Sortilin acts as an endocytic receptor for α-synuclein fibril.

Cell-to-cell spreading of misfolded α-synuclein (αSYN) is supposed to play a key role in the pathological progression of Parkinson's disease (PD) and other synucleinopathies. Receptor-mediated endocytosis has been shown to contributes to the uptake of αSYN in both neuronal and glial cells. To determine the receptor involved in αSYN endocytosis on the cell surface, we performed unbiased, and comprehensive screening using a membrane protein library of the mouse whole brain combined with affinity chromatography and mass spectrometry. The candidate molecules hit in the initial screening were validated by co-immunoprecipitation using cultured cells; sortilin, a vacuolar protein sorting 10 protein family sorting receptor, exhibited the strongest binding to αSYN fibrils. Notably, the intracellular uptake of fibrillar αSYN was slightly but significantly altered, depending on the expression level of sortilin on the cell surface, and time-lapse image analyses revealed the concomitant internalization and endosomal sorting of αSYN fibrils and sortilin. Domain deletion in the extracellular portion of sortilin revealed that the ten conserved cysteines (10CC) segment of sortilin was involved in the binding and endocytosis of fibrillar αSYN; importantly, pretreatment with a 10CC domain-specific antibody significantly hindered αSYN fibril uptake. The presence of sortilin in the core structure of Lewy bodies and glial cytoplasmic inclusions in the brain of synucleinopathy patients was confirmed via immunohistochemistry, and the expression level of sortilin in mesencephalic dopaminergic neurons may be altered with disease progression. These results provide compelling evidence that sortilin acts as an endocytic receptor for pathogenic form of αSYN, and yields important insight for the development of disease-modifying targets for synucleinopathies.

Parkinson's disease-linked DNAJC13 mutation aggravates alpha-synuclein-induced neurotoxicity through perturbation of endosomal trafficking.

Mutations in DNAJC13 gene have been linked to familial form of Parkinson's disease (PD) with Lewy pathology. DNAJC13 is an endosome-related protein and believed to regulate endosomal membrane trafficking. However, the mechanistic link between DNAJC13 mutation and α-synuclein (αSYN) pathology toward neurodegeneration remains poorly understood. In this study, we showed that PD-linked N855S-mutant DNAJC13 caused αSYN accumulation in the endosomal compartment, presumably due to defective cargo trafficking from the early endosome to the late and/or recycling endosome. In vivo experiments using human αSYN transgenic flies showed that mutant DNAJC13 not only increased the amount of insoluble αSYN in fly head but also induced dopaminergic neurodegeneration, rough eye phenotype and age-dependent locomotor impairment. Together, these findings suggest that DNAJC13 mutation perturbs multi-directional endosomal trafficking, resulting in the aberrant endosomal retention of αSYN, which might predispose to the neurodegenerative process that leads to PD.

Extracellular α-synuclein enters dopaminergic cells by modulating flotillin-1-assisted dopamine transporter endocytosis.

The neuropathological hallmarks of Parkinson's disease (PD) include the appearance of α-synuclein (α-SYN)-positive Lewy bodies (LBs) and the loss of catecholaminergic neurons. Thus, a potential mechanism promoting the uptake of extracellular α-SYN may exist in susceptible neurons. Of the various differentially expressed proteins, we are interested in flotillin (FLOT)-1 because this protein is highly expressed in the brainstem catecholaminergic neurons and is strikingly up-regulated in PD brains. In this study, we found that extracellular monomeric and fibrillar α-SYN can potentiate FLOT1-dopamine transporter (DAT) binding and pre-endocytic clustering of DAT on the cell surface, thereby facilitating DAT endocytosis and down-regulating its transporter activity. Moreover, we demonstrated that α-SYN itself exploited the DAT endocytic process to enter dopaminergic neuron-like cells, and both FLOT1 and DAT were found to be the components of LBs. Altogether, these findings revealed a novel role of extracellular α-SYN on cellular trafficking of DAT and may provide a rationale for the cell type-specific, functional, and pathologic alterations in PD.-Kobayashi, J., Hasegawa, T., Sugeno, N., Yoshida, S., Akiyama, T., Fujimori, K., Hatakeyama, H., Miki, Y., Tomiyama, A., Kawata, Y., Fukuda, M., Kawahata, I., Yamakuni, T., Ezura, M., Kikuchi, A., Baba, T., Takeda, A., Kanzaki, M., Wakabayashi, K., Okano, H., Aoki, M. Extracellular α-synuclein enters dopaminergic cells by modulating flotillin-1-assisted dopamine transporter endocytosis.

