Harmonizing multisite data with the ComBat method for enhanced Parkinson's disease diagnosis via DAT-SPECT.

Background: Dopamine transporter single-photon emission computed tomography (DAT-SPECT) is a crucial tool for evaluating patients with Parkinson's disease (PD). However, its implication is limited by inter-site variability in large multisite clinical trials. To overcome the limitation, a conventional prospective correction method employs linear regression with phantom scanning, which is effective yet available only in a prospective manner. An alternative, although relatively underexplored, involves retrospective modeling using a statistical method known as "combatting batch effects when combining batches of gene expression microarray data" (ComBat). Methods: We analyzed DAT-SPECT-specific binding ratios (SBRs) derived from 72 healthy older adults and 81 patients with PD registered in four clinical sites. We applied both the prospective correction and the retrospective ComBat correction to the original SBRs. Next, we compared the performance of the original and two corrected SBRs to differentiate the PD patients from the healthy controls. Diagnostic accuracy was assessed using the area under the receiver operating characteristic curve (AUC-ROC). Results: The original SBRs were 6.13 ± 1.54 (mean ± standard deviation) and 2.03 ± 1.41 in the control and PD groups, respectively. After the prospective correction, the mean SBRs were 6.52 ± 1.06 and 2.40 ± 0.99 in the control and PD groups, respectively. After the retrospective ComBat correction, the SBRs were 5.25 ± 0.89 and 2.01 ± 0.73 in the control and PD groups, respectively, resulting in substantial changes in mean values with fewer variances. The original SBRs demonstrated fair performance in differentiating PD from controls (Hedges's g = 2.76; AUC-ROC = 0.936). Both correction methods improved discrimination performance. The ComBat-corrected SBR demonstrated comparable performance (g = 3.99 and AUC-ROC = 0.987) to the prospectively corrected SBR (g = 4.32 and AUC-ROC = 0.992) for discrimination. Conclusion: Although we confirmed that SBRs fairly discriminated PD from healthy older adults without any correction, the correction methods improved their discrimination performance in a multisite setting. Our results support the utility of harmonization methods with ComBat for consolidating SBR-based diagnosis or stratification of PD in multisite studies. Nonetheless, given the substantial changes in the mean values of ComBat-corrected SBRs, caution is advised when interpreting them.

Pro-Hemorrhagic Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy Associated with NOTCH3 p.R75P Mutation with Low Vascular NOTCH3 Aggregation Property.

OBJECTIVES: Intracerebral hemorrhage (ICH) and cerebral microbleeds (CMB) in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy are more common in East Asian populations than in people of white European ancestry. We hypothesized that the ethnic difference is explained by the East Asian-specific NOTCH3 p.R75P mutation. METHODS: This retrospective observational study included 118 patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy in Japanese and Korean cohorts. We investigated whether the p.R75P mutation is associated with symptomatic ICH and multiple CMB (>5) using quasi-Poisson regression models. We predicted the NOTCH3 extracellular domain protein structures in silico and graded NOTCH3 extracellular domain immunostaining in skin vessels of some patients, with subsequent comparisons between p.R75P and other conventional mutations. RESULTS: Among 63 Japanese patients (median age 55 years; 56% men), 15 had a p.R75P mutation, significantly associated with symptomatic ICH (adjusted relative risk 9.56, 95% CI 2.45-37.31), multiple CMB (3.00, 1.34-6.71), and absence of temporopolar lesions (4.91, 2.29-10.52) after adjustment for age, sex, hypertension, and antithrombotics. In the Korean cohort (n = 55; median age 55 years; 51% men), the p.R75P mutation (n = 13) was also associated with symptomatic ICH (8.11, 1.83-35.89), multiple CMB (1.90, 1.01-3.56), and absence of temporopolar lesions (2.32, 1.08-4.97). Structural analysis revealed solvent-exposed free cysteine thiols in conventional mutations, directly causing aggregation, whereas a stereochemically incompatible proline residue structure in p.R75P lowers correct disulfide bond formation probability, indirectly causing aggregation. Pathologically, the p.R75P mutation resulted in less vascular NOTCH3 extracellular domain accumulation than the other conventional mutations. INTERPRETATION: NOTCH3 p.R75P mutation is associated with hemorrhagic presentations, milder temporopolar lesions, and distinct mutant protein structure properties. ANN NEUROL 2024;95:1040-1054.

