Increased brain volume among good grade patients with intracerebral hemorrhage. Results from the Antihypertensive Treatment of Acute Cerebral Hemorrhage (ATACH) study.

BACKGROUND: We ascertained the occurrence of global cerebral edema manifesting as increased brain volume in subjects with intracerebral hemorrhage (ICH) and explored the relationship between subject characteristics and three month outcomes. METHODS: A post-hoc analysis of a multicenter prospective study that recruited patients with ICH, elevated SBP ≥170 mm Hg, and Glasgow Coma Scale (GCS) score ≥8, who presented within 6 h of symptom onset was performed. Computed tomographic (CT) scans at baseline and 24 h, submitted to a core image laboratory, were analyzed to measure total brain, hematoma, and perihematoma edema volumes from baseline and 24-h CT scans using image analysis software. The increased brain volume was determined by subtracting the hematoma and perihematomal edema volumes from the total brain volume. RESULTS: A total of 18 (44 %) of 41 subjects had increased brain volume that developed between initial CT scan and 24-h CT scan. The median increase in brain volume among the 18 subjects was 35 cc ranging from 0.12 to 296 cc. The median baseline GCS score was 15 in both groups of subjects who experienced increased brain volume and those who did not, and the median hematoma volume was 10.18 and 6.73, respectively. Three of the 18 subjects with increased brain volume underwent concurrent neurological deterioration and one subject died during hospitalization. CONCLUSIONS: We found preliminary evidence of increased cerebral brain volume in subjects with good grade and small ICHs, which may be suggestive of global cerebral edema.

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 study's 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 trial's ability to demonstrate conclusive outcomes may lead to strategies to make trial enrollments more efficient and cost-effective.

Association of serum glucose concentrations during acute hospitalization with hematoma expansion, perihematomal edema, and three month outcome among patients with intracerebral hemorrhage.

BACKGROUND: There is some evidence that hyperglycemia increases the rate of poor outcomes in patients with intracerebral hemorrhage (ICH). We explored the relationship between various parameters of serum glucose concentrations measured during acute hospitalization and hematoma expansion, perihematomal edema, and three month outcome among subjects with ICH. METHODS: A post-hoc analysis of a multicenter prospective study recruiting subjects with ICH and elevated systolic blood pressure (SBP) ≥170 mmHg who presented within 6 h of symptom onset was performed. The serum glucose concentration was measured repeatedly up to 5 times over 3 days after admission and change over time was characterized using a summary statistic by fitting the linear regression model for each subject. The admission glucose, glucose change between admission and 24 hour glucose concentration, and estimated parameters (slope and intercept) were entered in the logistic regression model separately to predict the functional outcome as measured by modified Rankin scale (mRS) at 90 days (0-3 vs. 4-6); hematoma expansion at 24 h (≤33 vs. >33%); and relative perihematomal edema expansion at 24 h (≤40 vs. >40%). RESULTS: A total of 60 subjects were recruited (aged 62.0 ±15.1 years; 56.7% men). The mean of initial glucose concentration (±standard deviation) was 136.7 mg/dl (±58.1). Thirty-five out of 60 (58%) subjects had a declining glucose over time (negative slope). The risk of poor outcome (mRS 4-6) in those with increasing serum glucose levels was over two-fold relative to those who had declining serum glucose levels (RR = 2.64, 95% confidence interval [CI]: 1.03, 6.75). The RRs were 2.59 (95% CI: 1.27, 5.30) for hematoma expansion >33%; and 1.25 (95% CI: 0.73, 2.13) for relative edema expansion >40%. CONCLUSIONS: Decline in serum glucose concentration correlated with reduction in proportion of subjects with hematoma expansion and poor clinical outcome. These results provide a justification for a randomized controlled clinical trial to evaluate the efficacy of aggressive serum glucose reduction in reducing death and disability among patients with ICH.

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.

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 Sjögren's 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.

The significance of clinical trials.