Interstitial pneumonia and other adverse events in riluzole-administered amyotrophic lateral sclerosis patients: a retrospective observational study.

BACKGROUND: Riluzole is the only approved oral drug for amyotrophic lateral sclerosis (ALS). We performed a retrospective study including ALS patients treated with riluzole, focusing on adverse events. METHODS: Patients diagnosed with ALS according to the revised El Escorial criteria (World Federation of Neurology) in our center and who were administered 50 mg oral riluzole twice daily between January 2011 and September 2017 and followed up for at least 6 months from treatment initiation or until death were included. Data regarding sex, age, disease type, initial symptoms, biochemical analyses performed before and after riluzole administration, and medical history were collected. In case of withdrawal, cause of discontinuation and durations of disease and drug administration were recorded. RESULTS: A total of 92 cases were enrolled. Riluzole administration was discontinued in 20 cases (21.7%). The most frequent reason for discontinuation was elevated liver enzymes (n = 5, 5.4%), followed interstitial pneumonia (IP), nausea and appetite loss, dizziness, general malaise, tongue paresthesia, and urinary urgency. In two cases, administration was discontinued primarily because of progression of bulbar palsy. All adverse events occurred within 6 months from treatment initiation and improved soon after its discontinuation. Three IP cases developed severe respiratory failure and required steroid treatment. CONCLUSION: Riluzole administration was discontinued in 20 cases among total of 92 cases. Careful follow-up is important for the first six months after the initiation of riluzole administration, including through interviews, chemical analyses, and chest X-rays, as required.

Early neurosyphilis presenting with multiple cranial nerve palsies: A case report of management by combined penicillin-corticosteroid treatment.

Early neurosyphilis commonly appears in basilar meninges, and its meningeal inflammation can spread to neighboring cranial nerves, resulting in some cranial nerve palsies. Herein, we report a case of a 51-year-old man who presented with right peripheral facial nerve palsy. His symptoms completely disappeared with prednisolone monotherapy without antibiotics use and were not exacerbated during clinical treatment. However, 2 months after remission of seventh cranial neuropathy, fifth and eighth cranial neuropathies appeared on the right side. Serologic tests for syphilis were revealed to be abnormal. Finally, the patient was diagnosed with early neurosyphilis with multiple cranial palsies. His neurological symptoms were markedly improved by combined penicillin-corticosteroid treatment. Systemic corticosteroids could be effective as adjunctive therapy to ameliorate neurological sequelae in early neurosyphilis.

Paradoxical Cerebral Embolism after Gastrointestinal Endoscopy in a Patient with Crohn's Disease.

Development of paradoxical cerebral embolism requires both unstable venous thrombosis and right-to-left shunt (RLS). Gastrointestinal endoscopy (GE) has the potential to affect intrathoracic and abdominal venous thrombi and to enhance RLS because the procedure alters intrathoracic and abdominal pressure. We describe a patient with Crohn's disease who developed paradoxical cerebral embolism after GE. Both an unstable venous thrombus in the superior vena cava and RLS through patent foramen ovale were thought to be responsible for the stroke. Considering that patients with digestive system diseases undergo GE as a routine examination or therapy, screenings for hypercoagulable state and intrathoracic and abdominal thrombi are important to prevent thromboembolism related to GE.

