Jacek Dmochowski

Fatigue in multiple sclerosis and its relationship to depression and neurologic disability

We studied multiple sclerosis fatigue (MSF) and its relationship to depression and disability. Seventy-one patients [50 relapsing-remitting, 21 secondary progressive] were grouped by Fatigue Severity Scale (FSS) into MS-fatigue (MSF) (FSS55; n=46) or MS-nonfatigue (MSNF) (FSS44; n=20). Forty-one patients were grouped into MS-depression (MSD) (n=15) or MS-nondepression (MSND) (n=26) by interview. Higher expanded disability status scale (EDSS) scores were noted in MSF than MSNF patients (P=0.0003); EDSS scores correlated with FSS scores (rho=0.43, P=0.003). However, fatigue was present in 58% (n=29) of relapsing-remitting patients and in 52% (n=26) of patients with mild physical disability (EDSS53.5). Hamilton/Beck depression severity scores were higher in MSF than MSNF patients and correlated with FSS scores (P50.05). MSD had higher FSS scores than MSND patients (P=0.008). After controlling for EDSS, depression severity continued to correlate with FSS scores (rho=0.37, P=0.02). After controlling for depression, FSS scores no longer correlated with EDSS scores (rho=0.27, P=0.09). Thus, MSF is independent of physical disability, but is associated with depression, suggesting that common mechanisms play a role in MSF and MSD including psychological factors or brain lesions in specific neuroanatomic pathways. Further study is warranted to determine if antidepressant medications improve fatigue in MS.

Gray matter T2 hypointensity is related to plaques and atrophy in the brains of multiple sclerosis patients

Cortical and subcortical gray matter hypointensities on T2-weighted MR images (T2WI) occur commonly in MS brains and have been related to disease duration, clinical course, and the level of neurologic disability. These hypointensities have been reported to occur in the thalamus, basal ganglia, and rolandic cortex. We assessed whether T2 hypointensity is associated with the severity of white matter plaques and atrophy of MS brains. In 114 MS patients, hypointensity of the thalamus, putamen, caudate, and sensorimotor cortex was ordinally rated against age- and gender-matched normal controls on 1.5-T MRI fast spin-echo axial T2WI. Regional and global T2 hyperintense and T1 hypointense parenchymal lesion loads were ordinally rated. Enlargement of subarachnoid and ventricular spaces (atrophy) was ordinally rated vs. age- and gender-matched normal controls. T2 hypointensity was highly, positively correlated with many other MRI variables. Regression modeling showed that T2 hypointensity was related to total atrophy, total T2 lesion load, third ventricular enlargement, parietal atrophy, and to a lesser extent, frontal T1 lesions and cerebellar T2 lesions, but not related to gadolinium enhancement. Ordinal ratings of T2 lesions and central atrophy showed high correlations with quantitative computerized assessments. We conclude that gray matter hypointensity on T2WI may reflect pathologic iron deposition and brain degeneration in MS. This T2 hypointensity is associated with brain atrophy and other MR markers of tissue damage. Further study is warranted to determine if T2 hypointensity is predictive of disease course in MS and is a useful surrogate outcome measure in therapeutic trials.

Body Fat Distribution, Liver Enzymes, and Risk of Hypertension. Evidence From the Western New York Study

&ggr;-Glutamyltransferase (GGT) has been associated with hypertension (HTN); however, the nature of this association remains unclear. GGT is a marker of alcohol consumption, but it is also related to the infiltration of fat in the liver (fatty liver). The association between GGT and HTN was examined in a 6-year longitudinal investigation among 1455 men and women who returned for the follow-up visit. Baseline variables included serum GGT, blood pressure, and anthropometric measures. Incident HTN was defined as blood pressure ≥140/90 or on antihypertensive medication at the follow-up visit. To eliminate individuals with potential liver pathology, analyses focused only on individuals with GGT within its normal range (n=897). Participants were divided in quintiles (Q) based on their baseline GGT levels. Multiple logistic regression analyses [odds ratio (95% confidence intervals)] revealed a significant association of GGT with incident hypertension [2.1 (1.1 to 4.0) Q5 versus Q1]. In subgroup analyses, GGT and HTN were significantly associated among both noncurrent and current drinkers, but only for participants above the median of anthropometric measures [eg, body mass index >26.4, 2.3 (0.9 to 5.7), waist circumference >86.1 cm, 3.7 (1.4 to 9.9), and abdominal height >19.8 cm, 3.1 (1.2 to 8.5), for Q5 versus Q1, in fully adjusted models]. These findings suggest that the association between GGT and hypertension is not caused solely by alcohol consumption and indicate that serum GGT, within its normal range, may predict hypertension among individuals with increased central fat distribution, suggesting that fatty liver may represent an important underlying mechanism for this association.

