Mendelian Inheritance in Animals (OMIA) database (OMIA 002243-9913).

Memory CD8+ T cells mediate early pathogen-specific protection via localized delivery of chemokines and IFNγ to clusters of monocytes.

While cognate antigen drives clonal expansion of memory CD8+ T (CD8+ TM) cells to achieve sterilizing immunity in immunized hosts, not much is known on how cognate antigen contributes to early protection before clonal expansion occurs. Here, using distinct models of immunization, we establish that cognate antigen recognition by CD8+ TM cells on dendritic cells initiates their rapid and coordinated production of a burst of CCL3, CCL4, and XCL1 chemokines under the transcriptional control of interferon (IFN) regulatory factor 4. Using intravital microscopy imaging, we reveal that CD8+ TM cells undergo antigen-dependent arrest in splenic red pulp clusters of CCR2+Ly6C+ monocytes to which they deliver IFNγ and chemokines. IFNγ enables chemokine-induced microbicidal activities in monocytes for protection. Thus, rapid and effective CD8+ TM cell responses require spatially and temporally coordinated events that quickly restrict microbial pathogen growth through the local delivery of activating chemokines to CCR2+Ly6C+ monocytes.

Enlargement rate of geographic atrophy before and after secondary CNV conversion with associated anti-VEGF treatment.

BACKGROUND: To study the enlargement rate of primary geographic atrophy (GA) before and after diagnosis of a secondary choroidal neovascularization (CNV) treated with anti-vascular endothelial growth factor (VEGF) therapy. METHODS: Five hundred twenty-two consecutive eyes with primary GA were screened for the development of a complicating secondary CNV. Geographic atrophy was measured on blue autofluorescence (BAF) by two readers and calculated into mean growth rate before and after CNV diagnosis. RESULTS: Ten eyes of six patients were included in the study (six study eyes with GA complicated by CNV, four GA only partner eyes). Follow-up was 1.42 ± 0.48 years before and 3.64 ± 2.73 years after CNV. There was no significant difference between mean growth rate before and after CNV (1.58 ± 0.99 vs. 1.39 ± 0.65 mm2/year; p = 0.44) or between study and partner eyes (p = 0.86). Over a mean time of 3.64 ± 2.73 years, a mean of 8.3 ± 2.8 anti-VEGF injections were given. No correlation between the amount of anti-VEGF injections and change in growth rate could be observed (r = 0.58; p = 0.23). CONCLUSION: In this pilot study, primary GA enlargement did not seem to be influenced by a secondary CNV. No association between the intensity of anti-VEGF treatment and changes in atrophy enlargement rates were found. Further studies with larger sample sizes are warranted.

Effects of Remote Ischemic Pre-Conditioning to Prevent Contrast-Induced Nephropathy after Intravenous Contrast Medium Injection: A Randomized Controlled Trial.

OBJECTIVE: We aimed to assess the effects of remote ischemic pre-conditioning (RIPC) on the incidence of contrast-induced nephropathy (CIN) after an intravenous (IV) or intra-arterial injection of contrast medium (CM) in patient and control groups. MATERIALS AND METHODS: This prospective, randomized, single-blinded, controlled trial included 26 patients who were hospitalized for the evaluation of the feasibility of transcatheter aortic valve implantation and underwent investigations including contrast-enhanced computed tomography (CT), with Mehran risk scores greater than or equal to six. All the patients underwent four cycles of five minute-blood pressure cuff inflation followed by five minutes of total deflation. In the RIPC group (n = 13), the cuff was inflated to 50 mm Hg above the patient's systolic blood pressure (SBP); in the control group (n = 13), it was inflated to 10 mm Hg below the patient's SBP. The primary endpoint was the occurrence of CIN. Additionally, variation in the serum levels of cystatin C was assessed. RESULTS: One case of CIN was observed in the control group, whereas no cases were detected in the RIPC group (p = 0.48, analysis of 25 patients). Mean creatinine values at the baseline, 24 hours after injection of CM, and 48 hours after injection of CM were 88 ± 32 µmol/L, 91 ± 28 µmol/L and 82 ± 29 µmol/L, respectively (p = 0.73) in the RIPC group, whereas in the control group, they were 100 ± 36 µmol/L, 110 ± 36 µmol/L, and 105 ± 34 µmol/L, respectively (p = 0.78). Cystatin C values (median [Q1, Q3]) at the baseline, 24 hours after injection of CM, and 48 hours after injection of CM were 1.10 [1.08, 1.18] mg/L, 1.17 [0.97, 1.35] mg/L, and 1.12 [0.99, 1.24] mg/L, respectively (p = 0.88) in the RIPC group, whereas they were 1.11 [0.97, 1.28] mg/L, 1.13 [1.08, 1.25] mg/L, and 1.16 [1.03, 1.31] mg/L, respectively (p = 0.93), in the control group. CONCLUSION: The risk of CIN after an IV injection of CM is very low in patients with Mehran risk score greater than or equal to six and even in the patients who are unable to receive preventive hyperhydration. Hence, the Mehran risk score may not be an appropriate method for the estimation of the risk of CIN after IV CM injection.

