Total Synthesis of the Sesquiterpene (-)-Merrillianin.

The first total synthesis of (-)-merrillianin (1), which is a natural sesquiterpene with a tricyclic structure having a cyclopentane ring and five- and seven-membered lactone parts, is demonstrated. This asymmetric total synthesis enabled the absolute stereostructure determination of naturally occurring (-)-1.

Utility of the tibial nerve somatosensory evoked potentials in differentiating between neuromyelitis optica spectrum disorders and multiple sclerosis.

BACKGROUND: Somatosensory evoked potentials (SEPs) are widely used for the diagnosis and evaluation of neuromyelitis optica spectrum disorder (NMOSD) and multiple sclerosis (MS). However, whether the parameters of tibial nerve SEPs can help to distinguish NMOSD from MS remains unclear. Thus, the aim of this study was to investigate the utility of tibial nerve SEP parameters in differentiating patients with NMOSD and MS. METHODS: The clinical data of patients with NMOSD or MS treated in our institution between 2005 and 2021 were retrospectively extracted from our electronic database. Additional inclusion criteria were presentation with sensory symptoms in the lower extremities with corresponding lesions in the magnetic resonance images as well as available data on anti-aquaporin-4 antibodies and tibial nerve SEPs. The Z-scores of the N21-P38 interval (central sensory conduction time), P38 latency, and P38 amplitude were compared between the patients with NMOSD and MS. The relationship of disease severity with the parameters of the tibial nerve SEPs was also evaluated. RESULTS: Twenty patients with NMOSD and 13 patients with MS were enrolled. The Z-scores of the N21-P38 interval and P38 latency were significantly higher in the MS group than in the NMOSD group (p < 0.05 and p < 0.01, respectively), whereas there was no difference in the Z-scores of the P38 amplitude between the two groups. In the MS group, only the N21-P38 interval and P38 latency were significantly correlated with disease severity (p < 0.05 and p < 0.01, respectively). In contrast, none of the tibial nerve SEP parameters were significantly correlated with disease severity in the NMOSD group. CONCLUSION: Evaluation of the N21-P38 interval and P38 latency in tibial nerve SEPs potentially helps in differentiating between NMOSD and MS.

A Case of Mumps Presenting With Unilateral Submandibular Sialadenitis and Laryngeal Edema.

Mumps is a viral infection that primarily affects the parotid glands. Here, we report an atypical case of mumps presenting with unilateral submandibular sialadenitis and laryngeal edema. A 20-year-old woman with unremarkable medical history was referred to our hospital for the management of left submandibular sialadenitis. Laryngeal endoscopy revealed laryngeal edema. Contrast-enhanced computed tomography of the neck revealed swelling of the left submandibular gland with surrounding fluid density and increased density of the cervical subcutaneous adipose tissue. A few days later, both anti-mumps immunoglobulin M (IgM) and IgG antibodies were positive, and she was diagnosed with mumps. To date, there have been no reports of unilateral submandibular gland mumps complicated by laryngeal edema. It is important to keep in mind that the involvement of the submandibular gland in cases of mumps is probably a risk factor for laryngeal edema.

Appropriate window width for the "clustering index method" in the tibialis anterior muscle.

We previously reported a new quantitative analysis of single-channel surface electromyography (EMG), the "clustering index method" (CI method), in the tibialis anterior muscle, which achieved sufficiently good sensitivity to detect neurogenic or myogenic abnormalities. The window width is a fundamental parameter of the CI method, and was arbitrarily set at 15 ms in that study. In this study, we searched for the most appropriate window width using expanded patient data. The data from our previous study were reanalyzed, and new patients were enrolled. Window width in the CI method was changed from 5 to 27.5 ms with a step of 2.5 ms. For each window width, Z-score values of individual subjects were calculated and the diagnostic yield was investigated. We enrolled 67 controls, 29 subjects with neurogenic disorders, and 39 with myogenic disorders. When the window width was set at 22.5 ms, the highest sensitivity was achieved both for neurogenic (97%) and myogenic (72%) disorders, with a specificity of 97%. Seven of 10 patients with inclusion body myositis were also abnormal. Reliable results were obtained by collecting 15 epochs per subject. There are two conflicting effects that appear to be best balanced at a window width of 22.5 ms: a wider width decreases the chance that a motor unit potential (MUP) is divided into two adjacent windows, and a narrower width reduces the possibility that an MUP firing at a low-frequency is counted twice by the differential sequences. CI is promising as a non-invasive method to diagnose neuromuscular disorders.

