Biomedical subjects

C J Earley

Publications and source records attributed to C J Earley.

At least 19 recordsLinked to original sources

PubMed2004

Decreased transferrin receptor expression by neuromelanin cells in restless legs syndrome.

BACKGROUND: Restless legs syndrome (RLS) is a sensory-movement disorder affecting 5 to 10% of the population. Its etiology is unknown, but MRI analyses and immunohistochemical studies on autopsy tissue suggest the substantia nigra (SN) of patients with RLS has subnormal amounts of iron. METHODS: Neuromelanin cells from the SN of four RLS and four control brains were isolated by laser capture microdissection, and a profile of iron-management protein expression was obtained by immunoblot analysis. Binding assays for iron regulatory protein activity were performed on cell homogenates. RESULTS: Ferritin, divalent metal transporter 1, ferroportin, and transferrin receptor (TfR) were decreased in RLS neuromelanin cells compared with control. Transferrin was increased in RLS neuromelanin cells. This protein profile in RLS neuromelanin cells is consistent with iron deficiency with the exception that TfR expression was decreased rather than increased. The concentration and activity of the iron regulatory proteins (IRP1 and IRP2) were analyzed to determine whether there was a functional deficit in the post-transcriptional regulatory mechanism for TfR expression. Total IRP activity, IRP1 activity, and IRP1 protein levels were decreased in RLS, but total IRP2 protein levels were not decreased in RLS. CONCLUSION: Restless legs syndrome may result from a defect in iron regulatory protein 1 in neuromelanin cells that promotes destabilization of the transferrin receptor mRNA, leading to cellular iron deficiency.

Aged↗

PubMed2003

Neuropathological examination suggests impaired brain iron acquisition in restless legs syndrome.

OBJECTIVE: To assess neuropathology in individuals with restless legs syndrome (RLS). METHODS: A standard neuropathologic evaluation was performed on seven brains from individuals who had been diagnosed with RLS. The substantia nigra was examined in greater detail for iron staining and with immunohistochemistry for tyrosine hydroxylase and proteins involved in iron management. Five age-matched individuals with no neurologic history served as controls. RESULTS: There were no histopathologic abnormalities unique to the RLS brains. Tyrosine hydroxylase staining in the major dopaminergic regions appeared normal in the RLS brains. Iron staining and H-ferritin staining was markedly decreased in the RLS substantia nigra. Although H-ferritin was minimally detected in the RLS brain, L-ferritin staining was strong. However, the cells staining for L-ferritin in RLS brains were morphologically distinct from those in the control brains. Transferrin receptor staining on neuromelanin-containing cells was decreased in the RLS brains compared to normal, whereas transferrin staining in these cells was increased. CONCLUSIONS: RLS may not be rooted in pathologies associated with traditional neurodegenerative processes but may be a functional disorder resulting from impaired iron acquisition by the neuromelanin cells in RLS. The underlying mechanism may be a defect in regulation of the transferrin receptors.

Aged↗

PubMed2002

Increased CSF hypocretin-1 (orexin-A) in restless legs syndrome.

Hypocretin-1 levels were increased in evening CSF samples from subjects with restless legs syndrome, indicating altered hypocretin transmission in this sleep disorder. Increases in CSF hypocretin-1 levels were most striking in patients with early-onset restless legs syndrome.

Age of Onset↗

PubMed2002

Family history study of the restless legs syndrome.

BACKGROUND: Although there is a relatively high rate of occurrence of sporadic cases of restless legs syndrome (RLS), the systematic study of family history of RLS in populations of RLS patients has been very limited. The objective of the present study was to determine the risk of RLS for first- and second-degree relatives of a population of primary RLS patients not selected for the number of affected relatives in their families and to obtain an estimate of the degree of genetic involvement in RLS. METHODS: Consecutively consenting patients from two different sites who met the criteria for RLS completed a worksheet that asked them to indicate their current age, the date of their earliest RLS symptoms, and the names and RLS status of all of their first- and second-degree relatives. Controls with no clinical history of RLS also completed the worksheet. RESULTS: First- and second-degree relatives of patients with RLS had a significantly greater risk of RLS than the first- (P<0.001) and second-degree relatives (P<0.003) of controls. The risk of RLS was found to be greater for first-degree relatives of early-onset, rather than late-onset, RLS probands (P<0.001). CONCLUSIONS: This study provides a complete systematic examination of the risk of RLS among relatives of RLS probands and controls using the same assessment methodology. Although the results are consistent with a genetic etiology for RLS, they do not support the presence of one simple, Mendelian-inherited major gene in most RLS families.