Physiological Effects of Wearing Athletic Mouth Pieces While Performing Various Exercises.

The purpose of this study is to evaluate physiological responses associated with exercise using two different mouthpieces compared with not using a mouthpiece. Improved performance while using the PX3 Bite Regulator (PX3) may significantly reduce the risk of concussions by allowing an athlete to better prepare, react, absorb, and/or avoid impact completely compared with the restricted breathing or mandibular instability that occurs when using mouthguards. Twenty-three subjects completed a battery of five physiological tests; the 1.5-mile run, sit and reach, anaerobic endurance, leg press, and bench press. Each test battery was completed under three conditions: wearing a PX3, wearing a mouthguard, or no mouthpiece respectfully. The PX3 resulted in significantly faster 1.5-mile run times (667.4 ± 9.4 vs. 684.9 ± 9.2 vs. 679 ± 7.9 s, p ≤ 0.05) and significantly longer anaerobic endurance runs (311 ± 23 vs. 283 ± 18 vs. 286 ± 18yds, p ≤ 0.05) compared with the mouthguard and no mouthpiece. The leg press lifts (51.8 ± 4.1 vs. 46.0 ± 4.3, p ≤ 0.05) while wearing the PX3 were significantly greater than when wearing a mouthguard. There were improvements, but no significant differences for sit and reach (16.8 ± 0.8 vs. 15.9 ± 0.8 vs. 16.4 ± 0.8 in., p = 0.73) and bench press (17.7 ± 1.8 vs. 17.2 ± 1.6 vs. 17.2 ± 1.7 lifts, p = 0.94). The increased performance with the PX3 could be a result of better jaw alignment and/or decreased resistance to airflow.

Más notícias: significados atribuídos na prática assistencial neonatal/pediátrica / Bad news: meanings attributed in neonatal/pediatric care practices / Malas noticias: significados atribuidos en la práctica asistencial neonatal / pediátrica

Resumo Trata-se de estudo exploratório, descritivo e qualitativo, realizado com nove profissionais da saúde que atuam na área da medicina e enfermagem em unidade de terapia intensiva neonatal e pediátrica de hospital de ensino localizado no interior do estado do Rio Grande do Sul. O objetivo foi reconhecer significados atribuídos à comunicação de más notícias, evidenciados na prática profissional e nos sentimentos e emoções que essa tarefa desperta nos profissionais. Os dados foram levantados por entrevista semiestruturada e trabalhados por análise de conteúdo. A morte foi evidenciada como o principal significado atribuído às más notícias. Não foram observados protocolos ou rotinas padronizados na prática de comunicação de más notícias. Foi notório o significativo grau de sofrimento do profissional da saúde que realiza essa prática ocupacional. Os dados deste estudo enaltecem a importância de problematizar e refletir sobre a temática no ambiente hospitalar.

Abstract An exploratory, descriptive and qualitative study was conducted with nine health professionals working in the areas of medicine and nursing in the neonatal and pediatric intensive care unit of a teaching hospital located in the countryside of the state of Rio Grande do Sul, Brasil. The objective was to identify the meanings attributed to the communication of bad news, articulating them with professional practice and the manifested feelings andemotions that this task awakens in health professionals. The data were collected in a semi structured interview and studied with content analysis. Death was found to be the main meaning attributed to bad news. Standardized protocols or routines in the practice of reporting bad news were not observed. The significant degree of suffering of health professionals performing this occupational practice was evident. The data of the present study emphasize the importance of problematizing and reflecting on this theme in the hospital environment.