Sex Differences in Endothelial Function Markers Before Conversion to Pre-Diabetes: Does the Clock Start Ticking Earlier Among Women?: The Western New York Study

OBJECTIVE—We examined whether biomarkers of endothelial function, fibrinolysis/thrombosis and adiponectin, predict the progression from normal to pre-diabetes more strongly among women than men over 6 years of follow-up from the Western New York Health Study. RESEARCH DESIGN AND METHODS—In 2002–2004, 1,455 participants from the Western New York Health Study, who were free of type 2 diabetes and cardiovascular disease at baseline (1996–2001), were selected for reexamination. An incident case of pre-diabetes was defined as fasting glucose <100 mg/dl at the baseline examination and ≥100 and <126 mg/dl at the follow-up examination. Biomarkers of endothelial function (E-selectin and soluble intracellular adhesion molecule-1 [sICAM-1]), fibrinolysis/thrombosis (plasminogen activator inhibitor-1 [PAI-1]), and fasting insulin, adiponectin, and inflammation (high-sensitivity C-reactive protein) were measured in frozen (−190°C) baseline samples. RESULTS—Multivariate analyses revealed higher adjusted mean values of biomarkers of endothelial dysfunction (E-selectin and sICAM-1) and fibrinolysis (PAI-1) and lower mean values of adiponectin only among women who developed pre-diabetes compared with control subjects. Formal tests for interaction between sex and case/control status were statistically significant for E-selectin (P = 0.042), PAI-1 (P = 0.001), sICAM-1 (P = 0.011), and frequency of hypertension (P < 0.001). CONCLUSIONS—These results support the concept that women who progressed from normoglycemia to pre-diabetes have greater endothelial dysfunction than men as well as more hypertension and a greater degree of fibrinolysis/thrombosis. Whether this relates to the higher risk of heart disease among diabetic women awaits further study.

SHORT SLEEP DURATION IS ASSOCIATED WITH THE DEVELOPMENT OF IMPAIRED FASTING GLUCOSE: THE WESTERN NEW YORK HEALTH STUDY

PURPOSE To examine whether sleep duration was associated with incident-impaired fasting glucose (IFG) over 6 years of follow-up in the Western New York Health Study. METHODS Participants (N = 1,455, 68% response rate) who were free of type 2 diabetes and known cardiovascular disease at baseline (1996-2001) were reexamined in the period 2003-2004. A nested case-control study was conducted. Cases had fasting plasma glucose (FPG) less than 100 mg/dL at baseline and 100 to 125 mg/dL at follow-up: controls (n = 272) had FPG less than 100 mg/dL at both exams. Cases (n = 91) were individually matched to three controls (n = 272) on sex, race, and year of study enrollment. Average sleep duration was categorized as short (<6 hours), mid-range (6 to 8 hours), and long (>8 hours). RESULTS In multivariate conditional logistic regression after adjustment for several diabetes risk factors, the odds ratio (OR) of IFG among short sleepers was 3.0 (95% confidence limit [CL]: 1.05, 8.59) compared to mid-range sleepers. There was no association between long sleep and IFG: OR 1.6 (95% CL: 0.45, 5.42). Adjustment for insulin resistance attenuated the association only among short sleepers: OR 2.5 (95% CL: 0.83, 7.46). CONCLUSIONS Short sleep duration was associated with an elevated risk of IFG. Insulin resistance appears to mediate this association.

Elevated cystatin C concentration and progression to pre-diabetes: the Western New York study.