Journal Article↗

PubMed2001

MRI measurement of brain iron in patients with restless legs syndrome.

Brain iron insufficiency in the restless legs syndrome (RLS) has been suggested by a prior CSF study. Using a special MRI measurement (R2'), the authors assessed regional brain iron concentrations in 10 subjects (five with RLS, five controls). R2' was significantly decreased in the substantia nigra, and somewhat less significantly in the putamen, both in proportion to RLS severity. The results show the potential utility of this MRI measurement, and also indicate that brain iron insufficiency may occur in patients with RLS in some brain regions.

Aged↗

PubMed2001

CSF dopamine, serotonin, and biopterin metabolites in patients with restless legs syndrome.

PURPOSE: To evaluate the role of CNS dopaminergic systems in Restless Legs Syndrome (RLS), homovanillic acid (HVA), tetrahydrobiopterin (BH4), and neopterin (NEOP), were assayed in CSF from RLS patients. The serotonin metabolite, 5-hydroxyindoleacetic acid (5-HIAA), was also measured. METHODS: CSF was taken from 16 RLS patients after 2 weeks off medication and from 14 control subjects. The CSF metabolites were determined using HPLC techniques. RESULTS: There was no significant difference in HVA or 5-HIAA, but NEOP and BH4 were higher in RLS patients. The RLS group was significantly older than the control group (64.2 +/- 9.2 years vs. 51.4 +/- 6.3 years; P < 0.001). A multiple regression analysis showed a strong correlation between age and 5-HIAA (r = 0.46, P = 0.04) and between age and NEOP (r = 0.61, P < 0.01). To eliminate the potential error created by the age difference between groups, an age-adjusted subgroup of RLS and control subjects were compared. There was still no difference found for HVA; however, 5-HIAA was now significantly lower (P < 0.01) in the RLS subgroup. Age-adjustment eliminated the differences previously found for NEOP, (P = 0.12), but BH4 continued to remain higher in the RLS group (P < 0.01). CONCLUSION: Differences in CSF HVA concentrations were not found. The changes in 5-HIAA and BH4 are of unclear clinical significance and require further assessment with appropriate age-matched controls.

Age Factors↗

PubMed2001

Associations of aortic Windkessel function with age, gender and cardiovascular risk factors.

Aortic Windkessel function is thought to represent a potential cardiovascular risk factor. As an indicator for the function, we have recently introduced the decay index (DI). DI is the coefficient of an exponential function applied to the postpeak portion of internal carotid artery Doppler waveform, and is inversely associated with the function. This study compares DI with age, gender and traditional cardiovascular risk factors in 220 apparently healthy volunteers (59 +/- 16 years). DI increased linearly with age (r = 0.51, p < 0.001), and was higher in women than in men at all ages (p < 0.001). Also, DI was positively associated with systolic blood pressure (beta = 0.17, p < 0.01) and diabetic medication (beta = 0.14, p < 0.05), independent of age (beta = 0.49, p < 0.0001), gender (beta = 0.27, p < 0.0001) and other traditional cardiovascular risk factors (model r(2) = 0.36). Based on the present results, the Windkessel function as assessed by DI declines with age and is lower in women. However, the associations with cardiovascular risk factors need to be established on a larger sample at higher cardiovascular risk.

Adult↗

PubMed2001

Restless legs syndrome: a review of clinical and pathophysiologic features.

Restless legs syndrome (RLS), although long ignored and still much underdiagnosed, disrupts the life and sleep considerably of those who have it. Recent clinical and basic research provides for better definition and pathophysiologic understanding of the disorder. The body of knowledge about this disorder has been expanding rapidly during the past decade and it has altered our concepts of this disorder. This review of RLS covers history, diagnosis, morbidity of sleep disturbance, relation to periodic limb movements in both sleep and waking, secondary causes, severity assessment methods, phenotypes for possible genetic patterns, epidemiology, pathophysiology, and medical treatment considerations. The emphasis on pathophysiology includes consideration of central nervous system localization, neurotransmitter and other systems involved, and the role of iron metabolism. Studies to date support the authors' recently advanced iron-dopamine model of RLS.

Anemia, Iron-Deficiency↗

PubMed2001

Alcohol intake, type of beverage, and the risk of cerebral infarction in young women.