Updated size index valid for both neurogenic and myogenic changes.

BACKGROUND: Size index (SI) is a motor unit potential (MUP) parameter in concentric needle electromyography calculated from amplitude and area/amplitude, which can sensitively discriminate between control and neurogenic MUPs. In this study, we investigated the application of SI to myogenic MUPs based on expanded data. METHODS: MUPs were collected from the biceps brachii (BB) and tibialis anterior (TA) muscles. Muscles showing unequivocal neurogenic or myogenic changes by visual inspection were selected for patients. In addition to the original SI, a revised SI (rSI) was defined using the logarithmic scale for area/amplitude. The coefficient for area/amplitude was varied and that achieving the best sensitivity both for BB and TA was selected. RESULTS: Analyzed were 1619, 340, and 498 MUPs from the BB of 26, 10, and 14 subjects (control, neurogenic, and myogenic), respectively, and 1245, 536, and 473 MUPs from the TA of 23, 18, and 13 subjects (control, neurogenic, and myogenic), respectively. For neurogenic MUPs, the original SI and the newly defined rSIn were similarly sensitive (82.1% and 81.8% sensitivity for SI and rSIn, respectively, for BB, and 68.1% and 69.6% for TA), and were more sensitive than area (72.6% for BB and 57.6% for TA), the most sensitive parameter among conventional ones. For myogenic MUPs, the sensitivity of rSIm was 9.0% for BB and 24.5% for TA, which was not significantly different from duration (7.4% for BB and 21.8% for TA), the most sensitive parameter among conventional ones. CONCLUSIONS: SI, rSIn, and rSIm are promising as new MUP parameters.

Polypharmacy Associated with Cognitive Decline in Newly Diagnosed Parkinson's Disease: A Cross-Sectional Study.

AIMS: Polypharmacy is well known to affect cognitive function in community-dwelling older adults. However, the effect of polypharmacy on cognitive function in patients with newly diagnosed Parkinson's disease remains unknown. Here, we evaluated the association between polypharmacy and cognitive function in patients with newly diagnosed Parkinson's disease. METHODS: This cross-sectional study enrolled 131 consecutive hospitalized patients with newly diagnosed Parkinson's disease. Cognitive function was evaluated with the Mini-Mental State Examination and analyzed between groups of patients with or without polypharmacy. Comparisons were adjusted for confounders by performing inverse probability weighting with propensity scores. RESULTS: After inverse probability weighting, patients in the polypharmacy group had a significantly lower Mini-Mental State Examination score than patients in the nonpolypharmacy group (26.2 vs. 27.7, p = 0.001). CONCLUSION: Polypharmacy was associated with cognitive decline in patients with newly diagnosed Parkinson's disease. This finding suggests that medication reduction might serve as a promising intervention to prevent the development of dementia in patients with early Parkinson's disease. Further prospective studies are needed to determine whether medication reduction improves cognitive function in patients with newly diagnosed Parkinson's disease.

A Sporadic Case of Charcot-Marie-Tooth Disease Type 2 with Left Vocal Fold Palsy due to Mitofusin 2 Mutation.

A 33-year-old Japanese woman was referred for hoarseness. She had been diagnosed with Charcot-Marie-Tooth disease at age 3 and bilateral optic atrophy at age 15. Laryngoscopy revealed left vocal fold palsy. These findings suggested Charcot-Marie-Tooth disease type 2; the diagnosis was confirmed by a mitofusin 2 mutation analysis. Her symptoms remained stable for almost 10 years. Although vocal fold palsy and optic atrophy have been previously reported in patients with mitofusin 2 mutations, detailed clinical information and clinical course have never been documented. These data might contribute to the elucidation of the pathological conditions associated with mitofusin 2 mutations.

