System truncation accelerates binding affinity calculations with the fragment molecular orbital method: A benchmark study.

The fragment molecular orbital (FMO) method is a fast quantum-mechanical method that divides systems into pieces of fragments and performs ab initio calculations. The system truncation enables further speed improvement. In this article, we systematically study the effects of system truncations on binding affinity calculations obtained with FMO in combination with either the polarizable continuum model (FMO/PCM) or in combination with the Møller-Plesset method (FMO-MP2). We have used five protein complexes with ligands of several charged states. The calculated binding energies of the size variants of the truncated system, including only a restricted number of atoms around the ligand, are compared to the energy obtained from a full system. The result shows that the systems could be truncated to a radius of 8 Å from neutral ligands within an error of 0.7 kcal/mol, and 12 Å from charged ligands within an error of 1.1 kcal/mol for calculating the binding energy in solution.

Late-onset spinal form xanthomatosis without brain lesion: a case report.

BACKGROUND: Cerebrotendinous xanthomatosis (CTX) is a rare autosomal recessive sterol storage disease caused by a mutated sterol 27-hydroxylase (CYP27A1) gene. Patients with typical CTX show neurological dysfunction including bilateral cataracts, paresis, cerebral ataxia, dementia, and psychiatric disorders, and magnetic resonance imaging (MRI) has revealed symmetrical lesions in the cerebellar white matter. CASE PRESENTATION: We report the case of a patient with late-onset spinal form CTX without brain lesion. He showed pyramidal tract signs, and impaired joint position and vibration sensation in the lower limbs. Cervical sagittal MRI demonstrated a longitudinally extensive white matter abnormality in the dorsal column of the C2-C7 spinal cord; however, a brain MRI revealed an absence of lesions, including in the cerebellar white matter. Genetic analysis of CYP27A1 revealed that the patient was compound heterozygous for p.Gln85Arg in exon 1, a novel mutation, and p.Arg405Gln in exon 7, a previously reported mutation. CONCLUSION: This is the first report of late-onset spinal form CTX without typical neurological symptoms, and the first report of p.Gln85Arg in CYP27A1. We speculate that spinal form CTX without brain lesion is a clinically and radiologically rare variation of CTX. Therefore, spinal xanthomatosis should be included in the differential diagnosis of chronic myelopathy even with late-onset and/or no other typical neurological findings.

Relationship between cervical cord 1H-magnetic resonance spectroscopy and clinoco-electromyographic profile in amyotrophic lateral sclerosis.

INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the loss of motor neurons, leading to limb paralysis and respiratory failure. METHODS: C1-C3 cord (1) H-magnetic resonance spectroscopy ((1) H-MRS) was performed in 19 patients with ALS and 20 controls. N-acetylaspartate (NAA), choline-containing compounds, creatine plus phosphocreatine (Cr), and myo-Inositol (m-Ins) were measured. ALS functional rating scale-revised (ALSFRS) and forced vital capacity (FVC) were assessed. The rates of decline were calculated at 6 months before and after (1) H-MRS. RESULTS: NAA/Cr and NAA/m-Ins were decreased significantly, and m-Ins/Cr was increased significantly in ALS patients compared with controls. NAA/Cr and NAA/m-Ins were correlated with ALSFRS and FVC and inversely linked to the decline rates. NAA/Cr, NAA/m-Ins, and m-Ins/Cr were altered markedly in 9 patients with denervation and neurogenic changes in both C2 paraspinal and upper limb muscles. CONCLUSIONS: These metabolite ratios were associated with disease progression and ongoing denervation in neck and hand muscles. C1-C3 cord (1) H-MRS might reflect anterior horn cell damage causing neck/arm weakness and respiratory dysfunction in ALS patients.

Limb-onset amyotrophic lateral sclerosis patients visiting orthopedist show a longer time-to-diagnosis since symptom onset.