Dysregulation of stress granule dynamics by DCTN1 deficiency exacerbates TDP-43 pathology in Drosophila models of ALS/FTD.

The abnormal aggregation of TDP-43 into cytoplasmic inclusions in affected neurons is a major pathological hallmark of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Although TDP-43 is aberrantly accumulated in the neurons of most patients with sporadic ALS/FTD and other TDP-43 proteinopathies, how TDP-43 forms cytoplasmic aggregates remains unknown. In this study, we show that a deficiency in DCTN1, a subunit of the microtubule-associated motor protein complex dynactin, perturbs the dynamics of stress granules and drives the formation of TDP-43 cytoplasmic aggregation in cultured cells, leading to the exacerbation of TDP-43 pathology and neurodegeneration in vivo. We demonstrated using a Drosophila model of ALS/FTD that genetic knockdown of DCTN1 accelerates the formation of ubiquitin-positive cytoplasmic inclusions of TDP-43. Knockdown of components of other microtubule-associated motor protein complexes, including dynein and kinesin, also increased the formation of TDP-43 inclusions, indicating that intracellular transport along microtubules plays a key role in TDP-43 pathology. Notably, DCTN1 knockdown delayed the disassembly of stress granules in stressed cells, leading to an increase in the formation of pathological cytoplasmic inclusions of TDP-43. Our results indicate that a deficiency in DCTN1, as well as disruption of intracellular transport along microtubules, is a modifier that drives the formation of TDP-43 pathology through the dysregulation of stress granule dynamics.

Progress to Clarify How NOTCH3 Mutations Lead to CADASIL, a Hereditary Cerebral Small Vessel Disease.

Notch signaling is conserved in C. elegans, Drosophila, and mammals. Among the four NOTCH genes in humans, NOTCH1, NOTCH2, and NOTCH3 are known to cause monogenic hereditary disorders. Most NOTCH-related disorders are congenital and caused by a gain or loss of Notch signaling activity. In contrast, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) caused by NOTCH3 is adult-onset and considered to be caused by accumulation of the mutant NOTCH3 extracellular domain (N3ECD) and, possibly, by an impairment in Notch signaling. Pathophysiological processes following mutant N3ECD accumulation have been intensively investigated; however, the process leading to N3ECD accumulation and its association with canonical NOTCH3 signaling remain unknown. We reviewed the progress in clarifying the pathophysiological process involving mutant NOTCH3.

D-Dimer Trends Predict Recurrent Stroke in Patients with Cancer-Related Hypercoagulability.

INTRODUCTION: In patients with cancer-associated hypercoagulability (CAH)-related stroke, D-dimer trends after anticoagulant therapy may offer a biomarker of treatment efficacy. The purpose of this study was to clarify the association between D-dimer trends and recurrent stroke after anticoagulant therapy in patients with CAH-related stroke. METHODS: We performed retrospective cohort study of consecutive patients with CAH-related stroke at two stroke centers from 2011 to 2020. The ratio of posttreatment to pretreatment D-dimer levels (post/pre ratio) was used as an indicator of D-dimer trends after anticoagulant therapy. Fine-Gray models were used to evaluate the association between post/pre ratio and recurrent stroke. RESULTS: Among 360 acute ischemic stroke patients with active cancer, 73 patients with CAH-related stroke were included in this study. Recurrent stroke occurred in 13 patients (18%) during a median follow-up time of 28 days (interquartile range, 11-65 days). Multivariate analysis revealed that high post/pre ratio was independently associated with recurrent stroke (per 0.1 increase: hazard ratio 2.20, 95% confidence interval 1.61-3.01, p = 0.012). CONCLUSION: D-dimer levels after anticoagulant therapy were associated with recurrent stroke in CAH-related stroke patients. Patients with neutral trends in high D-dimer levels after anticoagulant therapy were at high risk of recurrent stroke.

Efficacy and Safety of Cilostazol in Mild Cognitive Impairment: A Randomized Clinical Trial.