BACKGROUND AND PURPOSE: The relationship between alcohol consumption and cerebral infarction remains uncertain, and few studies have investigated whether the relationship varies by alcohol type or is present in young adults. We examined the relationship between alcohol consumption, beverage type, and ischemic stroke in the Stroke Prevention in Young Women Study. METHODS: All 59 hospitals in the greater Baltimore-Washington area participated in a population-based case-control study of stroke in young women. Case patients (n=224) were aged 15 to 44 years with a first cerebral infarction, and control subjects (n=392), identified by random-digit dialing, were frequency matched by age and region of residence. The interview assessed lifetime alcohol consumption and consumption and beverage type in the previous year, week, and day. ORs were obtained from logistic regression models controlling for age, race, education, and smoking status, with never drinkers as the referent. RESULTS: Alcohol consumption, up to 24 g/d, in the past year was associated with fewer ischemic strokes (<12 g/d: OR 0.57, 95% CI 0. 38 to 0.86; 12 to 24 g/d: OR 0.38, 95% CI 0.17 to 0.86; >24 g/d: OR 0.95, 95% CI 0.43 to 2.10) in comparison to never drinking. Analyses of beverage type (beer, wine, liquor) indicated a protective effect for wine consumption in the previous year (<12 g/wk: OR 0.58, 95% CI 0.35 to 0.97; 12 g/wk to <12 g/d: OR 0.55, 95% CI 0.28 to 1.10; >/=12 g/d: OR 0.92, 95% CI 0.23 to 3.64). CONCLUSIONS: Light to moderate alcohol consumption appears to be associated with a reduced risk of ischemic stroke in young women.

Adolescent↗

PubMed2000

Insight into the pathophysiology of restless legs syndrome.

Restless Legs Syndrome (RLS) is a disorder of sensation with a prevalence of around 2-5% of the population. Relevant to understanding the possible pathophysiological mechanism is the fact that RLS is extremely responsive to dopaminergic agents. A second issue is that iron deficiency states may precipitate RLS in as much as 25-30% of people with iron deficiency. Studies looking at basal ganglia dopaminergic function using PET and SPECT techniques have shown a decrease in binding potential for the dopamine receptor and transporter. Similar phenomena occurs in iron-deficient animals. Using MRI techniques and CSF analysis of iron-related protein, studies have suggested a reduction in brain iron concentration occurs in RLS patients. The relevance of CNS iron metabolism to the pathophysiology of RLS is discussed.

Animals↗

PubMed2000

Subclinical sensory neuropathy in late-onset restless legs syndrome.

OBJECTIVE: To determine the prevalence of different forms of peripheral neuropathy in patients with restless legs syndrome (RLS) and correlate the findings with other clinical characteristics. BACKGROUND: RLS is characterized by a desire to move the extremities, often associated with paresthesias or dysesthesias, motor restlessness, worsening of symptoms with rest with relief by activity, and worsening of symptoms in the evening or night. The association between RLS and peripheral neuropathy remains controversial. The observation that many patients with small-fiber neuropathy also complain of RLS prompted this prospective case series. METHODS: Twenty-two consecutive patients with RLS were evaluated for evidence of large-fiber neuropathy (LFN) and small sensory fiber loss (SSFL). RESULTS: In eight of the 22 (36%) patients, neuropathy was identified. Three patients had pure LFN; two had mixed LFN and SSFL; and three had isolated SSFL. The SSFL group had a later onset of RLS (p < 0.009), reported pain in their feet with RLS more frequently (p < 0.001), and tended to have no family history of RLS (p < 0.078). Patients with LFN did not have similar associations with age at onset, family history status, or presence of pain. CONCLUSION: The results suggest that two forms of RLS exist: one is triggered by painful dysesthesias associated with SSFL, has later onset, and no family history; and one without involvement of SSF, with an earlier onset age, positive family history for RLS, and no pain. The authors hypothesize that patients with the SSFL subtype of RLS will preferentially respond to neuropathic pain medications.

Adult↗

PubMed2000

Abnormalities in CSF concentrations of ferritin and transferrin in restless legs syndrome.

CSF and serum were obtained from 16 patients with idiopathic restless legs syndrome (RLS) and 8 age-matched healthy control subjects. Patients with RLS had lower CSF ferritin levels (1. 11 +/- 0.25 ng/mL versus 3.50 +/- 0.55 ng/mL; p = 0.0002) and higher CSF transferrin levels (26.4 +/- 5.1 mg/L versus 6.71 +/- 1.6 mg/L; p = 0.018) compared with control subjects. There was no difference in serum ferritin and transferrin levels between groups. The presence of reduced ferritin and elevated transferrin levels in CSF is indicative of low brain iron in patients with idiopathic RLS.

Adult↗

PubMed2000

Lipoprotein (a) and the risk of ischemic stroke in young women.