Resumen Se trata de un estudio exploratorio, descriptivo y cualitativo, realizado con nueve profesionales de salud que trabajan en el área de medicina y enfermería en una unidad intensiva neonatal y pediátrica, en hospital universitario situado en el interior de Rio Grande do Sul, Brasil. El objetivo fue reconocer significados atribuidos a la comunicación de malas noticias, evidenciados en la práctica profesional y en los sentimientos y emociones que esta tarea despierta en los profesionales. Los datos fueron recolectados en entrevistas semiestructuradas y trabajados por medio de análisis de contenido. La muerte se destacó como el principal significado atribuido a las malas noticias. No se observaron rutinas o protocolos estandarizados en la práctica de la comunicación de malas noticias. Fue notorio el grado significativo de sufrimiento del profesional de la salud que realiza esta práctica en el trabajo. Los datos de este estudio enfatizan la importancia de problematizar y reflexionar sobre este tema en el ambiente hospitalario.

Formas utilizadas para tentativa de suicídio e características sociodemográficas dos pacientes atendidos no serviço de emergência de um hospital de ensino / Methods used in suicide attempts and sociodemographic characteristics of patients treated at the emergency department of a teaching hospital

OBJETIVOS: Caracterizar as formas utilizadas para tentativa de suicídio e características sociodemográficas de pacientes atendidos no serviço de emergência de um hospital de ensino. MÉTODOS: Estudo transversal retrospectivo, com busca ativa em prontuários eletrônicos de pacientes atendidos entre janeiro e dezembro de 2015 no serviço de emergência de um hospital de ensino, que integra a rede pública de saúde do interior do estado do Rio Grande do Sul, Brasil. Foram incluídos todos os casos de tentativa de suicídio, independente de sua forma. Não foram investigados os casos que resultaram em óbito por suicídio. Foi utilizada estatística descritiva e foram avaliadas associações por análise univariada, sendo aplicado o teste do quiquadrado de Pearson. RESULTADOS: No período estudado foram encaminhados 233 pacientes atendidos na emergência para realização de avaliação psiquiátrica, sendo 122 casos caracterizados por tentativa de suicídio. Desses, a média de idade dos pacientes foi de 36,8±14,3 anos, com mínima de 14 e máxima de 88 anos e, 74 (60,6%) eram do sexo feminino. As formas mais utilizadas de tentativa de suicídio foram ingesta de medicamentos (72 casos, 59%) e ingesta de agrotóxicos (14 casos, 11,5%). Do total de pacientes, 119 (97,5%) residiam no município de Santa Cruz do Sul, com predominância nos moradores da zona urbana (103 pacientes, 84,4%). Dos 50 (41,0%) encaminhamentos, 32 (64,0%) foram para o Centro de Atendimento Psicossocial, 7 (14%) para Centro de Atendimento Psicossocial da Infância e Adolescência, 6 (12%) para internação em unidade de saúde mental e 5 (10%) para o Centro de Atendimento Psicossocial Álcool e Drogas. Em 66 (54,1%) pacientes não foi encontrado nenhum registro em prontuário eletrônico sobre o desfecho após a alta e 6 (4,9%) pacientes evadiram. CONCLUSÕES: A maioria dos pacientes atendidos por tentativa de suicídio foram adultos jovens do sexo feminino. Como principal forma utilizada para a tentativa de suicídio identificou-se a ingesta de medicamentos e em seguida a de agrotóxicos.

AIMS: To describe the methods used in suicide attempts and sociodemographic characteristics of suicidal patients treated at the emergency department of a teaching hospital. METHODS: Observational and descriptive study, with active search for electronic medical records of patients treated at the emergency department of a public teaching hospital in the countryside of Rio Grande do Sul, Brazil, from January to December 2015. All cases of suicide attempt were included, regardless of the suicide methods used. Successful suicide cases were not investigated. The statistical analyses included descriptive statistics, univariate analysis, and Pearson's chi-square test. RESULTS: A total of 233 patients treated at the emergency department were referred for psychiatric evaluation, and 122 of them had attempted suicide. The mean age of the suicidal patients was 36.8±14.3 years, (minimum of 14 years and maximum of 88 years) and 74 (60.6%) of them were female. The most common suicide attempt methods were ingestion of medications (72 cases, 59%) and of pesticide (14 cases, 11.5%). Of all patients, 119 (97.5%) lived in Santa Cruz do Sul, predominantly in the urban area (103 patients, 84.4%). Of the 50 (41.0%) referrals, 32 (64.0%) were sent to the Center for Psychosocial Care, 7 (14%) to the Center for Children's and Adolescents' Psychosocial Care, 6 (12%) were admitted to a mental health unit, and 5 (10%) were sent to Psychosocial Care Center for Alcohol and Drug Abuse. Sixty-six (54.1%) patients had no electronic medical records of their outcome after discharge and 6 (4.9%) were lost to follow-up. CONCLUSIONS: Most of the treated suicidal patients were young adult females. The most common method of suicide attempt was the ingestion of medications, followed by the ingestion of pesticides.