Importance: Recent evidence indicates the efficacy of ß-amyloid immunotherapy for the treatment of Alzheimer disease, highlighting the need to promote ß-amyloid removal from the brain. Cilostazol, a selective type 3 phosphodiesterase inhibitor, promotes such clearance by facilitating intramural periarterial drainage. Objective: To determine the safety and efficacy of cilostazol in mild cognitive impairment. Design, Setting, and Participants: The COMCID trial (A Trial of Cilostazol for Prevention of Conversion from Mild Cognitive Impairment to Dementia) was an investigator-initiated, double-blind, phase 2 randomized clinical trial. Adult participants were registered between May 25, 2015, and March 31, 2018, and received placebo or cilostazol for up to 96 weeks. Participants were treated in the National Cerebral and Cardiovascular Center and 14 other regional core hospitals in Japan. Patients with mild cognitive impairment with Mini-Mental State Examination (MMSE) scores of 22 to 28 points (on a scale of 0 to 30, with lower scores indicating greater cognitive impairment) and Clinical Dementia Rating scores of 0.5 points (on a scale of 0, 0.5, 1, 2, and 3, with higher scores indicating more severe dementia) were enrolled. The data were analyzed from May 1, 2020, to December 1, 2020. Interventions: The participants were treated with placebo, 1 tablet twice daily, or cilostazol, 50 mg twice daily, for up to 96 weeks. Main Outcomes and Measures: The primary end point was the change in the total MMSE score from baseline to the final observation. Safety analyses included all adverse events. Results: The full analysis set included 159 patients (66 [41.5%] male; mean [SD] age, 75.6 [5.2] years) who received placebo or cilostazol at least once. There was no statistically significant difference between the placebo and cilostazol groups for the primary outcome. The least-squares mean (SE) changes in the MMSE scores among patients receiving placebo were -0.1 (0.3) at the 24-week visit, -0.8 (0.3) at 48 weeks, -1.2 (0.4) at 72 weeks, and -1.3 (0.4) at 96 weeks. Among those receiving cilostazol, the least-squares mean (SE) changes in MMSE scores were -0.6 (0.3) at 24 weeks, -1.0 (0.3) at 48 weeks, -1.1 (0.4) at 72 weeks, and -1.8 (0.4) at 96 weeks. Two patients (2.5%) in the placebo group and 3 patients (3.8%) in the cilostazol group withdrew owing to adverse effects. There was 1 case of subdural hematoma in the cilostazol group, which may have been related to the cilostazol treatment; the patient was successfully treated surgically. Conclusions and Relevance: In this randomized clinical trial, cilostazol was well tolerated, although it did not prevent cognitive decline. The efficacy of cilostazol should be tested in future trials. Trial Registration: ClinicalTrials.gov Identifier: NCT02491268.

Zinc Administration Favorably Affects Prophylactic Therapy-refractory Migraine Attacks: A Case Series.

Notably, certain nutrients are effective in preventing migraine. Nonetheless, zinc replacement therapy for migraine treatment has yet to be explored. We herein report four patients with migraine who were refractory to prophylactic therapy and whose headache frequency and severity improved with zinc supplementation. Zinc administration may be an option for treating patients with prophylaxis-refractory migraine. Further investigation is required to determine the efficacy of zinc replacement therapy as a treatment option for migraine.

Age Group Differences in the Association Between Sleep Status and Frailty Among Community-Dwelling Older Adults: The SONIC Study.

Objective: We aimed to determine whether the association of sleep status with frailty differs between age groups of older adults. Method: This cross-sectional study was part of the observational Septuagenarians, Octogenarians, Nonagenarians Investigation with Centenarians (SONIC) study. Subjects were community-dwelling older adults in their 70s and 80s. Frailty was evaluated using the Japanese version of the Cardiovascular Health Study criteria (J-CHS). Pittsburgh Sleep Quality Index (PSQI) was used to assess sleep status. Poor sleep quality was defined as a PSQI global score ≥6. Sleep duration was categorized as short (<6 hr), normal (6-8), and long (>8). We performed multivariable logistic regression to investigate the association between sleep status and frailty separately for each age group adjusted for multiple covariates. Results: In those in their 70s, long sleep duration and sleep medication use were independently associated with frailty. In those in their 80s, poor sleep quality was independently associated with frailty. Conclusions: The association between sleep status and frailty was different between age groups. The findings underscore the importance of incorporating the evaluation of sleep quantity and non-pharmacological therapies in those in their 70s and the evaluation of sleep quality in those in their 80s to help prevent the onset of frailty.