BACKGROUND: There have been several reports concerning the survival time after symptom onset in patients with amyotrophic lateral sclerosis (ALS). However, little is known about how the choice of physician (i.e., general practitioner, neurologist, etc.) may affect the time it takes for a diagnosis of ALS to be made. METHODS: We conducted a retrospective study, covering a 20-year period, comparing the type of physician first consulted by an ALS patient at the time of initial symptoms and the amount of time that elapsed to the final diagnosis of ALS. A total of 202 patients were diagnosed and stratified according to the onset of ALS symptoms (bulbar onset [BO] and limb onset [LO]). We noted the type of physician first seen by the patient. The diagnostic interval was calculated as the time between onset of symptoms and the final diagnosis of ALS. RESULTS: A total of 202 ALS patients were examined. Clinical BO and LO was observed in 78 (36.6%) and in 124 (61.4%) of these patients, respectively. The type of physician examining these patients at the first symptoms of disease was as follows (BO and LO): neurologist (38.5% and 25.8%), general practitioner (14.1% and 35.5%), orthopedist (12.8% and 35.5%), otolaryngologist (15.4% and 0%), and neurosurgeon (14.1% and 3.2%). Mean diagnostic interval (standard deviation) for patients with either set of symptoms was 13.1 (6.5) months; the diagnostic interval of patients with BO and LO was 9.2 (4.5) and 15.2 (7.7) months, respectively. ALS diagnosis in LO patients was delayed by more than 10 months when the patient first consulted an orthopedist rather than a neurologist. CONCLUSION: More than 50% of the ALS patients included in this study did not visit a neurologist at the first symptoms of disease onset. The diagnosis of ALS was prolonged in LO patients visiting an orthopedist. We speculate that this increase in the diagnostic interval in LO patients visiting an orthopedist was due to a lack of bulbar symptoms in the early stages of this disease.

Pulse wave velocity study in middle-aged migraineurs at low cardiovascular disease risk.

BACKGROUND: Migraine is associated with an increased risk for ischemic stroke and cardiovascular disease (CVD). Recent studies have suggested vascular dysfunction in the aorta, the brachial and femoral artery. Little is known about such arterial changes in Japanese midlife migraineurs. We aimed to evaluate arterial pulse wave velocity (PWV) and ankle-brachial index (ABI) in middle-aged migraineurs at low CVD risk. METHODS: Brachial-ankle PWV (baPWV) and ABI, using an oscillometric technique, were measured in 111 migraineurs (81 women and 30 men) and 110 controls. All participants had no CVD risk factors. Statistical comparison of baPWV and ABI between both groups and the relationship to clinical variables of migraineurs were analyzed. RESULTS: Twenty-two subjects had migraine with aura and 89 had migraine without aura. Mean age (SD) of migraineurs was 44.4 (8.4) years. Mean duration (SD) was 18.0 (10.8) years. Attack frequency was 60 subjects in ≥1 time/month and 51 subjects in <1 time/month. Mean score (SD) of Headache Impact Test-6 (HIT-6) was 61.4 (8.7). CVD risk profile did not differ statistically between migraineurs and controls. Mean baPWV (SD) of migraineurs was 1247 (189) cm/second in women and 1356 (126) in men. That of controls was 1138 (136) in women and 1250 (121) in men. baPWV was increased significantly in female and male migraineurs. Mean ABI (SD) was 1.05 (0.06; 1.04 [0.07] in men and 1.05 [0.06] in women) in migraineurs and 1.06 (0.07) in controls (1.05 [0.08] in men and 1.06 [0.08] in women). ABI did not differ statistically between migraineurs and controls. Migraine subtypes, duration, attack frequency, and HIT-6 score were not associated with baPWV and ABI. CONCLUSION: The present study indicated higher baPWV in midlife migraineurs without CVD risk factors. This pathogenesis could reflect distinct vascular reactivity rather than arterial stiffness due to atherosclerosis.

Cheiro-oral syndrome associated with lateral medullary infarction.

A 62-year-old man was admitted to our department because of the sudden onset of dysaesthesia in the right perioral region of the face and right hand. Neurological examination demonstrated a loss of pain and temperature sensation in both the right perioral region and in the fingers of the right hand. These findings suggested damage to parts of the ipsilateral spinothalamic and trigeminothalamic ascending tracts, producing restricted sensory impairment of the perioral region and ipsilateral hand. This is the first reported case of a medullary lesion causing cheiro-oral syndrome.

Root canal system of the maxillary canine.