Exercise transcutaneous oxygen pressure measurement has good sensitivity and specificity to detect lower extremity arterial stenosis assessed by computed tomography angiography.

Peripheral artery disease (PAD) is a highly prevalent disease diagnosed by the use of ankle-brachial index (ABI) at rest. In some clinical conditions (diabetes, renal insufficiency, advanced age), ABI can be falsely normal and other tests are required for the PAD diagnosis (American Heart Association statement). This study was conducted to determine the accuracy of exercise transcutaneous oxygen pressure measurement (exercise-TcPo2) in detection of arterial stenosis ≥50% using computed tomography angiography (CTA) as the gold standard.We retrospectively analyzed consecutive patients referred to our vascular unit (University Hospital, Rennes, France) for exercise-TcPo2 testing from 2014 to 2015. All included patients had a CTA performed within 3 months of the exercise-TcPo2 test. Exercise-TcPo2 was performed on treadmill (10% slope; 2 mph speed). We calculated the Delta from Resting Oxygen Pressure (DROP) index (expressed in mm Hg) at the proximal and distal levels. Two blinded physicians performed stenosis quantification on CTA. The receiver operating characteristic (ROC) curve was used to define a cutoff point to detect arterial stenosis ≥50%, stenosis ≥60%, and stenosis ≥70%.A total of 34 patients (mean age 64 ±â€Š2 years old; 74% men) were analyzed. The highest areas under the curve (AUC) were found for 60% stenosis at both proximal and distal levels. For stenosis ≥50%, sensitivity and specificity of proximal minimal DROP were 80.9% [67.1-89.7], 81.0% [59.3-92.7] respectively. For stenosis ≥50%, sensitivity and specificity of distal minimal DROP were 73.2% [60.3-83.1], 83.3% [53.8-96.2], respectively. For stenosis ≥60%, sensitivity and specificity of proximal minimal DROP were 82.5% [67.6-91.5] and 85.7% [67.7-94.8] respectively. For stenosis ≥60%, sensitivity and specificity of distal minimal DROP were 80.4% [67.3-89.1] and 88.2% [64.2-97.7], respectively. For stenosis ≥70%, sensitivity and specificity of proximal minimal DROP were 85.7% [67.7-94.8] and 75.0% [59.6-85.9] respectively. For stenosis ≥70%, sensitivity and specificity of distal minimal DROP were 86.0% [72.2-93.7] and 76.0% [56.1-88.7], respectively.Exercise-TcPo2 using a proximal minimal DROP value ≤-15 mm Hg or a distal minimal DROP value ≤-16 mm Hg is accurate to diagnose arterial stenosis especially stenosis ≥60% on the lower limbs. Exercise-TcPo2 is safe and noninvasive test that might be used in second line for PAD diagnosis.

Remote Ischemic Preconditioning and Contrast-Induced Nephropathy: A Systematic Review.

BACKGROUND: The use of imaging is increasing in clinical practice either for diagnosis or intervention. In these aims, contrast medium (CM) is widely used. However, CM administration can induce contrast-induced nephropathy (CIN). The incidence of CIN varies from 2% to 50% depending on patient risk factors, and CIN is the third cause of renal insufficiency. To date, methods such as hyperhydration to prevent CIN have a low level of evidence. Remote ischemic preconditioning (RIPC), which has already proved its efficiency in the cardiology field, seems to be a promising technique for CIN prevention. The aim of this work was to carry out a systematic review of the literature of the randomized clinical studies on RIPC in the prevention of CIN in man. METHODS: We conducted a systematic review of randomized clinical studies on the RIPC in the prevention of CIN in man. Documentary sources were PubMed articles published until June 2015. Randomized clinical trials of RIPC in preventing CIN in human were reviewed. RESULTS: Five articles were selected for the analysis. One article studied the impact of RIPC in a population at high risk of CIN, whereas the other 4 analyzed populations at low, moderate or unknown risk of CIN. In 4 studies, except the later one, the risk of CIN was based on the Mehran score that was previously published. In the high-risk population, a decrease in the incidence of CIN was found in the RIPC group compared with the control group (12% against 40%; P = 0.002). Among the 3 other studies using the Mehran's score, one also demonstrated the interest of such a procedure in a subgroup of high-risk patients. A second one found a low incidence of CIN in the RIPC group ([5 of 47; 10%] as compared with a control group [17 of 47; 36%] P = 0.003) in patients at the low risk of CIN. In another low-risk population, a significant lower level of a biological marker (liver-type fatty acid-binding protein) that assesses a renal impairment was found in the RIPC compared with the control group. CONCLUSIONS: Only 5 studies were found in this search, which may constitute a limitation. However, RIPC appears as a promising method to prevent CIN since it is a noninvasive, low cost, easy, and safe method. More randomized controlled trials are needed to confirm these preliminary results.

