Citations

AbstractIndolent systemic mastocytosis (SM) patients have a varied clinical presentation, ranging from predominantly cutaneous symptoms to recurrent systemic symptoms (eg, flushing, palpitations, dyspepsia, diarrhea, bone pain) that can be severe and potentially life threatening (anaphylaxis). Mastocytosis patients without skin involvement pose a diagnostic challenge; a high index of suspicion is needed in those with mast cell–degranulation symptoms, including anaphylaxis following Hymenoptera stings or other triggers. Modern-era molecular and flow-cytometric diagnostic methods are very sensitive and can detect minimal involvement of bone marrow with atypical/clonal mast cells; in some cases, full diagnostic criteria for SM are not fulfilled. An important aspect of treatment is avoidance of known symptom triggers; other treatment principles include a stepwise escalation of antimediator therapies and consideration of cytoreductive therapies for those with treatment-refractory symptoms. The perioperative management of mastocytosis patients is nontrivial; a multidisciplinary preoperative assessment, adequate premedications, and close intra- and postoperative monitoring are critical. Smoldering mastocytosis is a variant with high systemic mast cell burden. While its clinical course can be variable, there is greater potential need for cytoreductive therapies (eg, interferon-alpha, cladribine) in this setting. A systematic approach to the diagnosis and treatment of indolent SM using a case-based approach of representative clinical scenarios is presented here.

Delta opioid receptors are implicated in a variety of psychiatric and neurological disorders. These receptors play a key role in the reinforcing properties of drugs of abuse, and polymorphisms in OPRD1 (the gene encoding delta opioid receptors) are associated with drug addiction. Delta opioid receptors are also involved in protecting neurons against hypoxic and ischemic stress. Here, we first examined a large sample of 738 elderly participants with neuroimaging and genetic data from the Alzheimer's Disease Neuroimaging Initiative. We hypothesized that common variants in OPRD1 would be associated with differences in brain structure, particularly in regions relevant to addictive and neurodegenerative disorders. One very common variant (rs678849) predicted differences in regional brain volumes. We replicated the association of this single‐nucleotide polymorphism with regional tissue volumes in a large sample of young participants in the Queensland Twin Imaging study. Although the same allele was associated with reduced volumes in both cohorts, the brain regions affected differed between the two samples. In healthy elderly, exploratory analyses suggested that the genotype associated with reduced brain volumes in both cohorts may also predict cerebrospinal fluid levels of neurodegenerative biomarkers, but this requires confirmation. If opiate receptor genetic variants are related to individual differences in brain structure, genotyping of these variants may be helpful when designing clinical trials targeting delta opioid receptors to treat neurological disorders. Hum Brain Mapp 35:1226–1236, 2014 . © 2013 Wiley Periodicals, Inc.

Abstract Aims Exercise intolerance is a hallmark of heart failure with preserved ejection fraction (HFpEF), yet its mechanisms remain unclear. The current study sought to determine whether increases in cardiac output (CO) during exercise are appropriately matched to metabolic demands in HFpEF. Methods and results Patients with HFpEF (n = 109) and controls (n = 73) exercised to volitional fatigue with simultaneous invasive (n = 96) or non-invasive (n = 86) haemodynamic assessment and expired gas analysis to determine oxygen consumption (VO2) during upright or supine exercise. At rest, HFpEF patients had higher LV filling pressures but similar heart rate, stroke volume, EF, and CO. During supine and upright exercise, HFpEF patients displayed lower peak VO2 coupled with blunted increases in heart rate, stroke volume, EF, and CO compared with controls. LV filling pressures increased dramatically in HFpEF patients, with secondary elevation in pulmonary artery pressures. Reduced peak VO2 in HFpEF patients was predominantly attributable to CO limitation, as the slope of the increase in CO relative to VO2 was 20% lower in HFpEF patients (5.9 ± 2.5 vs. 7.4 ± 2.6 L blood/L O2, P = 0.0005). While absolute increases in arterial–venous O2 difference with exercise were similar in HFpEF patients and controls, augmentation in arterial–venous O2 difference relative to VO2 was greater in HFpEF patients (8.9 ± 3.4 vs. 5.5 ± 2.0 min/dL, P < 0.0001). These differences were observed in the total cohort and when upright and supine exercise modalities were examined individually. Conclusion While diastolic dysfunction promotes congestion and pulmonary hypertension with stress in HFpEF, reduction in exercise capacity is predominantly related to inadequate CO relative to metabolic needs.

