BACKGROUND AND PURPOSE: The receptor for advanced glycation end products (RAGE) may contribute to the development of diabetic neuropathy. To assess its relevance in humans, this study examined the expression of RAGE in the skin biopsy samples of patients with diabetes mellitus, and investigated its correlation with intraepidermal nerve-fiber density (IENFD) and clinical measures of neuropathy severity. METHODS: Forty-four patients who either had type 2 diabetes or were prediabetes underwent clinical evaluation and a 3-mm skin punch biopsy. The clinical severity of their neuropathy was assessed using the Michigan Diabetic Neuropathy Score. IENFD was measured along with immunohistochemical staining for RAGE in 29 skin biopsy samples. The expression of RAGE was also quantified by real-time reverse-transcription PCR in the remaining 15 patients. RESULTS: RAGE was localized mostly in the dermal and subcutaneous vascular endothelia. The staining was more intense in patients with a lower IENFD (p=0.004). The quantity of RAGE mRNA was significantly higher in patients with severe neuropathy than in those with no or mild neuropathy (p=0.003). The up-regulation of RAGE was related to dyslipidemia and diabetic nephropathy. There was a trend toward decreased sural nerve action-potential amplitude and slowed peroneal motor-nerve conduction with increasing RAGE expression. CONCLUSIONS: The findings of this study demonstrate up-regulation of RAGE in skin biopsy samples from patients with diabetic neuropathy, supporting a pathogenic role of RAGE in the development of diabetic neuropathy.
Biopsy* ; Diabetes Mellitus ; Diabetic Nephropathies ; Diabetic Neuropathies* ; Dyslipidemias ; Glycosylation End Products, Advanced* ; Humans ; Michigan ; Polymerase Chain Reaction ; Prediabetic State ; Rage ; RNA, Messenger ; Skin* ; Sural Nerve ; Up-Regulation* ; Advanced Glycosylation End Product-Specific Receptor

BACKGROUND AND PURPOSE: Process improvement (PI) is an approach for enhancing the existing quality improvement process by making changes while keeping the existing process. We have shown that implementation of a stroke code program using a computerized physician order entry system is effective in reducing the in-hospital time delay to thrombolysis in acute stroke patients. We investigated whether implementation of this PI could further reduce the time delays by continuous improvement of the existing process. METHODS: After determining a key indicator [time interval from emergency department (ED) arrival to intravenous (IV) thrombolysis] and conducting data analysis, the target time from ED arrival to IV thrombolysis in acute stroke patients was set at 40 min. The key indicator was monitored continuously at a weekly stroke conference. The possible reasons for the delay were determined in cases for which IV thrombolysis was not administered within the target time and, where possible, the problems were corrected. The time intervals from ED arrival to the various evaluation steps and treatment before and after implementation of the PI were compared. RESULTS: The median time interval from ED arrival to IV thrombolysis in acute stroke patients was significantly reduced after implementation of the PI (from 63.5 to 45 min, p=0.001). The variation in the time interval was also reduced. A reduction in the evaluation time intervals was achieved after the PI [from 23 to 17 min for computed tomography scanning (p=0.003) and from 35 to 29 min for complete blood counts (p=0.006)]. CONCLUSIONS: PI is effective for continuous improvement of the existing process by reducing the time delays between ED arrival and IV thrombolysis in acute stroke patients.
Blood Cell Count ; Emergency Medical Services ; Emergency Service, Hospital ; Humans ; Medical Order Entry Systems ; Quality Improvement ; Statistics as Topic ; Stroke*

BACKGROUND AND PURPOSE: Restless legs syndrome (RLS) is a common sleep-related movement disorder that is frequently associated with psychological disturbances. Personality traits are of considerable importance with respect to coping with chronic illness and disease vulnerability. This study assessed the temperament and character traits of RLS patients using an approach that involves the psychobiological model of personality. METHODS: The personality features of 65 newly diagnosed and untreated RLS patients with no neurological or psychiatric diseases and 109 healthy controls were determined using the Temperament and Character Inventory and compared using covariance analyses. The International RLS Study Group Severity Scale was used to assess the severity of the RLS symptoms, and the Beck Depression Inventory was used to assess the presence and severity of depressive symptoms. RESULTS: RLS patients scored significantly higher than healthy controls on the temperament dimension of harm avoidance (HA, p=0.02) and significantly lower on self-directedness (SD, p=0.001). No significant difference was observed in terms of the temperament dimension of novelty seeking (p=0.435). HA scores were significantly correlated with the BDI score but not with the RLS severity or duration. CONCLUSIONS: High HA and low SD scores are the main characterizing personality features of RLS patients. These personality dimensions may be among the factors predisposing patients to development of the depressive symptoms that are frequently associated with RLS.
Chronic Disease ; Depression* ; Dopamine ; Humans ; Movement Disorders ; Restless Legs Syndrome* ; Risk Factors* ; Serotonin ; Temperament*