A non-coding genomic duplication at the HMX1 locus is associated with crop ears in highland cattle.

Highland cattle with congenital crop ears have notches of variable size on the tips of both ears. In some cases, cartilage deformation can be seen and occasionally the external ears are shortened. We collected 40 cases and 80 controls across Switzerland. Pedigree data analysis confirmed a monogenic autosomal dominant mode of inheritance with variable expressivity. All affected animals could be traced back to a single common ancestor. A genome-wide association study was performed and the causative mutation was mapped to a 4 Mb interval on bovine chromosome 6. The H6 family homeobox 1 (HMX1) gene was selected as a positional and functional candidate gene. By whole genome re-sequencing of an affected Highland cattle, we detected 6 non-synonymous coding sequence variants and two variants in an ultra-conserved element at the HMX1 locus with respect to the reference genome. Of these 8 variants, only a non-coding 76 bp genomic duplication (g.106720058_106720133dup) located in the conserved region was perfectly associated with crop ears. The identified copy number variation probably results in HMX1 misregulation and possible gain-of-function. Our findings confirm the role of HMX1 during the development of the external ear. As it is sometimes difficult to phenotypically diagnose Highland cattle with slight ear notches, genetic testing can now be used to improve selection against this undesired trait.

Montelukast as an alternative to low-dose inhaled corticosteroids in the management of mild asthma (the SIMPLE trial): an open-label effectiveness trial.

OBJECTIVE: To evaluate the effectiveness of montelukast as monotherapy for patients with mild asthma who remain uncontrolled or unsatisfied while on inhaled corticosteroid (ICS) monotherapy. DESIGN: A multicentre, open-label study. Patients (six years of age or older) had ICS therapy discontinued and were treated with orally administered montelukast once daily for six weeks. MAIN OUTCOME MEASURES: The primary outcome measure was the rate at which asthma symptom control was achieved or maintained after six weeks of treatment. The secondary outcome measures were to compare compliance and physician satisfaction, and to further assess the safety and tolerability of montelukast. RESULTS: Of the 534 patients enrolled, 481 (90.1%) completed the study. Mean (+/- SD) age was 27.8+/-19.0 years. The number of patients with uncontrolled symptoms decreased from 455 (85.2%) at baseline to 143 (26.8%) at week 6 (P<0.001), and mean Asthma Control Questionnaire score decreased from 1.4+/-0.8 to 0.6+/-0.6 (P<0.001), representing a clinically significant improvement. Of the 79 patients with controlled asthma symptoms at baseline, 73.4% maintained asthma control at week 6. Compliance to asthma therapy increased from 41% at baseline for ICS to 88% at week 6 for montelukast (P<0.001). Physician satisfaction with treatment increased from 43% to 85% (P<0.001) and patient satisfaction increased from 45% at baseline to 94% at week 6. No serious adverse events were reported over the course of the study. CONCLUSION: Montelukast is an effective and well-tolerated alternative to ICS treatment in patients with mild asthma who are uncontrolled or unsatisfied with low-dose ICS therapy.

Montelukast as add-on therapy with inhaled corticosteroids alone or inhaled corticosteroids and long-acting beta-2-agonists in the management of patients diagnosed with asthma and concurrent allergic rhinitis (the RADAR trial).

