Jill Novitzke

Genetic association of the R620W polymorphism of protein tyrosine phosphatase PTPN22 with human SLE

We genotyped 525 independent North American white individuals with systemic lupus erythematosus (SLE) for the PTPN22 R620W polymorphism and compared the results with data generated from 1,961 white control individuals. The R620W SNP was associated with SLE (genotypic P=.00009), with estimated minor (T) allele frequencies of 12.67% in SLE cases and 8.64% in controls. A single copy of the T allele (W620) increases risk of SLE (odds ratio [OR]=1.37; 95% confidence interval [CI] 1.07-1.75), and two copies of the allele more than double this risk (OR=4.37; 95% CI 1.98-9.65). Together with recent evidence showing association of this SNP with type 1 diabetes and rheumatoid arthritis, these data provide compelling evidence that PTPN22 plays a fundamental role in regulating the immune system and the development of autoimmunity.

Effect of Systolic Blood Pressure Reduction on Hematoma Expansion, Perihematomal Edema, and 3-Month Outcome Among Patients With Intracerebral Hemorrhage: Results From the Antihypertensive Treatment of Acute Cerebral Hemorrhage Study

BACKGROUND Evidence indicates that systolic blood pressure (SBP) reduction may reduce hematoma expansion in patients with intracerebral hemorrhage (ICH) who are initially seen with acute hypertensive response. OBJECTIVE To explore the relationship between different variables of SBP reduction and hematoma expansion, perihematomal edema, and 3-month outcome among patients with ICH. DESIGN Post hoc analysis of a traditional phase 1 dose-escalation multicenter prospective study. SETTING Emergency departments and intensive care units. PATIENTS Patients having ICH with an elevated SBP of at least 170 mm Hg who were seen within 6 hours of symptom onset. INTERVENTION Systolic blood pressure reduction using intravenous nicardipine hydrochloride targeting 3 tiers of sequentially escalating SBP reduction goals (170-199, 140-169, or 110-139 mm Hg). MAIN OUTCOME MEASURES We evaluated the effect of SBP reduction (relative to initial SBP) on the following: hematoma expansion (defined as an increased intraparenchymal hemorrhage volume >33% on 24-hour vs baseline computed tomographic [CT] images), higher perihematomal edema ratio (defined as a >40% increased ratio of edema volume to hematoma volume on 24-hour vs baseline CT images), and poor 3-month outcome (defined as a modified Rankin scale score of 4-6). RESULTS Sixty patients (mean [SD] age, 62.0 [15.1] years; 34 men) were recruited (18, 20, and 22 patients in each of the 3 SBP reduction goal tiers). The median area under the curve (AUC) (calculated as the area between the hourly SBP measurements over 24 hours and the baseline SBP) was 1360 (minimum, 3643; maximum, 45) U. Comparing patients having less vs more aggressive SBP reduction based on 24-hour AUC analysis, frequencies were 32% vs 17% for hematoma expansion, 61% vs 40% for higher perihematomal edema ratio, and 46% vs 38% for poor 3-month outcome (P > .05 for all). The median SBP reductions were 54 mm Hg at 6 hours and 62 mm Hg at 6 hours from treatment initiation. Comparing patients having equal to or less vs more than the median SBP reduction at 2 hours, frequencies were 21% vs 31% for hematoma expansion, 42% vs 57% for higher perihematomal edema ratio, and 35% vs 48% for poor 3-month outcome (P > .05 for all). CONCLUSIONS We found no significant relationship between SBP reduction and any of the outcomes measured herein; however, the Antihypertensive Treatment of Acute Cerebral Hemorrhage study was primarily a safety study and was not powered for such end points. The consistent favorable direction of these associations supports further studies with an adequately powered randomized controlled design to evaluate the efficacy of aggressive pharmacologic SBP reduction.