BACKGROUND AND PURPOSE: Excessive daytime sleepiness and sudden sleep attacks are the main features of narcolepsy, but rapid-eye-movement sleep behavior disorder (RBD), hyposmia, and depression can also occur. The latter symptoms are nonmotor features in idiopathic Parkinson's disease (IPD). In the present study, IPD-proven diagnostic tools were tested to determine whether they are also applicable in the assessment of narcolepsy. METHODS: This was a case-control study comparing 15 patients with narcolepsy (PN) and 15 control subjects (CS) using the Scales for Outcomes in Parkinson's Autonomic Test (SCOPA-AUT), Parkinson's Disease Nonmotor Symptoms (PDNMS), University of Pennsylvania Smell Test, Farnsworth-Munsell 100 Hue test, Beck Depression Inventory, and the RBD screening questionnaire. RESULTS: Both the PN and CS exhibited mild hyposmia and no deficits in visual tests. Frequent dysautonomia in all domains except sexuality was found for the PN. The total SCOPA-AUT score was higher for the PN (18.47+/-10.08, mean+/-SD) than for the CS (4.40+/-3.09), as was the PDNMS score (10.53+/-4.78 and 1.80+/-2.31, respectively). RBD was present in 87% of the PN and 0% of the CS. The PN were more depressed than the CS. The differences between the PN and CS for all of these variables were statistically significant (all p<0.05). CONCLUSIONS: The results of this study provide evidence for the presence of dysautonomia and confirm the comorbidities of depression and RBD in narcolepsy patients. The spectrum, which is comparable to the nonmotor complex in IPD, suggests wide-ranging, clinically detectable dysfunction beyond the narcoleptic core syndrome.
Case-Control Studies ; Comorbidity ; Depression ; Humans ; Mass Screening ; Narcolepsy* ; Parkinson Disease ; Pennsylvania ; Primary Dysautonomias* ; Sexuality ; Smell ; Weights and Measures ; Surveys and Questionnaires

BACKGROUND AND PURPOSE: We examined the characteristics of sleep disturbances and sleep patterns in the caregivers of patients with amnestic mild cognitive impairment (aMCI) and dementia. METHODS: We prospectively studied 132 patients (60 with aMCI and 72 with dementia) and their caregivers, and 52 noncaregiver controls. All caregivers and controls completed several sleep questionnaires, including the Pittsburgh Sleep Quality Index (PSQI). The patients were administered neuropsychological tests and the neuropsychiatric inventory to evaluate their behavioral and neuropsychiatric symptoms of dementia (BPSD). RESULTS: The PSQI global score was 6.25+/-3.88 (mean+/-SD) for the dementia caregivers and 5.47+/-3.53 for the aMCI caregivers. The Insomnia Severity Index (ISI) and short form of the Geriatric Depression Scale (GDS-S) predicted higher PSQI global scores in aMCI caregivers, and higher scores for the ISI, Epworth Sleepiness Scale (ESS), and GDS-S in dementia caregivers. BPSD, including not only agitation, depression, and appetite change in dementia patients, but also depression, apathy, and disinhibition in aMCI patients, was related to impaired sleep quality of caregivers, but nighttime behavior was not. Age and gender were not risk factors for disturbed sleep quality. CONCLUSIONS: Dementia and aMCI caregivers exhibit impaired quality of sleep versus non-caregivers. ISI, GDS-S, and ESS scores are strong indicators of poor sleep in dementia caregivers. In addition, some BPSD and parts of the neuropsychological tests may be predictive factors of sleep disturbance in dementia caregivers.
Alzheimer Disease ; Apathy ; Appetite ; Caregivers* ; Dementia* ; Dementia, Vascular ; Depression ; Dihydroergotamine ; Humans ; Mild Cognitive Impairment* ; Neuropsychological Tests ; Prospective Studies ; Risk Factors ; Sleep Initiation and Maintenance Disorders ; Surveys and Questionnaires

BACKGROUND AND PURPOSE: The relationship between contingent negative variation (CNV), which is an event-related potential, and cognition in multiple sclerosis (MS) has not been examined previously. The primary objective of the present study was thus to determine the association between CNV and cognition in a sample of MS patients. METHODS: The subjects of this study comprised 66 MS patients [50 with relapsing-remitting MS (RRMS) and 16 with secondary progressive MS (SPMS)] and 40 matched healthy volunteers. A neuropsychological battery was administered to all of the subjects; CNV recordings were made from the Cz, Fz, and Pz electrodes, and the amplitude and area under the curve (AUC) were measured at each electrode. RESULTS: RRMS patients exhibited CNVs with lower amplitudes and smaller AUCs than the controls at Pz. SPMS patients exhibited CNVs with lower amplitudes and smaller AUCs than the controls, and CNVs with a smaller amplitude than the RRMS patients at both Cz and Pz. After correcting for multiple comparisons, a lower CNV amplitude at Pz was significantly associated with worse performance on measures of speed of information processing, verbal fluency, verbal learning, and verbal recall. CONCLUSIONS: CNV may serve as a marker for disease progression and cognitive dysfunction in MS. Further studies with larger samples and wider electrode coverage are required to fully assess the value of CNV in these areas.
Area Under Curve ; Automatic Data Processing ; Cognition ; Contingent Negative Variation* ; Disease Progression ; Electrodes ; Evoked Potentials ; Healthy Volunteers ; Humans ; Multiple Sclerosis* ; Multiple Sclerosis, Chronic Progressive ; Multiple Sclerosis, Relapsing-Remitting ; Neuropsychological Tests ; Verbal Learning