Injection of Onabotulinum Toxin A into the Bilateral External Oblique Muscle Attenuated Camptocormia: A Prospective Open-Label Study in Six Patients with Parkinson's Disease.

INTRODUCTION: Camptocormia (severe bending of the spine) is a debilitating complication of Parkinson's disease (PD) without established treatment. Botulinum toxin (BT) may be beneficial, but data is scarce regarding the efficacy of administration of BT into the bilateral external oblique (EO) muscle for treatment of camptocormia in PD. METHODS: Six patients with PD and camptocormia, with flexion of the thoracic spine, were enrolled in the study. BT (75 or 90 units, onabotulinum toxin A) were injected into each EO bilaterally under sonographic guidance. Camptocormia angle (CA) was defined as the angle between the acromion-greater trochanter line and a vertical line. CA and disabling symptoms were evaluated during the treatment course. RESULTS: Two weeks after the injection of BT, the mean CA showed significant attenuation [median (interquartile range); 38° (23.5°) vs. 18° (21°), p = 0.028]. Subjective relief was present in cases 1-3 and 6, and absent in cases 4 and 5. Cases 1-3 received repeated injections to maintain the amelioration; in cases 1 and 2, this was for 1 year or longer, while falls of case 3 limited the amelioration. CONCLUSION: Botulinum therapy into bilateral EO attenuated the angle of thoracic-level camptocormia in six patients with PD over the observation period of 2 weeks. The reproducibility of the results, long-term efficacy, and subjective relief of symptoms require further examination.

Atypical parkinsonism caused by Pro105Leu mutation of prion protein: A broad clinical spectrum.

OBJECTIVE: To delineate molecular and clinical characteristics of 3 families with PRNP P105L mutation, a variant of Gerstmann-Sträussler-Scheinker syndrome whose main motor symptoms were parkinsonism and/or involuntary movements. METHODS: The causative mutation was first determined in the affected patients of family 1 using whole-exome sequencing, and then mutational analysis was extended to families 2 and 3. The clinical features of the patients of these 3 families were summarized. Haplotype analysis was performed using high-density single nucleotide polymorphism array. RESULTS: The whole-exome sequencing revealed that the heterozygous mutation c.314C>T (p.P105L) in PRNP was the only known pathogenic mutation shared by the 3 patients of the family with autosomal dominant parkinsonism. We further identified the same mutation in patients of the other 2 families with autosomal dominant parkinsonism and/or involuntary movements. The clinical features of our patients with PRNP P105L mutation included various motor symptoms such as parkinsonism and involuntary movements in addition to progressive dementia. The clinical features in part overlapped with those of other forms of inherited prion diseases, such as fatal familial insomnia and Huntington disease-like type 1. The patients with PRNP P105L mutation shared a haplotype spanning 7.1 Mb around PRNP, raising the possibility that the mutations in the patients originated from a common founder. CONCLUSION: Most of the patients presented with parkinsonism in addition to progressive dementia. Although spastic paraparesis has been emphasized as the main clinical feature, the clinical spectrum of patients with PRNP P105L is broader than expected.

3'-functionalized adamantyl cannabinoid receptor probes.

The aliphatic side chain plays a pivotal role in determining the cannabinergic potency of tricyclic classical cannabinoids, and we have previously shown that this chain could be substituted successfully by adamantyl or other polycyclic groups. In an effort to explore the pharmacophoric features of these conformationally fixed groups, we have synthesized a series of analogues in which the C3 position is substituted directly with an adamantyl group bearing functionality at one of the tertiary carbon atoms. These substituents included the electrophilic isothiocyanate and photoactivatable azido groups, both of which are capable of covalent attachment with the target protein. Our results show that substitution at the 3'-adamantyl position can lead to ligands with improved affinities and CB1/CB2 selectivities. Our work has also led to the development of two successful covalent probes with high affinities for both cannabinoid receptors, namely, the electrophilic isothiocyanate AM994 and the photoactivatable aliphatic azido AM993 analogues.

[A 53-year-old man with herpes encephalitis showing acceleration of improvement in higher brain function after general anesthesia with sevoflurane: a case report].