BACKGROUND AND PURPOSE: lipoprotein (a) (lp (a)) is a lipid-containing particle similar to LDL which has been found in atherosclerotic plaque. The role of lp (a) in ischemic stroke remains controversial, but some studies suggest lp (a) is particularly important as a risk factor for stroke in young adults. We investigated the role of lp (a) as a risk factor for stroke in young women enrolled in the Stroke Prevention in Young Women Study. METHODS: subjects were participants in a population-based, case-control study of risk factors for ischemic stroke in young women. Cases were derived from surveillance of 59 regional hospitals in the central Maryland, Washington DC, Pennsylvania and Delaware area. Lp (a) was measured in 110 cases and 216 age-matched controls. Demographics, risk factors, and stroke subtype were determined by interview and review of medical records. RESULTS: lp (a) values were higher in blacks than whites, but within racial groups, the distribution of lp (a) values was similar between cases and controls. After adjustment for age, race, hypertension, diabetes, cigarette smoking, coronary artery disease, total cholesterol and HDL cholesterol, the odds ratio for an association of lp (a) and stroke was 1.36 (95% CI 0.80-2.29). There was no dose-response relationship between lp (a) quintile and stroke risk. Among stroke subtypes, only lacunar stroke patients had significantly elevated lp (a) values compared to controls. CONCLUSIONS: we found no association of lp (a) with stroke in a population of young women with ischemic stroke. Small numbers of patients limit conclusions regarding risk in ischemic stroke subtypes, but we could not confirm previous suggestions of an association of lp (a) with atherosclerotic stroke in young adults.

Adolescent↗

PubMed1999

Influence of age and postmenopausal estrogen replacement therapy on carotid arterial stiffness in women.

OBJECTIVE: This study examines the influence of age and current estrogen replacement therapy (ERT) on common carotid arterial (CCA) stiffness in women. METHODS: The subjects comprised 172 women (age 55.6 +/- 16.4 years) from the Baltimore Longitudinal Study of Aging, including 37 current postmenopausal ERT users. The ERT users included 18 women taking estrogen alone and 19 women taking estrogen and progesterone. Bilateral CCA were examined by B-mode carotid ultrasonography, and the stiffness index was defined as the logarithm of the ratio of systolic to diastolic blood pressure (BP) divided by the fractional diameter increase during the cardiac cycle. RESULTS: The stiffness index increased linearly with age (r = 0.69, p < 0.001), and was lower in ERT users than in postmenopausal nonusers (8.0 +/- 2.0 vs 9.7 +/- 3.1, p < 0.01). Furthermore, the effects of age (beta = 0.67, p < 0.0001) and ERT (beta = -0.23, p < 0.001) on the stiffness index persisted after adjustments for systolic BP (beta = 0.23, p < 0.01), diastolic BP (beta = -0.26, p < 0.001) and other cardiovascular risk factors (model r2 = 0.59, p < 0.0001). The stiffness index was similar in both ERT users with and without progesterone and lower than in postmenopausal nonusers (p < 0.05) after considering the age effects. CONCLUSION: Age-associated increases in CCA stiffness are reduced by postmenopausal ERT.

Aged↗

PubMed1999

Carotid arterial stiffness as a surrogate for aortic stiffness: relationship between carotid artery pressure-strain elastic modulus and aortic pulse wave velocity.

Common carotid arterial (CCA) stiffness can be assessed during carotid ultrasonography, but its association with aortic stiffness, a well-defined cardiovascular risk factor, has not been clarified. This study examines the relationship between CCA and aortic stiffness. CCA pressure-strain elastic modulus (Ep) and aortic pulse wave velocity (APWV) were evaluated in 110 healthy volunteers (age 56.2 +/- 14.6 y) by B-mode and Doppler ultrasonography. CCA Ep increased linearly with age and was higher in men than in women (model r2 = 0.50, p < 0.001). APWV increased quadratically with age (model r2 = 0.54, p < 0.001), similarly for women and men. Both CCA Ep and APWV were linearly associated with systolic blood pressure (BP) (r = 0.53 and 0.46, respectively) but not with diastolic BP. A linear relationship was found between CCA Ep and APWV (APWV = 194.7 + 5.67 x Ep [model r2 = 0.42, p < 0.001]). CCA Ep was associated with APWV (p < 0.001) independent of age, gender, and BP (model r2 = 0.62, p < 0.001), and the most parsimonious model to explain APWV included CCA Ep and age (APWV = 601.73 - 15.64 x age + 0.223 x age2 + 2.69 x Ep [model r2 = 0.60, p < 0.001]). Thus, CCA Ep is moderately associated with APWV. CCA stiffness as assessed by B-mode may be useful as a surrogate for aortic stiffness.