BACKGROUND AND PURPOSE: The aim of this study was to elucidate the role of therapy-related cardiotoxicity in multiple sclerosis (MS) patients treated with mitoxantrone and to identify potential predictors for individual risk assessment. METHODS: Within a multicenter retrospective cohort design, cardiac side effects attributed to mitoxantrone were analyzed in 639 MS patients at 2 MS centers in Germany. Demographic, disease, treatment, and follow-up data were collected from hospital records. Patients regularly received cardiac monitoring during the treatment phase. RESULTS: None of the patients developed symptomatic congestive heart failure. However, the frequency of patients experiencing cardiac dysfunction of milder forms after mitoxantrone therapy was 4.1% (26 patients) among all patients. Analyses of the risk for cardiotoxicity revealed that cumulative dose exposure was the only statistically relevant risk factor associated with cardiac dysfunction. CONCLUSIONS: The number of patients developing subclinical cardiac dysfunction below the maximum recommended cumulative dose is higher than was initially assumed. Interestingly, a subgroup of patients was identified who experienced cardiac dysfunction shortly after initiation of mitoxantrone and who received a low cumulative dose. Therefore, each administration of mitoxantrone should include monitoring of cardiac function to enhance the treatment safety for patients and to allow for early detection of any side effects, especially in potential high-risk subgroups (as determined genetically).
Cohort Studies* ; Follow-Up Studies ; Germany ; Heart Failure ; Hospital Records ; Humans ; Mitoxantrone* ; Multiple Sclerosis* ; Retrospective Studies ; Risk Assessment ; Risk Factors

Homocysteine (Hcy) is a sulfur-containing amino acid that is generated during methionine metabolism. It has a physiologic role in DNA metabolism via methylation, a process governed by the presentation of folate, and vitamins B6 and B12. Physiologic Hcy levels are determined primarily by dietary intake and vitamin status. Elevated plasma levels of Hcy (eHcy) can be caused by deficiency of either vitamin B12 or folate, or a combination thereof. Certain genetic factors also cause eHcy, such as C667T substitution of the gene encoding methylenetetrahydrofolate reductase. eHcy has been observed in several medical conditions, such as cardiovascular disorders, atherosclerosis, myocardial infarction, stroke, minimal cognitive impairment, dementia, Parkinson's disease, multiple sclerosis, epilepsy, and eclampsia. There is evidence from laboratory and clinical studies that Hcy, and especially eHcy, exerts direct toxic effects on both the vascular and nervous systems. This article provides a review of the current literature on the possible roles of eHcy relevant to various neurologic disorders.
Atherosclerosis ; Dementia ; DNA ; Eclampsia ; Epilepsy ; Female ; Folic Acid ; Homocysteine ; Hyperhomocysteinemia* ; Metabolism ; Methionine ; Methylation ; Methylenetetrahydrofolate Reductase (NADPH2) ; Multiple Sclerosis ; Myocardial Infarction ; Nervous System ; Nervous System Diseases* ; Parkinson Disease ; Plasma ; Pregnancy ; Stroke ; Vitamin B 12 ; Vitamins

Cerebral venous thrombosis (CVT) rarely recurs, and the factors associated with a recurrence remain unclear. Recently, however, elevated plasma coagulation factor VIII has been considered a factor related to recurrent venous thromboembolism. Here we report a patient who had recurrent CVT associated with significantly elevated levels of factor VIII despite the chronic use of an antiplatelet agent. Factor IX was also elevated in this patient. These findings suggest that elevated factor VIII is a factor underlying the recurrence of CVT, and that prolonged anticoagulation therapy may have to be considered in patients with elevated coagulation factor levels.
Blood Coagulation Factors ; Factor IX ; Factor VIII* ; Humans ; Plasma ; Recurrence ; Venous Thromboembolism ; Venous Thrombosis*

Lamotrigine is an effective antiepileptic drug with few adverse effects. Nystagmus is one of the commonly observable signs of lamotrigine overdose, which may result from central nervous system involvement. However, the physiologic basis of lamotrigine-induced nystagmus is not fully understood. Here we report a patient who presented with lamotrigine-associated nystagmus that was probably related to cerebellar dysfunction.
Central Nervous System ; Cerebellar Diseases ; Humans