To better assess the efficacy of mechanical preparation of root canals, transparent specimens of 250 extracted maxillary canines were investigated for canal configuration, thickness and curvature of the root canal, condition of any accessory canals, and location of the apical foramen. Fewer than 40% of the specimens showed accessory canals that were mechanically impossible to clean. The majority of the lateral branches were small, greater than a #15 file, and none of the branches were larger than a #20 file. Although apical foramina located away from the apex were observed in 30% of the maxillary teeth, 96% of all apical foramina were within 0.5 mm of the apex. Data on the thickness of the root and main canal in the apical portion and curvature of the root canal suggest that, for adequate apical preparation, a #60 file must be able to reach the apical constriction.

A case of Vernet syndrome with varicella zoster virus infection.

A 40-year-old man was admitted to our department, because of sudden onset of dysphagia, hoarseness, left neck pain and headache. There were no skin lesions. On neurological examination, there were paralysis of the left soft palate and constrictor muscles of the pharynx, weakness of the left sternocleidomastoid and left upper trapezius. In cerebrospinal fluid (CSF) examination, cell count and protein concentration were elevated. Antibody titer to varicella zoster virus (VZV) was elevated in both the serum and CSF. And VZV-DNA was detected by PCR from CSF. Gd enhanced MRI showed the nodular lesion at the left jugular foramen. The diagnosis of Vernet's syndrome (VS) associated with VZV infection was made. The patient's symptoms were immediately improved with 30 mg of prednisone and 3 g of varaciclovir daily for 14 days. Only a few cases of VS due to VZV have been reported previously. Our case is the first case that detected VZV-DNA in CSF by PCR.

[Cerebellar infarction restricted to bilateral inferior vermis presenting with floating sensation and then astasia].

A 76-year-old man suddenly experienced floating sensation, transient vertigo, and nausea. Neurological examination was unremarkable except for hypotonia and mild ataxia in the limbs, but orthostatic nausea and vomiting forced him to take a quiet, recumbent position. Magnetic resonance imaging of the brain showed cerebellar infarction restricted to the bilateral inferior vermis. During a course of recovery, he fell down in any directions while standing unattended. He was unable to keep the center of gravity on the feet base in an upright posture. The inferior vermis may participate in maintaining the center of gravity while standing.

[Listeria monocytogenes meningoencephalitis lacking meningeal signs].

We report a fatal case of meningoencephalitis due to Listeria monocytogenes. A 74-year old alcoholic man presented with high-grade fever lasting for four days without headache and meningeal signs. Routine blood analysis showed leukocytosis, but serum C-reactive protein (CRP) was not significantly elevated. He developed altered consciousness with focal seizure, and cerebrospinal fluid (CSF) examination showed a minor degree of pleocytosis, elevated protein, and hypoglycorrhachia. Repeated CSF examination four days later showed greater increases in cells and proteins as well as severely decreased glucose level. Bacterial culture from the initial CSF showed a growth of L. monocytogenes. Meningoencephalitis caused by L. monocytogenes may have atypical clinical and laboratory features, and should be listed in the differential diagnosis of immunocompromised or elderly patients presenting with fever of unknown origin associated with altered consciousness.

Cheiro-pedal syndrome following pontine infarction.

We report the case of a 64-year-old man with sudden onset of numbness in the right hand and foot. Neurological examinations were normal except for hypersthesia, and hyperalgesia of the right hand and foot. Brain MRI demonstrated a high signal intensity on T2-weighted image and a low signal intensity on T1-weighted image in the left tegmetum of the pons. He was diagnosed with pontine infarction presenting with cheiro-pedal syndrome (CPS). Damage in the sensory pathways can cause CPS. Difference in the threshold may explain the specific sensory pattern in this syndrome. Further examination of the relationship between sensory symptoms and localization on MRI is needed to clarify this syndrome.

Prevalence and clinical hallmarks of primary exercise headache in middle-aged Japanese on health check-up.