Association of thyroid peroxidase antibody with the RNF213 p.R4810K variant in ischemic stroke/transient ischemic attack.

BACKGROUND AND AIMS: RNF213 is a susceptibility gene for moyamoya disease and vasospastic angina, with a second hit considered necessary for their development. Elevated thyroid peroxidase antibody (TPO-Ab) levels have been observed in both diseases, suggesting a possible role of TPO-Ab as a second hit for developing RNF213-related vasculopathy. We investigated the association of TPO-Ab levels with RNF213-related ischemic stroke (IS)/transient ischemic attack (TIA), other than moyamoya disease. METHODS: From the National Cerebral and Cardiovascular Center Genome Registry, a multicenter, prospective, observational study, we enrolled patients with IS/TIA who were admitted within 1 week of onset. Patients with IS/TIA due to definite moyamoya disease or hemorrhagic stroke were excluded. Participants underwent genotyping for RNF213 p. R4810K, and baseline characteristics and TPO-Ab levels were compared between RNF213 p. R4810K variant carriers and non-carriers. RESULTS: In total, 2090 IS/TIA patients were analyzed [733 women (35.1%); median age 74 (interquartile range, 63-81) years, baseline NIHSS score 3 (2-6)], and 85 (4.1%) of them carried the variant. Median TPO-Ab levels were significantly higher in variant carriers (8.5 IU/mL vs. 2.1 IU/mL, p < 0.01), who also showed a higher frequency of elevated TPO-Ab levels (>16 IU/mL) (27.1% vs. 4.4%). In the multivariate analysis, presence of the RNF213 p. R4810K variant (adjusted odds ratio, 12.42; 95% confidential interval, 6.23-24.75) was significantly associated with elevated TPO-Ab levels. CONCLUSIONS: Elevated TPO-Ab levels may be significantly associated with presence of the RNF213 p. R4810K variant in IS/TIA patients. Thus, TPO-Ab may inherently modify IS/TIA development in RNF213 p. R4810K variant carriers.

Clinical characteristics and intracranial arterial lesions of non-young adult ischemic stroke patients with RNF213 p.R4810K variant.

BACKGROUND: Although RNF213 p.R4810K, a genetic susceptibility variant for moyamoya disease (MMD), is associated with intracranial artery stenosis/occlusion (ICASO), the impact of this variant on ischemic stroke patients in non-young adults is unclear. We aimed to determine the characteristics of non-young adult stroke patients with RNF213 p.R4810K. METHODS: We retrospectively identified acute ischemic stroke patients ≥50 years who were admitted to our hospital and underwent intracranial vascular imaging. We reviewed the patients with RNF213 p.R4810K and compared stroke characteristics and the frequency and location of ICASO between patients with and without the variant. RESULTS: Among 341 patients, RNF213 p.R4810K was identified in 7 patients (2.1%). Five of the 7 patients with the variant (71%) had multiple ICASO without any finding of MMD and remaining 2 patients had no ICASO. The presumed etiologies of ICASO were atherosclerosis in 3 cases, vasculitis in 1, and undetermined vasculopathy in 1. ICASO in the anterior circulation was more common in patients with the variant than in those without (71% vs. 25%). The internal carotid artery, the M1 segment of the middle cerebral artery, the A1 segment of the anterior cerebral artery, and the P1 segment of the posterior cerebral artery, which were the most frequently affected arteries in MMD, were more often affected in the variant group. CONCLUSIONS: Non-young adult stroke patients with RNF213 p.R4810K are more likely to have ICASO in arterial segments commonly affected in MMD. The etiology of their ICASO exhibited diverse mechanisms, possibly depending on vascular risk and other environmental factors.

Contribution of amyloid and putative Lewy body pathologies in neuropsychiatric symptoms.