Aortic Diseases↗

PubMed1999

Decay Index: a new carotid Doppler waveform measure associated with the Windkessel function of elastic arteries.

The Windkessel function of elastic arteries determines the postpeak contour of the internal carotid artery (ICA) Doppler waveform. To introduce an indicator for the function, the postpeak contour was reproduced by an exponential function, and the exponential coefficient was termed "Decay Index" (DI). DI obtained from 108 stenosis-free ICAs (55.2 +/- 15.8 y) was compared with surrogate measures for the Windkessel function (aortic pulse wave velocity, pulse pressure) and ICA peripheral resistance (resistive index, pulsatility index, systolic-to-diastolic ratio). DI was moderately correlated with the Windkessel and the resistance measures (r ranged 0.44-0.57). To clarify these intercorrelations, principal component analysis revealed two components. The first was loaded by the resistance measures (component load > or = 0.93) although the second was loaded by the Windkessel measures and DI (> or = 0.70), supporting an association between DI and the Windkessel function. Thus, DI is likely to represent an indicator for the Windkessel function.

Aorta↗

PubMed1999

Distribution and correlates of elevated total homocyst(e)ine: the Stroke Prevention in Young Women Study.

PURPOSE: To determine the distribution and correlates of elevated total homocyst(e)ine (tHcy) concentration in a population of premenopausal black and white women. METHODS: Data from the Stroke Prevention in Young Women Study (N = 304), a population-based study of risk factors for stroke in women aged 15-44 years of age, were used to determine the distribution and correlates of elevated tHcy in black (N = 103) and white women (N = 201). RESULTS: The mean tHcy level for the population was 6.58 micromol/L (range 2.89-26.5 micromol/L). Mean tHcy levels increased with age, cholesterol level, alcohol intake, and number of cigarettes smoked (all: p < 0.05). There were no race differences (mean tHcy 6.72 micromol/L among blacks and 6.51 micromol/L among whites; p = 0.4346). Regular use of multivitamins and increasing education was associated with significant reductions in tHcy concentration. Approximately 13% of the sample had elevated tHcy levels, defined as a tHcy concentration > or = 10.0 micromol/L. Multivariate-adjusted correlates of elevated tHcy included education > 12 vs. < or = 12 (odds ratio [OR] = 0.4, 95% confidence interval [CI] = 0.2-0.8); smoking > or = 20 cigarettes/day vs. nonsmokers (OR = 2.8, 95% CI = 1.1-7.3); and the regular use of multivitamins (OR = 0.4, 95% CI = 0.2-0.9). CONCLUSIONS: These results suggest that a substantial proportion of healthy young premenopausal women have tHcy levels that increase their risk for vascular disease. A number of potentially modifiable behavioral and environmental factors appear to be significantly related to elevated tHcy levels in young women.

Adolescent↗

PubMed1999

Elevated tissue plasminogen activator antigen and stroke risk: The Stroke Prevention In Young Women Study.

BACKGROUND AND PURPOSE: Abnormalities in endogenous fibrinolysis are associated with an increased risk for stroke in men and older adults. We tested the hypothesis that elevated plasma tissue plasminogen activator (tPA) antigen, a marker for impaired endogenous fibrinolysis, is an independent risk factor for stroke in young women. METHODS: Subjects were 59 nondiabetic females ages 15 to 44 years with cerebral infarction from the Baltimore-Washington area and 97 control subjects frequency-matched for age who were recruited by random-digit dialing from the same geographic area. A history of cerebrovascular disease risk factors was obtained by face-to-face interview. Plasma tPA antigen was measured by enzyme-linked immunosorbent assay. RESULTS: Mean plasma tPA antigen levels were significantly higher in stroke patients than control subjects (4. 80+/-4.18 versus 3.23+/-3.67 ng/mL; P=0.015). After adjustment for age, hypertension, cigarette smoking, body mass index, and ischemic heart disease, there was a dose-response association between tPA antigen and stroke with a 3.9-fold odds ratio of stroke (95% CI, 1.2 to 12.4; P=0.03) for the upper quartile (>4.9 ng/mL) of tPA antigen compared with the lowest quartile. The dose-response relationship between tPA antigen and stroke was equally present in white and nonwhite women, and further adjustment for total and HDL cholesterol levels only modestly attenuated this association. CONCLUSIONS: This population-based case-control study shows that elevated plasma tPA antigen level is independently associated with an increased risk for ischemic stroke in nondiabetic females 15 to 44 years of age. These findings support the hypothesis that impaired endogenous fibrinolysis is an important risk factor for stroke in young women.

Adolescent↗