Peak Systolic Velocity Measured by Continuous-Wave Doppler Ultrasonography without Angle Correction in Patients with Internal Carotid Artery Stenosis.

BACKGROUND: Peak systolic velocity (PSV) is measured with pulse-wave (PW) Doppler with angle correction in patients with internal carotid artery stenosis (ICAS). However, the correlation between conventional angiography and PSV shows considerable scattering. We hypothesized that measuring PSV without angle correction would lead to better inter-rater reliability. This hypothesis was tested using a sector probe and continuous-wave (CW) Doppler without angle correction. METHODS: Consecutive patients with more than 50% ICAS were enrolled from a prospective database. PSV was measured with PW Doppler with angle correction (PW PSV) and CW Doppler without angle correction (CW PSV) by 2 examiners. The inter-rater reliabilities of PW PSV and CW PSV were analyzed by Spearman's rank correlation test. RESULTS: A total of 37 ICAS sites (median 67 [interquartile range 57-78] % stenosis) were enrolled. Measuring PSV using a sector probe insonating nearly parallel to the flow was feasible in all cases. Inter-rater reproducibility of CW PSV (Spearman's ρ = .810) was similar to that of PW PSV (Spearman's ρ = .796). When limited to patients with a PSV greater than 200 cm/s with both PW Doppler examinations (25 ICAS sites), inter-rater reliability was relatively higher for CW PSV (Spearman's ρ = .674) than for PW PSV (Spearman's ρ = .423). CONCLUSIONS: Measuring PSV with CW Doppler using a sector probe was feasible. Inter-rater reliability was similar between PW Doppler with angle correction and CW Doppler without angle correction in evaluating PSV in patients with ICAS. CW Doppler appears to have better inter-rater reproducibility than PW Doppler in assessing high PSV.

Isolated Posterior Inferior Cerebellar Artery Dissection as a Cause of Ischemic Stroke: Clinical Features and Prognosis.

BACKGROUND: The purpose of this study was to clarify the incidence, clinical and radiological features and outcomes of isolated posterior inferior cerebellar artery (PICA) dissection in isolated PICA territory infarctions. METHODS: We retrospectively reviewed consecutive inpatients with ischemic stroke secondary to isolated PICA dissection from our stroke database between January 2004 and December 2013 and reviewed the literature with regard to those patients. RESULTS: Of 167 consecutive patients with an isolated PICA territory infarction, a total of 10 patients (6.0%, 3 women, 48.1 ± 7.1 years) were diagnosed as having an isolated PICA dissection. Patients with PICA dissection were younger (p < 0.001), more commonly experienced headache at onset (p = 0.008), less commonly had hyperlipidemia (p = 0.044) and showed a lower modified Rankin Scale score at discharge (p = 0.002) when compared with patients without arterial dissection. In 6 of these 10 patients, PICA dissections had not been suspected on initial magnetic resonance angiography (MRA) and were confirmed by follow-up MRA or digital subtraction angiography. In the follow-up period (median 1.5 years, interquartile range 0.5-6.3 years), there were no recurrent ischemic or hemorrhagic stroke events. CONCLUSIONS: Isolated PICA dissection as an etiological mechanism in isolated PICA territory infarctions may be more common than was previously recognized to be. The diagnosis of PICA dissection is often difficult and requires close and repeated morphological evaluation. We should carefully identify PICA dissections as a possible cause of PICA territory infarctions.

Clinical and genetic investigation of 17 Japanese patients with hyperekplexia.

