Citations

SummaryNuclear factor (NF)-κB is a transcription factor implicated in the pathogenesis of autoimmune disorders such as rheumatoid arthritis (RA). Here we have examined the effect of intra-articular administration of the IKK inhibitor, NEMO-binding domain peptide (NBD), on the severity of collagen-induced arthritis (CIA). NBD peptides were injected intra-articularly into the knee joints of DBA/1J mice after the onset of disease. Collagen-injected mice given a scrambled peptide served as controls. Arthritis severity was determined by visual examination of paws. Intra-articular NBD injection reduced the arthritis score and ameliorated morphological signs of bone destruction compared to the controls. Serum levels of type-II collagen-specific immunoglobulin (Ig)G2a antibodies were lower in NBD-treated mice versus the control mice, whereas the levels of type-II collagen-specific IgG1 antibodies were increased by NBD treatment. NBD treatment diminished the proinflammatory cytokines interleukin (IL)-17 and interferon (IFN)-γ in serum, but increased the regulatory cytokine IL-10. NBD-treated CIA mice exhibited significantly higher percentages and numbers of forkhead box protein 3 (FoxP3+)CD4+CD25+ regulatory T cells than controls. Immunofluorescence analysis of NBD-treated mice revealed that FoxP3 and Ym1, a marker of alternatively activated macrophages, were juxtaposed to each other within draining inguinal lymph nodes. Intra-articular administration of NBD peptide is effective as an experimental therapy in a murine model of RA. Nevertheless, the intra-articular treatment modality is still associated with systemic effects on the immune system.

AbstractBackgroundRecent studies have demonstrated that cytomegalovirus (CMV) infection and disease are associated with increased risk of graft loss and death in high‐risk (donor CMV seropositive/recipient CMV seronegative) liver transplant recipients (LTR) despite effective antiviral chemoprophylaxis. Predictors of CMV infection and disease in this important population are incompletely defined.MethodsA retrospective cohort study of 227 high‐risk first LTR who received primary anti‐CMV chemoprophylaxis during the first 100 days after transplant was performed. A large number of patient, donor, operative, and post‐transplant potential risk factors were collected. Associations of potential risk factors for CMV infection or disease that occurred during the first year after transplant were assessed using Cox regression models. After Bonferroni adjustment for multiple testing, P‐values ≤0.00125 (associations with CMV infection) and ≤0.00122 (associations with CMV disease) were considered as statistically significant.ResultsCMV infection and disease occurred in 91 (40%) and 43 (19%) of LTR, respectively. In multivariable analysis, increased risk of CMV infection was observed for patients with lower model for end‐stage liver disease (MELD) score (P = 0.025), lower total bilirubin (P = 0.014), and longer operative time (P = 0.038), whereas increased risk of CMV disease was seen in patients with lower MELD score (P = 0.026), lower total bilirubin (P = 0.044), and lower international normalized ratio (P = 0.043). However, after adjustment for multiple testing, none of these findings approached statistical significance.ConclusionOur results suggest that interventions designed to prevent CMV infection and disease should be applied to all high‐risk LTR until more definitive predictors of these complications are identified.

Neuromotor control of skeletal muscles, including respiratory muscles, is ultimately dependent on the structure and function of the motor units (motoneurons and the muscle fibers they innervate) comprising the muscle. In most muscles, considerable diversity of contractile and fatigue properties exists across motor units, allowing a range of motor behaviors. In diseases such as chronic obstructive pulmonary disease (COPD), there may be disproportional primary (disease related) or secondary effects (related to treatment or other concomitant factors) on the size and contractility of specific muscle fiber types that would influence the relative contribution of different motor units. For example, with COPD there is a disproportionate atrophy of type IIx and/or IIb fibers that comprise more fatigable motor units. Thus fatigue resistance may appear to improve, while overall motor performance (e.g., 6-min walk test) and endurance (e.g., reduced aerobic exercise capacity) are diminished. There are many coexisting factors that might also influence motor performance. For example, in COPD patients, there may be concomitant hypoxia and/or hypercapnia, physical inactivity and unloading of muscles, and corticosteroid treatment, all of which may disproportionately affect specific muscle fiber types, thereby influencing neuromotor control. Future studies should address how plasticity in motor units can be harnessed to mitigate the functional impact of COPD-induced changes.

AbstractThe lack of reliable outcome predictors and the delayed onset of therapeutic response to antidepressants are among the clinical challenges in the treatment of depression. Identifying clinical correlates associated with antidepressant response would reduce symptom severity and morbidity for patients with depression. Twenty‐three subjects with major depression were treated with citalopram 20 mg/day in a 6‐week open trial and were also simultaneously randomized to either adjunctive triiodothyronine (T3) 25 μg BID (n = 7), pindolol 5 mg BID (n = 8), or placebo (n = 8). Baseline thyroid‐stimulating hormone (TSH), FT4, FT3, and TT3 were measured for potential relationships to treatment response across groups. In males only, there was a significant inverse correlation between baseline free T4 and time to response (r = −0.7, P = 0.034). In both males and females across all treatment conditions, as measured by Kaplan–Meier (K–M) maintenance failure time, baseline TSH below the mean (1.5 ng/dL) was associated with a shorter time to response (50% reduction in Montgomery and Asberg Depression Rating Scale [MADRS] score) (χ2 = 4.53, df = 1, P = 0.03). Patients with baseline TSH above the mean were less likely to reach full remission (MADRS ≤ 7) (χ2 = 4.38, df = 1, P = 0.03). No significant differences between groups emerged in the mean response time. Baseline thyroid function, as measured by serum free T4 and TSH, may predict a patient's response time to antidepressant treatment with citalopram.