Role for Msh5 in the regulation of Ig class switch recombination

Ig class switch recombination (CSR) and somatic hypermutation serve to diversify antibody responses and are orchestrated by the activity of activation-induced cytidine deaminase and many proteins involved in DNA repair and genome surveillance. Msh5, a gene encoded in the central MHC class III region, and its obligate heterodimerization partner Msh4 have a critical role in regulating meiotic homologous recombination and have not been implicated in CSR. Here, we show that MRL/lpr mice carrying a congenic H-2b/b MHC interval exhibit several abnormalities regarding CSR, including a profound deficiency of IgG3 in most mice and long microhomologies at Ig switch (S) joints. We found that Msh5 is expressed at low levels on the H-2b haplotype and, importantly, a similar long S joint microhomology phenotype was observed in both Msh5 and Msh4-null mice. We also present evidence that genetic variation in MSH5 is associated with IgA deficiency and common variable immune deficiency (CVID) in humans. One of the human MSH5 alleles identified contains two nonsynonymous polymorphisms, and the variant protein encoded by this allele shows impaired binding to MSH4. Similar to the mice, Ig S joints from CVID and IgA deficiency patients carrying disease-associated MSH5 alleles show increased donor/acceptor microhomology, involving pentameric DNA repeat sequences and lower mutation rates than controls. Our findings suggest that Msh4/5 heterodimers contribute to CSR and support a model whereby Msh4/5 promotes the resolution of DNA breaks with low or no terminal microhomology by a classical nonhomologous end-joining mechanism while possibly suppressing an alternative microhomology-mediated pathway.

Prevalence, severity, and predictors of fatigue in subjects with primary Sjögren's syndrome

OBJECTIVE To investigate the relationship of fatigue severity to other clinical features in primary Sjögrens syndrome (SS) and to identify factors contributing to the physical and mental aspects of fatigue. METHODS We identified 94 subjects who met the American-European Consensus Group criteria for the classification of primary SS. Fatigue was assessed with a visual analog scale, the Fatigue Severity Scale (FSS), and the Profile of Fatigue (ProF). Associations with fatigue were compared using multivariate regression. RESULTS Abnormal fatigue, defined as an FSS score >or=4, was present in 67% of the subjects. Pain, helplessness, and depression were the strongest predictors of fatigue according to the FSS and the somatic fatigue domain of the ProF (ProF-S), both with and without adjustment for physiologic and serologic characteristics. Depression was associated with higher levels of fatigue; however, the majority of subjects with abnormal fatigue were not depressed. Anti-Ro/SSA-positive subjects were no more likely to report fatigue than seronegative subjects. The regression models explained 62% of the variance in FSS and 78% of the variance in ProF-S scores. Mental fatigue was correlated with depression and helplessness, but the model predicted only 54% of the variance in mental fatigue scores. CONCLUSION Psychosocial variables are determinants of fatigue, but only partially account for it. Although fatigue is associated with depression, depression is not the primary cause of fatigue in primary SS. Investigation of the pathophysiologic correlates of physical and mental aspects of fatigue is needed to guide the development of more effective interventions.

Systolic Blood Pressure Reduction and Risk of Acute Renal Injury in Patients with Intracerebral Hemorrhage

BACKGROUND Aggressive systolic blood pressure reduction may precipitate acute renal injury because of underlying hypertensive nephropathy in patients with intracerebral hemorrhage. The studys objective was to determine the rate and determinants of acute renal injury during acute hospitalization among subjects with intracerebral hemorrhage using a post hoc analysis of a multicenter prospective study. METHODS Subjects with intracerebral hemorrhage and elevated systolic blood pressure of 170 mm Hg or greater who presented within 6 hours of symptom onset and underwent treatment of acute hypertensive response and fluid management as per study and local protocols, respectively. Acute renal injury was defined post hoc using the criteria used in Acute Kidney Injury Network classifications within 72 hours of admission. Descriptive statistics and standard statistical tests were used to characterize and evaluate the effect of systolic blood pressure reduction parameters (relative to initial systolic blood pressure) and average maximum hourly dose of nicardipine on the occurrence of acute renal injury. RESULTS A total of 60 subjects were recruited (57% were men; mean age of 62.0 ± 15.1 years). Five subjects (9%) had stage I acute renal injury according to the Acute Kidney Injury Network criteria. None of the subjects had stage II or III acute renal injury. The serum creatinine course for the first 3 days suggested that the peak elevation of creatinine was seen at 18, 30, 57, 58, and 71 hours after baseline measurements in these 5 subjects, all of which except for the first one were beyond the protocol-specified treatment period. The incidences of neurologic deterioration and symptomatic hematoma expansion were significantly greater in the subjects with stage I renal impairment. The systolic blood pressure reduction parameters (in particular, the area under the curve depicting the 24-hour systolic blood pressure summary statistic) and the higher average maximum hourly nicardipine dose were strongly associated with stage I renal impairment. CONCLUSIONS Although acute renal injury is infrequent and mild among subjects with intracerebral hemorrhage undergoing systolic blood pressure reduction, a trend in association between systolic blood pressure reduction and renal impairment was observed in this small study. Therefore, it is important to carefully monitor the renal function when administering treatment to reduce systolic blood pressure in patients with intracerebral hemorrhage.