OBJECTIVE— We conducted a nested case-control investigation to examine whether elevated baseline concentrations of cystatin C predicted progression from normoglycemia to pre-diabetes over 6 years of follow-up from the Western New York Health Study. RESEARCH DESIGN AND METHODS— In 2002–2004, 1,455 participants from the Western New York Health Study, who were free of type 2 diabetes and known cardiovascular disease at baseline (1996–2001), were reexamined. An incident case of pre-diabetes was defined as an individual with fasting glucose <100 mg/dl at the baseline examination and ≥100 and ≤125 mg/dl at the follow-up examination, thereby eliminating individuals with prevalent pre-diabetics. All case patients (n = 91) were matched 1:3 to control participants based on sex, race/ethnicity, and year of study enrollment. All control subjects had fasting glucose levels <100 mg/dl at both baseline and follow-up examinations. Cystatin C concentrations and the urinary albumin-to-creatinine ratio were measured from frozen (−196°C) baseline blood and urine samples. Serum creatinine concentrations were available from the baseline examination only. RESULTS— Multivariate conditional logistic regression analyses adjusted for age, baseline glucose level, homeostasis model assessment of insulin resistance, BMI, hypertension, estimated glomerular filtration rate, cigarette smoking, and alcohol use revealed a significantly increased risk of progression to pre-diabetes among those with elevated baseline concentrations of cystatin C (odds ratio 3.28 [95% CI 1.43–7.54]) (upper quintile versus the remainder). Results of secondary analyses that considered high-sensitivity C-reactive protein, interleukin-6, E-selectin, or soluble intercellular adhesion molecule-1 did not alter these results. CONCLUSIONS— These results suggest that cystatin C was associated with a threefold excess risk of progression to pre-diabetes in this population.

Elevated cystatin-C concentration is associated with progression to prediabetes: the Western New York Study

OBJECTIVE— We conducted a nested case-control investigation to examine whether elevated baseline concentrations of cystatin C predicted progression from normoglycemia to pre-diabetes over 6 years of follow-up from the Western New York Health Study. RESEARCH DESIGN AND METHODS— In 2002–2004, 1,455 participants from the Western New York Health Study, who were free of type 2 diabetes and known cardiovascular disease at baseline (1996–2001), were reexamined. An incident case of pre-diabetes was defined as an individual with fasting glucose <100 mg/dl at the baseline examination and ≥100 and ≤125 mg/dl at the follow-up examination, thereby eliminating individuals with prevalent pre-diabetics. All case patients (n = 91) were matched 1:3 to control participants based on sex, race/ethnicity, and year of study enrollment. All control subjects had fasting glucose levels <100 mg/dl at both baseline and follow-up examinations. Cystatin C concentrations and the urinary albumin-to-creatinine ratio were measured from frozen (−196°C) baseline blood and urine samples. Serum creatinine concentrations were available from the baseline examination only. RESULTS— Multivariate conditional logistic regression analyses adjusted for age, baseline glucose level, homeostasis model assessment of insulin resistance, BMI, hypertension, estimated glomerular filtration rate, cigarette smoking, and alcohol use revealed a significantly increased risk of progression to pre-diabetes among those with elevated baseline concentrations of cystatin C (odds ratio 3.28 [95% CI 1.43–7.54]) (upper quintile versus the remainder). Results of secondary analyses that considered high-sensitivity C-reactive protein, interleukin-6, E-selectin, or soluble intercellular adhesion molecule-1 did not alter these results. CONCLUSIONS— These results suggest that cystatin C was associated with a threefold excess risk of progression to pre-diabetes in this population.

Periodontal disease and risk of myocardial infarction: the role of gender and smoking

Background: Studies examining the association between periodontal disease and coronary heart disease have shown a consistent but weak to moderate relationship. Limited data have been reported in women and the role of smoking has not been fully clarified. Methods/Results: A population-based case–control study examining the association between periodontal disease (PD) and acute non-fatal myocardial infarction (MI) was conducted in Erie and Niagara counties in Western New York State. Cases (574) were discharged alive from local hospitals with MI diagnosis. Controls (887) were county residents randomly selected from the NY State Department of Motor Vehicles rolls and Health Care Financing Administration files. Periodontal disease was assessed using clinical attachment loss (CAL). Among men (415 cases), the odds ratio (OR) of the association between mean CAL (mm) and MI, adjusting for the effects of age, body mass index (BMI), physical activity, hypertension, cholesterol, diabetes, and total pack-years of cigarette smoking was 1.34 (1.15–1.57). In women (120 cases), the corresponding OR was 2.08 (1.47–2.94). The estimate of this association among non-smokers, also adjusting for age, gender, BMI, physical activity, hypertension, cholesterol, diabetes, and total pack-years of cigarette smoking, was 1.40 (1.06–1.86), while it was 1.49 (1.26–1.77) among smokers. Conclusions: This study provides evidence of an association between PD and incident MI in both genders. This association appears to be independent from the possible confounding effect of smoking.