OBJECTIVES: Neuropsychiatric symptom could be useful for detecting patients with prodromal dementia. Similarities and differences in the NPSs between preclinical/prodromal Alzheimer's disease (AD) and prodromal Parkinson's disease dementia (PDD)/Dementia with Lewy bodies (DLB) may exist. This study aimed to compare the NPSs between preclinical/prodromal AD and prodromal PDD/DLB. METHODS: One hundred and three participants without dementia aged ≥50 years were included in this study. The mild behavioral impairment (MBI) total score and the MBI scores for each domain were calculated using the neuropsychiatric inventory questionnaire score. Participants were divided into five groups based on the clinical diagnosis by neurologists or psychiatrists in each institution based on the results of the amyloid positron emission tomography and dopamine transporter single photon emission computed tomography (DAT-SPECT): Group 1: amyloid-positive and abnormal DAT-SPECT, Group 2: amyloid-negative and abnormal DAT-SPECT, Group 3: amyloid-positive and normal DAT-SPECT, Group 4: mild cognitive impairment unlikely due to AD with normal DAT-SPECT, and Group 5: cognitively normal with amyloid-negative and normal DAT-SPECT. RESULTS: The MBI abnormal perception or thought content scores were significantly higher in Group 1 than Group 5 (Bonferroni-corrected p = 0.012). The MBI total score (Bonferroni-corrected p = 0.011) and MBI impulse dyscontrol score (Bonferroni-corrected p = 0.033) in Group 4 were significantly higher than those in Group 5. CONCLUSION: The presence of both amyloid and putative Lewy body pathologies may be associated with psychotic symptoms.

FUS regulates RAN translation through modulating the G-quadruplex structure of GGGGCC repeat RNA in C9orf72-linked ALS/FTD.

Abnormal expansions of GGGGCC repeat sequence in the noncoding region of the C9orf72 gene is the most common cause of familial amyotrophic lateral sclerosis and frontotemporal dementia (C9-ALS/FTD). The expanded repeat sequence is translated into dipeptide repeat proteins (DPRs) by noncanonical repeat-associated non-AUG (RAN) translation. Since DPRs play central roles in the pathogenesis of C9-ALS/FTD, we here investigate the regulatory mechanisms of RAN translation, focusing on the effects of RNA-binding proteins (RBPs) targeting GGGGCC repeat RNAs. Using C9-ALS/FTD model flies, we demonstrated that the ALS/FTD-linked RBP FUS suppresses RAN translation and neurodegeneration in an RNA-binding activity-dependent manner. Moreover, we found that FUS directly binds to and modulates the G-quadruplex structure of GGGGCC repeat RNA as an RNA chaperone, resulting in the suppression of RAN translation in vitro. These results reveal a previously unrecognized regulatory mechanism of RAN translation by G-quadruplex-targeting RBPs, providing therapeutic insights for C9-ALS/FTD and other repeat expansion diseases.

Recurrence of intracranial artery dissection more than a half year after the initial event.

INTRODUCTION: The management of intracranial artery dissection (IAD) has not been established, partly because the long-term course of the disease is not well-known. We retrospectively investigated the long-term course of IAD without subarachnoid hemorrhage (SAH) as an initial clinical presentation. METHODS: Of 147 consecutive spontaneous first-ever IAD patients hospitalized between March 2011 and July 2018, 44 with SAH were excluded, and the remaining 103 were investigated. We divided the patients into two groups: Recurrence group as those with recurrent intracranial dissection >1 month after the initial dissection, and Non-recurrence group as those without them. Clinical characteristics were compared between those two groups. RESULTS: The mean follow-up period was 33 months from the initial event. Recurrent dissection occurred in 4 patients (3.9%) >7 months after the initial dissection, none of whom were on antithrombotic treatments at recurrence. Three had ischemic stroke and the other had local symptoms [range: 8 to 44 months]. Nine (8.7%) had an ischemic stroke within 1 month of the initial event. There was no recurrent dissection between 1 and 7 months after the initial event. There was no significant difference in baseline characteristics between Recurrence and Non-recurrence groups. CONCLUSIONS: Four out of the 103 (3.9%) IAD patients had recurrent IAD >7 months after the initial event. IAD patients should be followed up for more than a half year after the initial event, with consideration given to the recurrence of IAD. Further research is needed on recurrence prevention measures to IAD patients.

[Charcot-Marie-Tooth disease Patient Registry in Japan].