AIM: The aim of the study was to determine clinical and genetic characteristics of Japanese patients with hyperekplexia. METHOD: Clinical courses, responses to antiepileptic drugs, outcomes, and genetic testing were investigated in 17 Japanese patients (nine males, eight females, median age 1y, range birth-45y) with hyperekplexia. RESULTS: In all patients, muscle stiffness and startle responses appeared soon after birth. Only seven patients were diagnosed with hyperekplexia before 1 year of age. Seven patients had been misdiagnosed with other disorders such as epilepsy and adult-onset anxiety neurosis. Umbilical/inguinal hernias were seen in 10 patients. Life-threatening events were noted in four patients. Clonazepam was the most effective drug. Muscle stiffness completely disappeared in 12 patients before 5 years of age, whereas startle responses resolved in only three patients. Mutations in the GLRA1 and GLRB genes were identified in 16 patients and one patient respectively. In 14 patients, the mutation showed autosomal dominant inheritance; in the other three, inheritance was autosomal recessive. p.R271Q of GLRA1 was the most frequent mutation, found in 10 patients. Novel mutations, p.A272P and p.A384P of GLRA1, were detected. Clinical severity and outcome varied even in the same family. INTERPRETATION: Early correct diagnosis is essential for prevention of accidental injuries and to provide appropriate treatments for hyperekplexia. Clonazepam is effective, although the time taken for startle responses to resolve varied.

Continuous antihypertensive therapy throughout the initial 24 hours of intracerebral hemorrhage: the stroke acute management with urgent risk-factor assessment and improvement-intracerebral hemorrhage study.

BACKGROUND AND PURPOSE: A short duration (<24 hours) of antihypertensive therapy (AHT) after acute intracerebral hemorrhage (ICH) may be sufficient because active bleeding generally ceases within several hours. We aimed to determine the association between sequential systolic blood pressure (SBP) levels during AHT and outcomes in ICH patients. METHODS: In 211 hyperacute ICH patients who underwent AHT based on predefined protocol, the mean of hourly SBP (mSBP) measurements was calculated over 1 to 8 hours (first mSBP), 9 to 16 hours (second mSBP), and 17 to 24 hours (third mSBP) after the initiation of AHT. Outcomes included neurological deterioration (72-hour Glasgow Coma Scale decrease ≥2 or National Instititutes of Health Stroke Scale increase ≥4), hematoma expansion (>33%), and unfavorable outcome (3-month modified Rankin Scale score 4-6). RESULTS: The median first, second, and third mSBPs were 132, 131, and 137 mm Hg, respectively. A higher first mSBP (odds ratio [OR], 2.41; 95% confidence interval [CI], 1.34-4.69 per 10 mm Hg) or second mSBP (OR, 2.08; 95% CI, 1.20-3.80) was independently associated with neurological deterioration, and a higher second mSBP (OR, 1.40; 95% CI, 1.02-2.00) or third mSBP (OR, 1.45; 95% CI, 1.05-2.05) was associated with unfavorable outcome. None of the mSBPs was associated with hematoma expansion. CONCLUSIONS: The continuation of AHT throughout the initial 24 hours after ICH may improve outcomes.

Blood pressure variability on antihypertensive therapy in acute intracerebral hemorrhage: the Stroke Acute Management with Urgent Risk-factor Assessment and Improvement-intracerebral hemorrhage study.