Lymphocyte subpopulations and cytokines in nasal polyps: is there a local immune system in the nasal polyp?

PURPOSE: The pathogenesis of chronic hyperplastic rhinosinusitis with massive nasal polyposis is still not entirely known. The present study evaluates the lymphocyte subpopulations and their production of cytokines using a technique for detection of intracytoplasmic cytokines by flow cytometry. This information may allow us to determine whether the source of these lymphocytes is from peripheral blood, the common mucosal immune system, or both. METHODS: Detection of intracytoplasmic cytokines by flow cytometry was performed using a fluoresceinated monoclonal antibody directed against CD4+ and CD8+ lymphocytes and a rhodaminelabeled intracytoplasmic monoclonal antibody directed against four cytokines. In this way, the percentage of lymphocytes synthesizing TH1 and TH2 cytokines were identified in nasal polyp lymphocytes and the corresponding peripheral blood lymphocytes of 13 patients. RESULTS: Lymphocytes producing interferongamma and IL-2, as well as IL-4 and IL-5, were found in the nasal polyps, suggesting that the nasal polyp possesses both TH1 and TH2 cytokine expression. There are also significant differences between the percentage of lymphocytes producing these cytokines between nasal polyps and peripheral blood, suggesting that nasal polyp lymphocytes derive from at least another source than only peripheral blood lymphocytes. Statistical analysis of four groups of patients demonstrated that no statistically significant difference in the lymphocyte subpopulations in atopic versus non-atopic patients, nor aspirin-intolerant versus aspirin-tolerant patients. In general, CD8 cells always produce more interferon-gamma than IL-2 in both peripheral blood and nasal polyps. In contrast with this data, CD4 cells produce more IL-2 in the peripheral blood than in nasal polyps. CONCLUSIONS: Data support the concept that nasal polyp lymphocyte subpopulations may be derived from both the local mucosal immune system as well as from random migration of peripheral blood lymphocytes secondary to adhesion molecules and chemokines, which are known to be present in nasal polyps.

Early Computed Tomography Hypodensity Predicts Hemorrhage After Intravenous Tissue Plasminogen Activator in Acute Ischemic Stroke

Parenchymal hypodensity is a proposed risk factor for hemorrhage after recombinant tissue plasminogen activator (TPA) thrombolysis for ischemic stroke. In Buffalo, NY, and Houston, TX, the authors reviewed 70 patients who were treated with intravenous TPA for acute middle cerebral artery (MCA) stroke. Two observers blinded to clinical outcome analyzed initial noncontrast head computed tomography (CT) scans. Basal ganglia CT hypodensity was quantitated in Hounsfield units (HUs). Contralateral‐ipsilateral difference in density was calculated using the asymptomatic side as a control. Ictus time to TPA averaged 2.5 hours. Six patients developed symptomatic intraparenchymal hematomas (2 fatal). The hemorrhage group had more severe basal ganglia hypodensity (mean 7.5 ± 1.4, range 6–10 HU) than the nonhemorrhage group (2.2 ± 1.4, range 0–9 HU) (P < .0001). The hemorrhage group had hypodensity of > 5 HU; the nonhemorrhage group had hypodensity of ≤4 HU, except 1 patient with hypodensity of 9 HU. In predicting hemorrhage, the positive predictive value of hypodensity > 5 HU was 86%; the negative predictive value was 100%. Prethrombolysis NIH Stroke Scale (NIHSS) deficit (P= .0007) and blood glucose (P= .005) were also higher in the hemorrhage group. Age, gender, smoking, hypertension, and ictus time to TPA infusion did not differ between the 2 groups. Logistic regression indicated that basal ganglia hypodensity was the best single predictor of hemorrhage. Hypodensity and NIHSS score together predicted all cases of hemorrhage. The authors conclude that basal ganglia hypodensity quantified by CT may be a useful method of risk stratification to select acute MCA stroke patients for thrombolytic therapy.