To clarify the natural courses, medical conditions, and problems in daily life and medical care of the patients with Charcot-Marie-Tooth disease (CMT) in Japan, we have developed a patient registration system (CMT Patient Registry (CMTPR)). We analyzed data of questionnaires from 303 patients (males: 162, females: 141, mean age: 45.9 years old) who registered for CMTPR. The age of onset was less than 15 years old in 45% and more than 60 years old in 5% of the patients. Genetic testing was performed in 65%, and about half of the patients with genetic testing had a duplication of the PMP22 gene. Seventy-six percent of the patients had regular visits to medical facilities. Five percent of patients had no history of hospital visits. Fifteen percent of all patients needed assistance with daily activities due to motor function impairment in the upper extremities, and 25% required assistance due to lower limb impairment. There were no significant differences in the need for assistance by gender or age. Of the 267 adult patients, 18% had difficulty working due to reasons related to the disease, although none of the junior patients reported any problem attending school. This was the first nationwide epidemiological study with healthcare and welfare information on patients with CMT in Japan. We hope the results of this study will lead to better welfare and medical care in CMT patients.

Assessment of motor unit firing by high-density surface electromyography detects motor neuronal hyperexcitable state in amyotrophic lateral sclerosis.

INTRODUCTION/AIMS: In amyotrophic lateral sclerosis (ALS), the impact of motor neuron dysfunction on the motor unit (MU) firing pattern remains to be elucidated. The aim of this study was to clarify the characteristics of the MU firing rate and its association with clinical factors in ALS patients using high-density surface electromyography (HDSEMG) and MU decomposition analysis. METHODS: Nineteen ALS patients and 20 controls prospectively underwent HDSEMG recording of the vastus lateralis muscle during ramp-up (30% of maximum voluntary contraction) and sustained (10% of maximal voluntary contraction for 60 seconds) contractions on performing isometric knee extension. After decomposition analysis, instantaneous firing rates (IFRs) of individually identified MUs were calculated. Comparison of IFRs and clinical variables between ALS patients and controls and analysis of the correlation between individual mean IFR and clinical variables in ALS patients were performed. RESULTS: The number of identified MUs was lower in ALS patients than in controls (P = .017). Mean IFRs of MUs (i.e., mean MU firing rates) were higher in ALS patients than in controls at some force levels on ramp-up contraction (P < .05) and at 50 to 60 seconds during sustained contraction (9.1 [ALS] vs 8.3 [controls] pulses per second; P = .036). There was no correlation between the clinical parameters and mean IFR of each patient. DISCUSSION: ALS patients had a higher MU firing rate during muscle contraction at a low force level. Noninvasive assessment of the MU firing rate by HDSEMG can detect a motor neuronal hyperexcitable state in ALS patients.

Serum leucine-rich α2 glycoprotein as a potential biomarker for systemic inflammation in Parkinson's disease.

There is ample epidemiological and animal-model evidence suggesting that intestinal inflammation is associated with the development of Parkinson's disease (PD). Leucine-rich α2 glycoprotein (LRG) is a serum inflammatory biomarker used to monitor the activity of autoimmune diseases, including inflammatory bowel diseases. In this study, we aimed to investigate whether serum LRG could be used a biomarker of systemic inflammation in PD and to help distinguish disease states. Serum LRG and C-reactive protein (CRP) levels were measured in 66 patients with PD and 31 age-matched controls. We found that serum LRG levels were statistically significantly higher in the PD group than in the control group (PD: 13.9 ± 4.2 ng/mL, control: 12.1 ± 2.7 ng/mL, p = 0.036). LRG levels were also correlated with Charlson comorbidity index (CCI) and CRP levels. LRG levels in the PD group were correlated with Hoehn and Yahr stages (Spearman's r = 0.40, p = 0.008). LRG levels were statistically significantly elevated in PD patients with dementia as compared to those without dementia (p = 0.0078). Multivariate analysis revealed a statistically significant correlation between PD and serum LRG levels after adjusting for serum CRP levels, and CCI (p = 0.019). We conclude that serum LRG levels could be considered a potential biomarker for systemic inflammation in PD.

Compound muscle action potential duration ratio for differentiation between Charcot-Marie-Tooth disease and CIDP.

