Obstructive sleep apnea (OSA) is characterized by recurrent complete and partial upper airway obstructive events, resulting in intermittent hypoxemia, autonomic fluctuation, and sleep fragmentation. ...Approximately 34% and 17% of middle-aged men and women, respectively, meet the diagnostic criteria for OSA. Sleep disturbances are common and underdiagnosed among middle-aged and older adults, and the prevalence varies by race/ethnicity, sex, and obesity status. OSA prevalence is as high as 40% to 80% in patients with hypertension, heart failure, coronary artery disease, pulmonary hypertension, atrial fibrillation, and stroke. Despite its high prevalence in patients with heart disease and the vulnerability of cardiac patients to OSA-related stressors and adverse cardiovascular outcomes, OSA is often underrecognized and undertreated in cardiovascular practice. We recommend screening for OSA in patients with resistant/poorly controlled hypertension, pulmonary hypertension, and recurrent atrial fibrillation after either cardioversion or ablation. In patients with New York Heart Association class II to IV heart failure and suspicion of sleep-disordered breathing or excessive daytime sleepiness, a formal sleep assessment is reasonable. In patients with tachy-brady syndrome or ventricular tachycardia or survivors of sudden cardiac death in whom sleep apnea is suspected after a comprehensive sleep assessment, evaluation for sleep apnea should be considered. After stroke, clinical equipoise exists with respect to screening and treatment. Patients with nocturnally occurring angina, myocardial infarction, arrhythmias, or appropriate shocks from implanted cardioverter-defibrillators may be especially likely to have comorbid sleep apnea. All patients with OSA should be considered for treatment, including behavioral modifications and weight loss as indicated. Continuous positive airway pressure should be offered to patients with severe OSA, whereas oral appliances can be considered for those with mild to moderate OSA or for continuous positive airway pressure-intolerant patients. Follow-up sleep testing should be performed to assess the effectiveness of treatment.
Objective: This study examines the potential role of candidate genes in moderating treatment effects of methylphenidate (MPH) in attention-deficit/hyperactivity disorder (ADHD). Method: Eighty-two ...subjects with ADHD aged 6 to 17 years participated in a prospective, double-blind, placebo-controlled, multiple-dose, crossover titration trial of immediate release MPH three times daily. The subjects were assessed on a variety of parent and clinician ratings and a laboratory math test. Data reduction based on principal components analysis identified statistically derived efficacy and side effect outcomes. Results: Attention-deficit/hyperactivity disorder symptom response was predicted by polymorphisms at the serotonin transporter ("SLC6A4") intron 2 VNTR (p = 0.01), with a suggested trend for catechol-O-methyltransferase ("COMT") (p = 0.04). Gene x dose interactions were noted on math test outcomes for the dopamine D4 receptor ("DRD4") promoter (p = 0.008), "DRD4" exon 3 "VNTR" (p = 0.006), and "SLC6A4" promoter insertion/deletion polymorphism ("5HTTLPR") (p = 0.02). Irritability was predicted by COMT (p = 0.02). Vegetative symptoms were predicted by "5HTTLPR" (p = 0.003). No significant effects were noted for the dopamine transporter ("SLC6A3") or synaptosomal-associated protein 25 ("SNAP25"). Conclusions: This article confirms and expands previous studies suggesting that genes moderate ADHD treatment response. The ADHD outcomes are not unitary but reflect both behavioral and learning domains that are likely influenced by different genes. Future research should emphasize candidate gene and genome-wide association studies in larger samples, symptom reduction as well as side effects outcomes, and responses over full therapeutic dose ranges to assess differences in both gene and gene x dose interactive effects. (Contains 4 tables and 2 figures.)
It is the prevailing view that adaptive immune responses are initiated in secondary lymphoid organs. Studies using alymphoplastic mice have shown that secondary lymphoid organs are essential to ...initiate allograft rejection of skin, heart, and small bowel. The high immunogenicity of lungs is well recognized and allograft rejection remains a major contributing factor to poor outcomes after lung transplantation. We show in this study that alloreactive T cells are initially primed within lung allografts and not in secondary lymphoid organs following transplantation. In contrast to other organs, lungs are acutely rejected in the absence of secondary lymphoid organs. Two-photon microscopy revealed that recipient T cells cluster predominantly around lung-resident, donor-derived CD11c(+) cells early after engraftment. These findings demonstrate for the first time that alloimmune responses following lung transplantation are initiated in the graft itself and therefore identify a novel, potentially clinically relevant mechanism of lung allograft rejection.