Background. Sepsis is characterized by dysfunctional activation of platelets, and antiplatelet therapy could improve the outcomes of septic patients.Methods. We performed a retrospective cohort study of severe sepsis or septic shock adult patients. Outcomes of patients on antiplatelet therapy were compared to those that were not taking antiplatelet therapy by univariate analysis followed by a propensity score analysis based on the probability of receiving antiplatelet therapy.Results. Of 651 patients included in the study 272 (42.8%) were on antiplatelet therapy before the development of severe sepsis or septic shock. After adjusting for important confounding variables antiplatelet therapy was not associated with a decreased risk of hospital mortality (odds ratio 0.73, 95% confidence interval 0.46–1.16). Antiplatelet therapy was associated with a decreased incidence of acute respiratory distress syndrome/acute lung injury (odds ratio 0.50, 95% confidence interval 0.35–0.71) and reduced need of mechanical ventilation (odds ratio 0.62, 95% confidence interval 0.45–87). Incidence of acute kidney injury was similar between both groups (odds ratio 1.08, 95% confidence interval 0.73–1.59).Conclusions. The use of antiplatelet therapy before the diagnosis of severe sepsis or septic shock was not associated with decreased hospital mortality. Antiplatelet therapy was associated with a decreased incidence of acute lung injury/acute respiratory distress syndrome.

Purpose To assess the effects of ruxolitinib on symptom burden and quality of life (QoL) and to evaluate the ability of the modified Myelofibrosis Symptom Assessment Form (MFSAF) v2.0 to measure meaningful changes in myelofibrosis-related symptoms in patients with myelofibrosis. Patients and Methods COMFORT-I (Controlled Myelofibrosis Study With Oral JAK Inhibitor Treatment–I) is a double-blind, placebo-controlled phase III study evaluating ruxolitinib in patients with intermediate-2 or high-risk myelofibrosis. Exploratory analyses were conducted on the following patient-reported outcomes (PROs) assessments: modified MFSAF v2.0 (individual symptoms and Total Symptom Score [TSS]), European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30), Patient Reported Outcomes Measurement Information System (PROMIS) Fatigue Scale, and Patient Global Impression of Change (PGIC). Results Patients receiving ruxolitinib experienced improvements in individual myelofibrosis-related symptoms, although patients receiving placebo experienced worsening (P < .001). The majority (91%) of ruxolitinib-treated patients designated as ≥ 50% TSS responders (≥ 50% TSS improvement) self-reported their condition as either “Much improved” or “Very much improved” on the PGIC. These patients achieved significant improvements in the EORTC QLQ-C30 functional domains and Global Health Status/QoL versus patients receiving placebo, who experienced worsening on these measures (P ≤ .0135). Ruxolitinib-treated patients with a lesser degree of symptom improvement (< 50% TSS responders) also achieved improvements over placebo on these measures. The degree of spleen volume reduction with ruxolitinib correlated with improvements in TSS, PGIC, PROMIS Fatigue Scale, and EORTC Global Health Status/QoL. Ruxolitinib-treated patients who achieved a ≥ 35% reduction in spleen volume experienced the greatest improvements in these PROs. Conclusion Ruxolitinib-treated patients achieved clinically meaningful improvements in myelofibrosis-related symptoms and QoL, but patients receiving placebo reported worsening of symptoms and other PROs.

Key PointsIn this study, African American MM patients have a significantly lower frequency of IgH translocations than European American patients.

Objective: Therapeutic goals for chronic mental disorders like major depressive disorder (MDD) and schizophrenia have evolved in parallel with the growing medical knowledge about the course and treatment of these disorders. Although the knowledge base regarding the clinical course of ADHD, a chronic psychiatric disorder, has evolved beyond symptomatic improvement and short-term treatment response, long-term goals, such as functional remission, have not yet been clearly defined. Method: A PubMed literature search was conducted to investigate the therapeutic goals of pharmacologic treatment referenced in the published literature from January 1998 through February 2010 using the following commonly used ADHD treatments as keywords: amphetamine, methylphenidate, atomoxetine, lisdexamfetamine, guanfacine, and clonidine. This search was then combined with an additional search that included the following outcome keywords: remission, relapse, remit, response, normal, normalization, recovery, and effectiveness. Results: Our search identified 102 publications. The majority (88.2% [90/102]) of these contained predefined criteria for treatment response. Predefined criteria for normalization and remission and/or relapse were presented in 4.9% (5/102), 12.7% (13/102), and 3.9% (4/102) of publications, respectively. There was a lack of consistency between the instruments used to measure outcomes as well as the criteria used to define treatment response, normalization, and remission as well as relapse. Conclusion: The therapeutic goals in treating ADHD should address optimal treatment outcomes that go beyond modest reductions of ADHD symptoms to include syndromatic, symptomatic, and functional remission. Future work should focus on reliable and valid tools to measure these outcomes in the clinical trial setting.