BACKGROUND AND PURPOSE: The associations between early blood pressure (BP) variability and clinical outcomes in patients with intracerebral hemorrhage after antihypertensive therapy, recently clarified by a post hoc analysis of Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage Trial 2 (INTERACT2), were confirmed using the Stroke Acute Management with Urgent Risk-factor Assessment and Improvement (SAMURAI)-intracerebral hemorrhage study cohort. METHODS: Patients with hyperacute (<3 hours from onset) intracerebral hemorrhage with initial systolic BP (SBP) >180 mm Hg were registered in a prospective, multicenter, observational study. All patients received antihypertensive therapy based on a predefined standardized protocol to lower and maintain SBP between 120 and 160 mm Hg using intravenous nicardipine. BPs were measured hourly during the initial 24 hours. BP variability was determined as SD and successive variation. The associations between BP variability and hematoma expansion (>33%), neurological deterioration within 72 hours, and unfavorable outcome (modified Rankin Scale, 4-6) at 3 months were assessed. RESULTS: Of the 205 patients, 33 (16%) showed hematoma expansion, 14 (7%) showed neurological deterioration, and 81 (39%) had unfavorable outcomes. The SD and successive variation of SBP were 13.8 (interquartile range, 11.5-16.8) and 14.9 (11.7-17.7) mm Hg, respectively, and those of diastolic BP were 9.4 (7.5-11.2) and 13.1 (11.2-15.9) mm Hg, respectively. On multivariate regression analyses, neurological deterioration was associated with the SD of SBP (odds ratio, 2.75; 95% confidence interval, 1.45-6.12 per quartile) and the successive variation of SBP (2.37; 1.32-4.83), and unfavorable outcome was associated with successive variation of SBP (1.42; 1.04-1.97). Hematoma expansion was not associated with any BP variability. CONCLUSIONS: SBP variability during the initial 24 hours of acute intracerebral hemorrhage was independently associated with neurological deterioration and unfavorable outcomes. Stability of antihypertensive therapy may improve clinical outcomes.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy without anterior temporal pole involvement: a case report.

The location of white matter lesions, especially in the anterior temporal poles (ATP), is helpful in the diagnosis of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). We report a 49-year-old man with CADASIL who developed migraine with atypical aura, silent lacunar infarcts, and leukoencephalopathy without involvement of the ATP. The prevalence of migraine with aura in subjects with CADASIL is several times greater than that in the general population. Particularly in patients with CADASIL, the aura is often atypical (hemiplegic, basilar, or prolonged). A diagnosis of CADASIL should be considered in patients with lacunar infarcts, leukoencephalopathy, and migraine with atypical aura, even in the absence of white matter lesion in the ATPs.

Clinical significance of fluid-attenuated inversion recovery vascular hyperintensities in transient ischemic attack.

BACKGROUND AND PURPOSE: Fluid-attenuated inversion recovery vascular hyperintensity (FVH) is often identified in patients with acute ischemic stroke. The purpose of this study was to determine the clinical significance of FVH in patients with transient ischemic attack (TIA). METHODS: Consecutive inpatients with TIA who underwent MRI within 24 hours of symptom onset were studied. The frequency, relative factors, and time course of FVH were determined. RESULTS: Of the 202 patients who were enrolled (76 women, mean age, 69.0 ± 13.2 years), FVH was identified in 41 patients (20%). Multivariate analysis showed that atrial fibrillation (odds ratio, 7.14; 95% confidence interval [CI], 2.69-18.1), arterial occlusive lesion (odds ratio, 4.89; 95% CI, 3.03-12.2), and hemiparesis (odds ratio, 2.81; 95% CI, 1.17-7.48) was independently associated with FVH. Of 23 recurrence-free patients with FVH positive undergoing follow-up MRI at a median of 7 days after the onset, FVH was no longer positive in 15 patients (65%). Atrial fibrillation was more common (P=0.027) and arterial occlusive lesion was less common (P<0.001) in patients with transient FVH compared with those with persistent FVH. Within 90 days after the onset, 13 patients developed recurrent TIA or ischemic stroke. After Cox proportional hazard analysis, FVH (hazard ratio, 3.65; 95% CI, 1.09-12.7), arterial occlusive lesion (hazard ratio, 4.15; 95% CI, 1.18-17.1), and coexistence of FVH and arterial occlusive lesion (hazard ratio, 13.9; 95% CI, 3.36-71.0) were significantly associated with recurrent TIA or ischemic stroke. CONCLUSIONS: The presence of FVH early after symptom onset may help to diagnosis TIA, to identify the potential mechanisms of TIA and to predict recurrence risk after a TIA.

Systolic blood pressure after intravenous antihypertensive treatment and clinical outcomes in hyperacute intracerebral hemorrhage: the stroke acute management with urgent risk-factor assessment and improvement-intracerebral hemorrhage study.