Lung transplantation remains the only therapeutic option for many patients suffering from end-stage pulmonary disease. Long-term success after lung transplantation is severely limited by the ...development of bronchiolitis obliterans. The murine heterotopic tracheal transplantation model has been widely used for studies investigating pathogenesis of obliterative airway disease and immunosuppressive strategies to prevent its development. Despite its utility, this model employs proximal airway that lacks airflow and is not vascularized. We have developed a novel model of orthotopic vascularized lung transplantation in the mouse, which leads to severe vascular rejection in allogeneic strain combinations. Here we characterize differences in the fate of airway epithelial cells in nonimmunosuppressed heterotopic tracheal and vascularized lung allograft models over 28 days. Up-regulation of growth factors that are thought to be critical for the development of airway fibrosis and interstitial collagen deposition were similar in both models. However, while loss of airway epithelial cells occurred in the tracheal model, airway epithelium remained intact and fully differentiated in lung allografts, despite profound vascular rejection. Moreover, we demonstrate expression of the anti-apoptotic protein Bcl-2 in airway epithelial cells of acutely rejected lung allografts. These findings suggest that in addition to alloimmune responses, other stimuli may be required for the destruction of airway epithelial cells. Thus, the model of vascularized mouse lung transplantation may provide a new and more physiologic experimental tool to study the interaction between immune and nonimmune mechanisms affecting airway pathology in lung allografts.
Acute rejection continues to present a major obstacle to successful lung transplantation. Although CD4(+) T lymphocytes are critical for the rejection of some solid organ grafts, the role of CD4(+) T ...cells in the rejection of lung allografts is largely unknown. In this study, we demonstrate in a novel model of orthotopic vascularized mouse lung transplantation that acute rejection of lung allografts is independent of CD4(+) T cell-mediated allorecognition pathways. CD4(+) T cell-independent rejection occurs in the absence of donor-derived graft-resident hematopoietic APCs. Furthermore, blockade of the CD28/B7 costimulatory pathways attenuates acute lung allograft rejection in the absence of CD4(+) T cells, but does not delay acute rejection when CD4(+) T cells are present. Our results provide new mechanistic insight into the acute rejection of lung allografts and highlight the importance of identifying differences in pathways that regulate the rejection of various organs.
Serelaxin and acute heart failure Tietjens, Jeremy; Teerlink, John R
Heart (British Cardiac Society),
01/2016, Letnik:
102, Številka:
2
Journal Article
Recenzirano
Attempts at developing novel therapeutic agents for acute heart failure (AHF) over the past two decades have been marked by disappointment. Relaxin is a human peptide hormone believed to mediate many ...adaptive haemodynamic changes that occur during pregnancy. Because these effects may be useful for treating AHF, a recombinant version of human relaxin-2, serelaxin, has been developed as a novel therapeutic agent. Studies have confirmed serelaxin's haemodynamic effects of decreasing pulmonary and systemic resistance and increasing renal blood flow. A 1161-patient, placebo-controlled Phase III trial, RELAX-AHF, demonstrated significant improvement in symptoms, reduced worsening of heart failure, decreased hospital length of stay and increased 180-day survival after index hospitalisation. Additional Phase III trials (RELAX-AHF-2; RELAX-AHF-ASIA) are underway to further evaluate the efficacy of serelaxin in patients with AHF. This article will review the physiological function, mechanism of action, clinical trial results and future directions of serelaxin in the treatment of AHF.
Background
Appendicitis is the most common reason children undergo acute general surgery but international, population‐level disparities exist. This is hypothesised to be caused by preoperative delay ...and differential access to surgical care. The impact of prehospital factors on paediatric appendicitis severity in New Zealand is unknown.
Methods
A prospective, multicentre cohort study with nested parental questionnaire was conducted by a national trainee‐led collaborative group. Across 14 participating hospitals, 264 patients aged ≤16 years admitted between January and June 2020 with suspected appendicitis were screened. The primary outcome was the effect of prehospital factors on the American Association for the Surgery of Trauma (AAST) anatomical severity grade.
Results
Overall, 182 children had confirmed appendicitis with a median age of 11.6. The rate of complicated appendicitis rate was 38.5% but was significantly higher in rural (44.1%) and Māori children (54.8%). Complicated appendicitis was associated with increased prehospital delay (47.8 h versus 20.1 h; P < 0.001), but not in‐hospital delay (11.3 h versus 13.3 h; P = 0.96). Multivariate analysis revealed increased anatomical severity in rural (OR 4.33, 95% CI 1.78–7.25; P < 0.001), and Māori children (OR 2.39, 95% CI 1.24–5.75; P = 0.019), as well as in families relying on external travel sources or reporting unfamiliarity with appendicitis symptomology.
Conclusion
Prehospital delay and differential access to prehospital determinants of health are associated with increased severity of paediatric appendicitis. This manifested as increased severity of appendicitis in rural and Māori children. Understanding the pre‐hospital factors that influence the timing of presentation can better inform health‐system improvements.
This trainee‐led project prospectively studied 182 children with appendicitis across New Zealand, with data supplemented by a parental survey.
We found that delay in surgical treatment is primarily a result of prehospital delay, rather than differential in‐hospital management.
Rural and Maori children were at higher risk of complicated appendicitis and more severe outcomes.
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