Objective We examined the prevalence and clinical features of primary exercise headache (PEH) in middle-aged Japanese population. Methods A headache specialist interviewed middle-aged subjects serially on health check-up. The primary headaches were diagnosed according to the International Classification of Headache Disorders (ICHD-III beta). Cardiovascular disease (CVD) risk and radiological findings were analyzed. Prevalence of PEH and clinical features were assessed. Results Among 2,546 subjects (1,588 men and 958 women), thirty subjects (13 men and 17 women) were diagnosed with PEH. The prevalence of PEH was 1.19%, 0.82% in men and 1.77% in women. The mean age [standard deviation (SD)] of the subjects was 44.3 (8.8) years and their mean duration (SD) of PEH was 4.5 (7.0) months. Headache occurred bilaterally (23 patients) or unilaterally (7 patients), and in the occipital (16 patients), frontal (10 patients) or diffuse region (4 patients). The persistent headache time ranged from 5 minutes to 12 hours. The degree of headache severity was classified as mild (13 patients), moderate (5 patients) or severe degree (12 patients). PEH was triggered by gym training (16 patients), swimming (6 patients), running (6 patient) and skiing (2 patients). All patients were exercise beginners or played a sport occasionally. No patients visited physicians for headache consultation. Other primary headaches coexisted in 20 patients (67%). Twenty patients had migraine without aura (MO). Seven patients had headache associated with sexual activity. Five patients had cough headache. Two patients had CVD risk factors. Conclusion The present study of PEH indicated the prevalence of 1.2% and the female/male ratio of 2.1 in middle-aged Japanese. The comorbidity rate of MO was high. PEH may not be an uncommon headache in middle-aged MO sufferers and sport beginners.

Domperidone effective in preventing rivastigmine-related gastrointestinal disturbances in patients with Alzheimer's disease.

OBJECTIVE: While acetylcholinesterase inhibitors, such as donepezil, galantamine, and rivastig-mine, are beneficial in treating behavioral symptoms of patients with Alzheimer's disease (AD), their dose-limiting effects include gastrointestinal disturbances, such as nausea, vomiting, and diarrhea. We aimed to predict the occurrence of these gastrointestinal disturbances with rivastigmine therapy for optimal drug choice and improved compliance. MATERIALS AND METHODS: Thirty patients with mild-to-moderate AD (scores 10-22 on the MiniMental State Examination) were administered a rivastigmine 18 mg patch with domperidone 30 mg (RWD) and without domperidone (RWOD; n = 15 each) for 20 weeks. Gastrointestinal disturbances were evaluated using a frequency scale for symptoms of gastroesophageal reflux disease (FSSG), Bristol stool form scale, laboratory data (hemoglobin, albumin, total cholesterol), body weight, and amount of food intake. RESULTS: After 12 weeks, FSSG scores were higher in the RWOD group compared to baseline scores; however, no significant differences were noted between the RWD and RWOD groups. We then subdivided each group based on high and low baseline scores; the RWOD high-score (≥4) subgroup showed increased FSSG after 12 weeks compared with the baseline score. In both RWD and RWOD groups, the low-score (≤3) subgroups showed no changes during the dose-escalation phase. CONCLUSION: For AD patients with higher FSSG scores at baseline, domperidone was effective in preventing rivastigmine-related gastrointestinal disturbances.

Clinically meaningful treatment responses after switching to galantamine and with addition of memantine in patients with Alzheimer's disease receiving donepezil.

Clinical trials have shown the benefits of acetylcholinesterase inhibitors, such as donepezil and galantamine, and an N-methyl-D-aspartate receptor antagonist, memantine, in patients with Alzheimer's disease (AD). However, little is known regarding the effects of switching from donepezil 5 mg/day to galantamine 16 or 24 mg/day, or regarding the effects of adding memantine to established therapy compared with increasing the dose of donepezil. This report discusses two studies conducted to evaluate treatment with galantamine and memantine with respect to cognitive benefits and caregiver evaluations in patients with AD receiving donepezil 5 mg/day for more than 6 months. Patients with mild or moderate AD (scores 10-22 on the Mini-Mental State Examination) were enrolled in the Galantamine Switch study and switched to galantamine (maximum doses 16 mg versus 24 mg). Patients with moderate to severe AD (Mini-Mental State Examination scores 3-14) were enrolled in the Donepezil Increase versus Additional Memantine study and either had their donepezil dose increased to 10 mg/day or memantine 20 mg/day added to their existing donepezil dose. Patients received the study treatment for 28 weeks and their Disability Assessment for Dementia, Mental Function Impairment Scale, Cohen-Mansfield Agitation Inventory, and Neuropsychiatric Inventory scores were assessed with assistance from their caregivers. For the Galantamine Switch study after 8 weeks, agitation evaluated by the Cohen-Mansfield Agitation Inventory improved in both the 16 mg and 24 mg groups compared with baseline. However, there were no significant differences between the two galantamine groups. Agitation was also less in patients in the additional memantine group than in the donepezil increase group. In summary, switching to galantamine from donepezil and addition of memantine in patients with AD receiving donepezil were both safe and meaningful treatment options, and particularly efficacious for suppression of agitation.