OBJECTIVE: To elucidate the utility of the proximal to distal compound muscle action potential (CMAP) duration ratio to distinguish between demyelinating Charcot-Marie-Tooth disease (CMT) and chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) compared with nerve ultrasound. METHODS: Thirty-nine demyelinating CMT patients and 19 CIDP patients underwent nerve conduction studies (NCS) and nerve ultrasound. NCS parameters including CMAP duration ratio calculated by dividing the value at the proximal site by that at the distal site and nerve cross-sectional area (CSA) measured by ultrasound were compared between the two groups. The diagnostic sensitivity and specificity of each parameter were analysed. RESULTS: CMT patients showed a significantly lower CMAP duration ratio than CIDP patients (p < 0.05). The area under the curve (AUC) value of the CMAP duration ratio exceeded 0.95 when CMT was considered "positive", and a cut-off value of 1.13 resulted in high diagnostic sensitivity and specificity (84.6 and 100 % for median nerve, 97.4 and 85.7 % for ulnar nerve, respectively), whereas the AUC value of nerve CSA ranged from 0.70 to 0.81. CONCLUSIONS: The CMAP duration ratio could effectively distinguish between demyelinating CMT and CIDP. SIGNIFICANCE: Adding the CMAP duration ratio to a routine NCS may improve the accuracy of the diagnosis of demyelinating CMT.

Early high-dose intravenous immunoglobulin for refractory heparin-induced thrombocytopenia with stroke: Two case reports.

BACKGROUND: High-dose intravenous immunoglobulin (IVIg) can be effective for patients with refractory autoimmune heparin-induced thrombocytopenia (HIT). We report two patients with autoimmune HIT (aHIT) successfully treated with early high-dose IVIg. CASE DESCRIPTION: Case 1 was a 48-year-old male who had persisting HIT with recurrent ischemic stroke after mitral valve replacement. Case 2 was a 71-year-old male who had flush heparin HIT with cerebral venous thrombosis after total hip arthroplasty. High-dose IVIg was administered 6 and 4 days after starting argatroban due to non-improved thrombocytopenia and persistently high D-dimer values, respectively. Both patients achieved favorable functional recovery at discharge as well as improvements of thrombocytopenia and hypercoagulation. CONCLUSIONS: Early high-dose IVIg may be effective for patients with aHIT and hypercoagulability.

Immunohistochemical characterization of transient receptor potential vanilloid types 2 and 1 in a trinitrobenzene sulfonic acid-induced rat colitis model with visceral hypersensitivity.

Transient receptor potential vanilloid type 2 (TRPV2) and type 1 (TRPV1) are originally identified as heat-sensitive TRP channels. We compared the expression patterns of TRPV2 and TRPV1 in the rat distal colon and extrinsic primary afferent neurons, and investigated their roles in visceral hypersensitivity in 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced colitis rats. Both TRPV2 and TRPV1 expressions in the colon, dorsal root ganglion (DRG), and nodose ganglion (NG) were significantly upregulated in the TNBS-induced colitis model. TRPV2 cell bodies co-localized with the intrinsic primary afferent marker NeuN and the inhibitory motor neuronal marker nNOS in the myenteric plexus. TRPV2 expressions were further detected in the resident macrophage marker ED2 in the mucosa. In contrast, no TRPV1-expressing cell bodies were detected in the myenteric plexus. Both TRPV2- and TRPV1-positive cell bodies in the DRG and NG were double-labeled with the neuronal retrograde tracer fluorescent fluorogold. Large- and medium-sized TRPV2-positive neurons were labeled with the A-fiber marker NF200, calcitonin gene-related peptide (CGRP), and substance P (SP) in the DRG while small-sized TRPV1-positive neurons were labeled with the C-fiber markers IB4, CGRP, and SP. TRPV2- and TRPV1-positive NG neurons were labeled with NF200 and IB4. TNBS treatment increased p-ERK1/2-positive cells in TRPV2 and TRPV1 neurons but did not affect the TRPV2 and TRPV1 subpopulations in the DRG and NG. Both TRPV2 and TRPV1 antagonists significantly alleviated visceral hypersensitivity in TNBS-induced colitis model rats. These findings suggest that intrinsic/extrinsic TRPV2- and extrinsic TRPV1-neurons contribute to visceral hypersensitivity in an experimental colitis model.