AbstractPosterior reversible encephalopathy syndrome (PRES) is a disorder characterized by gray and white matter abnormalities in the temporal, parietal, and occipital lobes of the brain. Its etiology has been attributed to renal failure, immunosuppressive drugs such as cyclosporine and tacrolimus, and other potential entities leading to acute hypertension. Clinical findings include headaches, altered mental status, seizures, visual changes, and focal neurologic deficits. We report the case of a child who developed PRES with intracerebral and subarachnoid hemorrhages associated with tacrolimus exposure 10 days after heart transplantation for restrictive cardiomyopathy. The patient initially presented with complex partial seizures, headache, agitation, and hypertension. Head MRI was suggestive of PRES along with intracerebral and subarachnoid hemorrhages. Tacrolimus was discontinued and blood pressure was controlled. The patient's encephalopathy resolved, but he has had ongoing neurologic symptoms secondary to hemorrhage. Generally, PRES is less common in children than in the adult population and is a rare complication of calcineurin inhibitors (CNI). Presentation with secondary hemorrhage also can occur. In children receiving CNIs presenting with new neurologic symptoms, PRES should be considered as prompt discontinuation of the offending agent can induce resolution of symptoms. Children can develop hemorrhage in the context of PRES, leading to increased morbidity.

Abstract In the 45 years since its development, the pyrimidine analog 5-fluorouracil (5-FU) has become an integral component of many cancer treatments, most notably for the management of colorectal cancer. An appreciable fraction of patients who receive 5-FU suffer severe adverse toxicities, which in extreme cases may result in death. Dihydropyrimidine dehydrogenase (DPD, encoded by DPYD) rapidly degrades 85% of administered 5-FU, and as such, limits the amount of drug available for conversion into active metabolites. Clinical studies have suggested that genetic variations in DPYD increase the risk for 5-FU toxicity, however, there is not a clear consensus about which variations are relevant predictors. In the present study, DPYD variants were expressed in mammalian cells, and the enzymatic activity of expressed protein was determined relative to wild-type (WT). Relative sensitivity to 5-FU for cells expressing DPYD variations was also measured. The DPYD*2A variant (exon 14 deletion caused by IVS14+1G>A) was confirmed to be catalytically inactive. Compared with WT, two variants, S534N and C29R, showed significantly higher enzymatic activity. Cells expressing S534N were more resistant to 5-FU–mediated toxicity compared with cells expressing WT DPYD. These findings support the hypothesis that selected DPYD alleles are protective against severe 5-FU toxicity, and, as a consequence, may decrease the effectiveness of 5-FU an antitumor drug in carriers. In addition, this study shows a method that may be useful for phenotyping other genetic variations in pharmacologically relevant pathways. Cancer Res; 73(6); 1958–68. ©2013 AACR.

Health disparities and solutions are heterogeneous within and among racial and ethnic groups, yet existing administrative databases lack the granularity to reflect important sociocultural distinctions. We measured the efficacy of a natural-language–processing algorithm to identify a specific immigrant group. The algorithm demonstrated accuracy and precision in identifying Somali patients from the electronic medical records at a single institution. This technology holds promise to identify and track immigrants and refugees in the United States in local health care settings.

Although comorbidity among complex diseases (e.g., drug dependence syndromes) is well documented, genetic variants contributing to the comorbidity are still largely unknown. The discovery of genetic variants and their interactions contributing to comorbidity will likely shed light on underlying pathophysiological and etiological processes, and promote effective treatments for comorbid conditions. For this reason, studies to discover genetic variants that foster the development of comorbidity represent high‐priority research projects, as manifested in the behavioral genetics studies now underway. The yield from these studies can be enhanced by adopting novel statistical approaches, with the capacity of considering multiple genetic variants and possible interactions. For this purpose, we propose a bivariate Mann‐Whitney (BMW) approach to unravel genetic variants and interactions contributing to comorbidity, as well as those unique to each comorbid condition. Through simulations, we found BMW outperformed two commonly adopted approaches in a variety of underlying disease and comorbidity models. We further applied BMW to datasets from the Study of Addiction: Genetics and Environment, investigating the contribution of 184 known nicotine dependence (ND) and alcohol dependence (AD) single nucleotide polymorphisms (SNPs) to the comorbidity of ND and AD. The analysis revealed a candidate SNP from CHRNA5, rs16969968, associated with both ND and AD, and replicated the findings in an independent dataset with a P‐value of 1.06 × 10–03.