Sudden deafness and facial diplegia in Guillain-Barré Syndrome: radiological depiction of facial and acoustic nerve lesions.

We herein report a 26-year-old man with Guillain-Barré Syndrome (GBS) coexisting facial nerve palsy (FP) and deafness. He developed deafness, facial weakness, and limb weakness and numbness. Neurological examination showed facial diplegia, bilateral hypoacusia, areflexia and sensorimotor deficits in the distal limbs. The nerve conduction study findings supported the diagnosis of the demyelinating polyneuropathy. An audiogram revealed sensorineural hearing loss of 40-50 dB. Auditory brainstem responses disclosed no elicitation of waves I to IV on both sides. Magnetic resonance imaging depicted abnormal enhancement in bilateral facial and acoustic nerves. Physicians should pay more attention to auditory dysfunction in GBS patients with FP.

Olfactory dysfunction in Parkinson's disease: Benefits of quantitative odorant examination.

Olfactory involvement is well recognized in patients with Parkinson's disease (PD). The purpose of this study was to examine smell function quantitatively, using different types and concentrations of odorants in PD patients. We aimed to elucidate whether a specific odor can affect the severity and duration of PD patients. A total of 89 nondemented PD patients and 20 age-matched controls participated in the study. Quantitative evaluation of smell function was performed using the T and T olfactometer test. This test contains five kinds of odorants at different concentrations. Recognition threshold (RT) scores for all five odorants and for each individual odorant were measured in five groups of PD patients with Hoehn and Yale (HY) stages I (n = 12), II (n = 24), III (n = 43), and IV (n = 10), as well as in control subjects (n = 20). One-way analysis of variance and Ryan's method were used for statistical comparison between the five groups. Compared with controls and HY I patients, total RT scores were significantly higher in HY II, III, and IV patients. There were no statistically significant differences in RT scores between HY I patients and controls. However, total RT scores for three HY I patients (25%) were higher than the mean + two standard deviations of controls. On single odorant testing, significant higher RT scores for methylcyclopentenolone and skatol were found in HY II, III, and IV patients, in comparison with controls and HY I patients. The remaining three odorants did not differ statistically between PD patients and control subjects. The present study indicated that hyposmia in PD patients increased from HY II onwards. A single odorant of methyl cyclopentenolone or skatol had benefits for olfactory evaluation in PD patients. Our data also clarified that olfactory deficits occurred in a subset of HY I patients. Further prospective study is needed to elucidate whether a distinct profile of PD exists between HY I patients with and without hyposmia.

A case of gliomatosis cerebri mimicking limbic encephalitis: malignant transformation to glioblastoma.

Gliomatosis cerebri (GC) is a specific entity defined as diffuse infiltration of neoplastic glial cells into at least three cerebral lobes and preservation of the surrounding neuronal architecture. We report a patient with secondary GC that mimicked clinicoradiological features of limbic encephalitis (LE). A 72-year-old man had developed headache and disorientation insidiously 2 weeks previously. On admission, neurological examination showed confusion and hyperreflexia in the right extremities. Brain magnetic resonance imaging (MRI) revealed T2-hyperintensity in bilateral frontal, the left parietal, the left temporal lobes and bilateral posterior periventricular zones. Slight enhancement existed in the left lower temporal region. Cerebral angiography exhibited no tumor stains. Repeated cerebrospinal fluid studies showed mild pleocytosis and cytology of class I. There were no infectious pathogenic agents. His neurological symptoms were ameliorated at 7 days after treatment with dexamethasone and glycerol. Follow-up MRI showed no pathognomonic changes. Mild memory dysfunction remained. He was diagnosed as LE of unknown cause. Three months later he became disorientated. Brain CT revealed a hemorrhagic mass with surrounding edema in the left temporal, frontal and parietal lobes. MRI displayed marked enhancement in these regions. Urgent neurosurgery was performed and glioblastoma multiforme (GM) was confirmed pathologically. The early clinicoradiological course of this patient suggested similarities to LE. At 3 months after clinical onset, the neuroradiological features reflected rapid transformation from secondary GC to massive GM. Thus, it is important to pay more attention to the differential diagnoses of GC and LE in patients who have memory deficits and widespread MRI lesions.