BACKGROUND AND PURPOSE: Blood pressure (BP) lowering is often conducted as part of general acute management in patients with acute intracerebral hemorrhage. However, the relationship between BP after antihypertensive therapy and clinical outcomes is not fully known. METHODS: Hyperacute (<3 hours from onset) intracerebral hemorrhage patients with initial systolic BP (SBP) >180 mm Hg were included. All patients received intravenous antihypertensive treatment, based on predefined protocol to lower and maintain SBP between 120 and 160 mm Hg. BPs were measured every 15 minutes during the initial 2 hours and every 60 minutes in the next 22 hours (a total of 30 measurements). The mean achieved SBP was defined as the mean of 30 SBPs, and associations between the mean achieved SBP and neurological deterioration (≥2 points' decrease in Glasgow Coma Score or ≥4 points' increase in National Institutes of Health Stroke Scale score), hematoma expansion (>33% increase), and unfavorable outcome (modified Rankin Scale score 4-6 at 3 months) were assessed with multivariate logistic regression analyses. RESULTS: Of the 211 patients (81 women, median age 65 [interquartile range, 58-74] years, and median initial National Institutes of Health Stroke Scale score 13 [8-17]) enrolled, 17 (8%) showed neurological deterioration, 36 (17%) showed hematoma expansion, and 87 (41%) had an unfavorable outcome. On multivariate regression analyses, mean achieved SBP was independently associated with neurological deterioration (odds ratio, 4.45; 95% confidence interval, 2.03-9.74 per 10 mm Hg increment), hematoma expansion (1.86; 1.09-3.16), and unfavorable outcome (2.03; 1.24-3.33) after adjusting for known predictive factors. CONCLUSIONS: High achieved SBP after standardized antihypertensive therapy in hyperacute intracerebral hemorrhage was independently associated with poor clinical outcomes. Aggressive antihypertensive treatment may ameliorate clinical outcomes.

Pituitary ischemic apoplexy in a young woman using oral contraceptives: a case report.

Estrogen is suggested to be one of the plausible risk factors for pituitary hemorrhagic apoplexy through pituitary hyperemia. We experienced a 33-year-old woman with pituitary ischemic apoplexy of a nonfunctional macroadenoma under oral contraceptive use. Our case indicates that hypercoagulable state, but not hyperemia, associated with estrogen may promote pituitary ischemic apoplexy.

Novel G37V mutation of SOD1 gene in autopsied patient with familial amyotrophic lateral sclerosis.

We report a novel missense mutation (G37V) in exon 2 of the superoxide dismutase-1 gene in a 63-years-old Japanese male with purely lower motor neuron disease. His disease duration was 14 months, and he died of respiratory failure. The disease in this patient with the G37V mutation showed a rapid progression, although patients with G37R mutation are known to have a long survival.

18F-THK5351 Positron Emission Tomography Imaging in Neurodegenerative Tauopathies.

Introduction: We aimed to determine whether in vivo tau deposits and monoamine oxidase B (MAO-B) detection using 18F-THK5351 positron emission tomography (PET) can assist in the differential distribution in patients with corticobasal syndrome (CBS), progressive supranuclear palsy (PSP), and Alzheimer's disease (AD) and whether 18F-THK5351 retention of lesion sites in CBS and PSP can correlate with clinical parameters. Methods: 18F-THK5351 PET was performed in 35 participants, including 7, 9, and 10 patients with CBS, PSP, and AD, respectively, and 9 age-matched normal controls. In CBS and PSP, cognitive and motor functions were assessed using the Montreal Cognitive Assessment, Addenbrooke's Cognitive Examination-Revised, and Frontal Assessment Battery, Unified Parkinson's Disease Rating Scale Motor Score, and PSP Rating Scale. Results: 18F-THK5351 retention was observed in sites susceptible to disease-related pathologies in CBS, PSP, and AD. 18F-THK5351 uptake in the precentral gyrus clearly differentiated patients with CBS from those with PSP and AD. Furthermore, 18F-THK5351 uptake in the inferior temporal gyrus clearly differentiated patients with AD from those with CBS and PSP. Regional 18F-THK5351 retention was associated with the cognitive function in CBS and PSP. Conclusion: Measurement of the tau deposits and MAO-B density in the brain using 18F-THK5351 may be helpful for the differential diagnosis of tauopathies and for understanding disease stages.