BACKGROUND: Clinical trials are essential for the development of new treatments. Whether a person should participate depends on their understanding of the risks and benefits for themselves and for society as a whole. DISCUSSION: There are rules in place to protect human research subjects and all studies involving humans are reviewed locally to ensure that subjects are treated safely, fairly, and confidentially. Nevertheless, each subject should consider for themselves whether participation is consistent with their values. CONCLUSION: Clinical trials, when well-designed, can benefit the participants as well as the investigators, the sponsors, and the medical community.

The rising cost of falling: Strategies to combat a common post-stroke foe.

BACKGROUND: As a person ages, falls and strokes each become more likely, and because stroke patients are independently at increased risk for falling, the risk of falls is compounded in this population. DISCUSSION: There are a number of preventive measures that can be easily implemented to decrease the risk of falling. These are well known to physical and occupational therapists, so a consultation is well-advised. Four areas of focus are: (1) Exercise, to increase strength, balance, and coordination. (2) Vision, to assure that the subject sees as well as possible. (3) Medication, to minimize side effects that could influence falling. (4) Environment, to remove obstacles, add assists, and provide optimal lighting. CONCLUSION: Falls among stroke patients are costly in terms of risk to the individual and treatment demands on the healthcare system. However, simple attention to details can reduce the risk of falling.

An interferon signature in the peripheral blood of dermatomyositis patients is associated with disease activity.

Recent studies have shown increased expression of interferon (IFN)-regulated genes in the peripheral blood cells of patients with systemic lupus erythematosus. A similar interferon signature has been observed in affected muscle tissue from patients with dermatomyositis (DM), but it has not yet been determined if this signature extends to the peripheral blood in DM. We performed global gene expression profiling of peripheral blood cells from adult and juvenile DM patients and healthy controls. Several interesting groups of genes were differentially expressed in DM, including genes with immune function, and others that function in muscle or are involved in mitochondrial/oxidative phosphorylation. Investigation of type I IFN-regulated transcripts revealed a striking interferon signature present in most DM patients studied. Levels of type I IFN-regulated proteins were also elevated in DM serum samples. Furthermore, both the transcript and serum protein IFN signatures were associated with disease activity. These data suggest that the IFN signature may be a useful marker for DM disease activity, and that sampling peripheral blood may be a more practical alternative to muscle biopsy for measuring this signature.

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-2(b/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-2(b) 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.

Analysis of families in the multiple autoimmune disease genetics consortium (MADGC) collection: the PTPN22 620W allele associates with multiple autoimmune phenotypes.

Autoimmune disorders constitute a diverse group of phenotypes with overlapping features and a tendency toward familial aggregation. It is likely that common underlying genes are involved in these disorders. Until very recently, no specific alleles--aside from a few common human leukocyte antigen class II genes--had been identified that clearly associate with multiple different autoimmune diseases. In this study, we describe a unique collection of 265 multiplex families assembled by the Multiple Autoimmune Disease Genetics Consortium (MADGC). At least two of nine "core" autoimmune diseases are present in each of these families. These core diseases include rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), type 1 diabetes (T1D), multiple sclerosis (MS), autoimmune thyroid disease (Hashimoto thyroiditis or Graves disease), juvenile RA, inflammatory bowel disease (Crohn disease or ulcerative colitis), psoriasis, and primary Sjogren syndrome. We report that a recently described functional single-nucleotide polymorphism (rs2476601, encoding R620W) in the intracellular tyrosine phosphatase (PTPN22) confers risk of four separate autoimmune phenotypes in these families: T1D, RA, SLE, and Hashimoto thyroiditis. MS did not show association with the PTPN22 risk allele. These findings suggest a common underlying etiologic pathway for some, but not all, autoimmune disorders, and they suggest that MS may have a pathogenesis that is distinct from RA, SLE, and T1D. DNA and clinical data for the MADGC families are available to the scientific community; these data will provide a valuable resource for the dissection of the complex genetic factors that underlie the various autoimmune phenotypes.

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.