Low Patient Enrollment Sites in Multicenter Randomized Clinical Trials of Cerebrovascular Diseases: Associated Factors and Impact on Trial Outcomes

Wide variability in patient enrollment among participating sites is a common phenomenon in multicenter trials. We examined stroke trial-related factors associated with the proportion of sites with low patient enrollment and the effect of these low-enrollment sites on trial outcome. We identified efficacy clinical trials enrolling patients with cerebrovascular diseases between 1980 and 2008 using an electronic database. The trials included in our analyses were multicenter randomized controlled trials (RCTs) comparing efficacy endpoints between two or more treatment groups and having >5 sites. Sites enrolling <10 patients or <2% of total trial patients were defined as low- enrollment sites. Trials were classified into tertiles based on the proportion of low-enrollment sites. Factors associated with trials that could be ascertained through a systematic review of published data were identified and examined. The association between low enrollment and a conclusive trial designation (defined by the ability to reject the primary null hypothesis either at or before target enrollment or demonstrate equivalence/noninferiority with adequate statistical power, depending on the initial design) was assessed using a multivariate logistic regression model. We identified 51 trials that met the inclusion criteria and provided information regarding patients enrolled per center. A total of 3059 participating centers enrolled a total of 53,742 trial participants; 78% of the participating sites enrolled <2% of trial participants. Trials enrolling acute stroke patients (within 24 hours of symptom onset) or those evaluating endovascular/surgical intervention had a higher proportion of low-enrollment sites (<10 patients per site). Studies with a higher proportion of low-enrollment sites were more likely to target acute stroke patients and less likely to randomize ≥1000 patients, use general efficacy endpoints, and stratify by site. There was no association between the studies with a higher proportion of low-enrollment sites and designation as a conclusive trial. A better understanding of factors associated with low-enrollment sites in clinical trials and the impact on a trials ability to demonstrate conclusive outcomes may lead to strategies to make trial enrollments more efficient and cost-effective.

Clinical site activation times for multicenter clinical trials: Lessons learned from the Antihypertensive Treatment of Acute Cerebral Hemorrhage trial

Site activation activities, including institutional review board and contract approvals, are an integral part of multicenter clinical trials. Our objective was to report the time invested in completing the required site activation activities. Data from our experience are relevant for planning purposes by prospective coordinating centers in optimizing time and financial resources. We analyzed data from the Antihypertensive Treatment of Acute Cerebral Hemorrhage trial, which collected details about the activities and time in hours involved with initiating each site. We determined the amount of time required for each of the following start-up tasks: site assessment and protocol feasibility, contract finalization and approval, institutional review board approvals, regulatory files, and protocol training for site investigators and coordinators. We also calculated the number of months expended to complete all of the required tasks from initial site assessment to readiness for enrolling participants. Data from all 12 clinical sites were analyzed. The average time for a site to complete all activities was 196 hours over the course of 11 months. The completion process ranged from a period of 6-22 months among the sites because of varying site-specific edits, available staff, and other delays. The contracts and budget portion of the site activation process was considerably more time intensive than the other activities. Furthermore, a negative correlation existed between the number of months to initiate a site and the number of participants that site enrolled. Analysis of the data from the Antihypertensive Treatment of Acute Cerebral Hemorrhage trial suggests that the time required to prepare a site for readiness to enroll participants is considerable. Allotting sufficient time for completion of site start-up activities is crucial to positioning clinical coordinating centers to succeed in meeting enrollment goals in harmony with established timetables. Clinical trial registration: ClinicalTrials.gov identifier NCT00415610.