OBJECTIVE: To evaluate the effectiveness of montelukast as add-on therapy for patients diagnosed with asthma and concurrent allergic rhinitis who remain uncontrolled while receiving inhaled corticosteroid (ICS) monotherapy or ICS/long-acting beta-2-agonist (LABA) therapy in a community practice setting. DESIGN: An eight-week, multicentre, open-label, observational study. Patients were 15 years of age or older and, while treated with an ICS or ICS/LABA, had allergic rhinitis and uncontrolled asthma symptoms by at least two criteria as per the Canadian Asthma Consensus Guidelines. The primary outcome measure was the percentage of patients with controlled asthma symptoms after eight weeks of treatment with montelukast 10 mg once daily added to ICS or ICS/LABA therapy. RESULTS: In total, 1004 patients participated in the survey phase of the study. Of these patients, 319 continued in the treatment phase and 301 (94.4%) completed the eight-week assessment. At baseline, all patients had uncontrolled asthma symptoms based on the Canadian Asthma Consensus Guidelines; at the eight-week assessment, 229 patients (76.1%) achieved asthma control. According to the Asthma Control Questionnaire (as determined by scores of 0.75 or less), 164 patients (54.7%) achieved well-controlled asthma at week 8. The mean (+/- SD) Asthma Control Questionnaire score decreased from 2.03+/-0.80 to 0.92+/-0.80 (P<0.001) for all patients, representing a clinically significant improvement. A statistically and clinically significant reduction in the overall Mini Rhinitis Quality of Life Questionnaire score was achieved with a decrease from 2.57+/-1.20 to 1.12+/-1.00 (-1.45+/-1.35; P<0.001). Patient and physician satisfaction rates with montelukast add-on therapy were also significantly increased when compared with baseline treatment. CONCLUSION: Montelukast add-on therapy is effective for managing asthma and allergic rhinitis symptoms in patients who were previously uncontrolled with ICS or ICS/LABA treatment.

Finasteride monotherapy maintains stable lower urinary tract symptoms in men with benign prostatic hyperplasia following cessation of alpha blockers.

OBJECTIVE: Our Canadian multicentre open-label study sought to evaluate, in patients with moderate/severe lower urinary symptoms (LUTS) secondary to benign prostatic hyperplasia, the effect on symptoms of 9 months of monotherapy with finasteride 5 mg following 9 months of combination treatment (finasteride with an alpha-blocker) as quantified according to the International Prostate Symptom Score (IPSS). METHODS: The primary outcome measure for efficacy was the maintenance of IPSS response after cessation of the alpha-blocker. Subjects were treated with a combination of finasteride and an alpha-blocker for 9 months and then with finasteride alone for 3 or 9 months. RESULTS: Results showed that the IPSS scores after 3 months of monotherapy were within the criteria for equivalence to those after 9 months of combination therapy. Symptom control equivalence was also found after 9 months of monotherapy. The IPSS response rate was also similar for combination and monotherapy. The safety profile was similar and as expected with these medications. CONCLUSION: Control of LUTS associated with BPH thus appears to be maintained for at least 9 months with finasteride alone, following a 9-month course of combination therapy with finasteride and an alpha-blocker, with similar safety profiles.

Convergent transcriptional profiles induced by endogenous estrogen and distinct xenoestrogens in breast cancer cells.

Estrogen receptors display high levels of promiscuity in accommodating a wide range of ligand structures, but the functional consequence of changing receptor conformations in complex with distinct agonists is highly controversial. To determine variations in the transactivation capacity induced by different estrogenic agonists, we assessed global transcriptional profiles elicited by natural or synthetic xenoestrogens in comparison with the endogenous hormone 17beta-estradiol. Human MCF7 and T47D carcinoma cells, representing the most frequently used model systems for tumorigenic responses in the mammary gland, were synchronized by hormone starvation during 48 h. Subsequently, a 24 h exposure was carried out with equipotent concentrations of the selected xenoestrogens or 17beta-estradiol. Analysis of messenger RNA was performed on high-density oligonucleotide microarrays that display the sequences of 33,000 human transcripts, yielding a total of 181 gene products that are regulated upon estrogenic stimulation. Surprisingly, genistein (a phytoestrogen), bisphenol-A and polychlorinated biphenyl congener 54 (two synthetic xenoestrogens) produced highly congruent genomic fingerprints by regulating the same range of human genes. Also, the monotonous genomic signature observed in response to xenoestrogens is identical to the transcriptional effects induced by physiological concentrations of 17beta-estradiol. This striking functional convergence indicates that the transcription machinery is largely insensitive to the particular structure of estrogen receptor agonists. The occurrence of such converging transcriptional programs reinforces the hypothesis that multiple xenoestrogenic contaminants, of natural or anthropogenic origin, may act in conjunction with the endogenous hormone to induce additive effects in target tissues.