[Emerging Disease-modifying Strategies Targeting α-synuclein in Parkinson's Disease].

Parkinson's disease (PD) is the second most common neurodegenerative disease after Alzheimer's disease. Although the standard dopamine replacement therapy can alleviate motor symptoms, presently there is no available treatment to stop or reverse disease progression. Thus, there is an urgent need for the development of novel disease-modifying therapies to prevent the accumulation of cytotoxic α-synuclein (αS), a protein involved in PD pathogenesis, in the nervous system. Furthermore, emerging evidence suggests that the toxic αS species can move from one cell to another, thereby affecting the normal physiological state of the neighboring cells in a prion-like manner. The transmissible, extracellular αS is considered to be an ideal target for the disease-modifying treatments including antibody-based therapy. In this review, we will describe the molecular structure and functions of αS, its relevance to PD pathogenesis, and will discuss the current status and future perspectives of disease-modifying strategies targeting αS in PD.

Sensitivity and specificity of meningeal signs in patients with meningitis.

BACKGROUND: Several types of physical examinations are used in the diagnosis of meningitis, including nuchal rigidity, jolt accentuation, Kernig's sign, and Brudzinski's sign. Jolt accentuation was reported to have sensitivity of nearly 100% and to be highly efficient for excluding meningitis, but more recent studies showed that a number of patients with meningitis may present negative in this test. METHODS: We systematically reviewed studies on the above-mentioned physical examination tests and performed meta-analysis of their diagnostic characteristics to evaluate the clinical usefulness. Nine studies, comprising a total of 599 patients with pleocytosis in the cerebrospinal fluid (CSF) and 1216 patients without CSF pleocytosis, were enrolled in the analysis. RESULTS: Jolt accentuation showed a decent level of odds ratio (3.62; 99% confidence interval (CI): 1.13-11.60, P = 0.004) comparable to that in nuchal rigidity (2.52; 1.21-5.27, P = 0.001) for the correct prediction of CSF pleocytosis among subjects with suspected meningitis. The estimated sensitivity was relatively high (40%-60%) in nuchal rigidity or jolt accentuation tests. On the other hand, Kernig's and Brudzinski's signs exhibited relatively low sensitivity (20%-30%). The estimated specificity was higher in Kernig's and Brudzinski's signs (85%-95%) than in nuchal rigidity or jolt accentuation tests (65%-75%). CONCLUSION: Approximately half of the patients with meningitis may not present typical meningeal signs upon physical examination. Combining several examinations for the detection of meningeal signs may decrease the risk of misdiagnosis.

DnaJ/Hsp40 Family and Parkinson's Disease.

Parkinson's disease (PD) is the second most common devastating neurodegenerative disorder after Alzheimer's disease. The precise molecular and cellular basis underlying PD still remains uncertain; however, accumulating evidence suggests that neuronal cell death is caused by a combination of environmental and genetic factors. Over the previous two decades, more than 20 genes have been identified as the cause of and/or risk for PD. Because sporadic and familial forms of PD have many similarities in clinical and neuropathological features, common molecular pathways, such as aberrant mitochondrial and protein homeostasis, are likely to exist in both conditions. Of the various genes and proteins involved in PD, the versatile DnaJ/Hsp40 co-chaperones have attracted particular attention since several genes encoding this protein family have been successively identified as the cause of the familial forms of PD/Parkinsonism. In this review, we will introduce the current knowledge regarding the integratory and modulatory effect of DnaJ/Hsp40 in various cellular functions and argue how the failure of these proteins may initiate and/or facilitate of the disease.