We experienced a right-handed 53-year-old man who presented with disturbance of consciousness and fever. Herpes simplex encephalitis (HSE) was diagnosed based on the detection of herpes simplex virus DNA in the cerebrospinal fluid. The administration of acyclovir for 42 days improved his consciousness level. Drowsiness, fever and seizures reappeared 20 days after stopping acyclovir treatment (day 67) and he responded well to vidarabine and methylprednisolone pulse therapy. An assessment of aphasia on day 98 revealed transcortical sensory aphasia. Brain MRI showed lesion in the left temporal lobe, bilateral insular cortexes and bilateral frontal lobe. His higher brain dysfunction continued. On day 156, he underwent hip replacement arthroplasty under general anesthesia sevoflurane. His higher brain dysfunction rapidly improved thereafter. We concluded that the accelerated improvement in our patient's higher brain function was related to the protective effect of sevoflurane. Some reports also show the protective effects of sevoflurane in experimental allergic encephalomyelitis by inhibition of T cell activation. These protective and anti-inflammatory effects may explain the accelerated improvement in higher brain function after general anesthesia.

A new maneuver for repetitive nerve stimulation testing in the trapezius muscle.

INTRODUCTION: The repetitive nerve stimulation (RNS) test in the trapezius muscle is used widely for the evaluation of myasthenia gravis. However, pseudofacilitation is often difficult to avoid in this muscle and may compromise the detection of small decremental responses. We have devised a new maneuver to reduce pseudofacilitation. METHODS: Using our maneuver, the shoulder of a supine subject is elevated passively and is held firmly by the examiner. Four conventional maneuvers as well as ours were compared with regard to pseudofacilitation that was maximal at the second wave in 14 control subjects. RESULTS: Pseudofacilitation at the second and fourth waves was the smallest using our maneuver. Up to 15% pseudofacilitation was observed using the other maneuvers. CONCLUSION: Pseudofacilitation in the trapezius muscle is mainly due to shortening of the muscle belly. It can be reduced greatly by shortening the muscle in advance.

An antibody to the GM1/GalNAc-GD1a complex correlates with development of pure motor Guillain-Barré syndrome with reversible conduction failure.

Antibodies to a ganglioside complex consisting of GM1 and GalNAc-GD1a (GM1/GalNAc-GD1a) are found in sera from patients with Guillain-Barré syndrome (GBS). To elucidate the clinical significance of anti-GM1/GalNAc-GD1a antibodies in GBS, clinical features of 58 GBS patients with IgG anti-GM1/GalNAc-GD1a antibodies confirmed by enzyme-linked immunosorbent assay and thin layer chromatography immunostaining were analyzed. Compared to GBS patients without anti-GM1/GalNAc-GD1a antibodies, anti-GM1/GalNAc-GD1a-positive patients more frequently had a preceding respiratory infection (n=38, 66%, p<0.01) and were characterized by infrequency of cranial nerve deficits (n=9, 16%, p<0.01) and sensory disturbances (n=26, 45%, p<0.01). Of the 28 anti-GM1/GalNAc-GD1a-positive patients for whom electrophysiological data were available, 14 had conduction blocks (CBs) at intermediate segments of motor nerves, which were not followed by evident remyelination. Eight of 10 bedridden cases were able to walk independently within one month after the nadir. These results show that the presence of anti-GM1/GalNAc-GD1a antibodies correlated with pure motor GBS characterized by antecedent respiratory infection, fewer cranial nerve deficits, and CBs at intermediate sites of motor nerves. The CB may be generated through alteration of the regulatory function of sodium channels in the nodal axolemma.

[Case of pure motor Guillain-Barré syndrome with motor conduction block and anti-GM1/GalNAc-GD1a antibody].

A 38-year-old man presented with distal-dominant limb weakness two weeks after an upper respiratory infection. He had no sensory and autonomic signs and no cranial nerve involvement during the course of the disease. Tendon reflexes were preserved except for an absent Achilles' tendon reflex. His disability at nadir was grade 2 on the Hughes functional scale. Cerebrospinal fluid analysis showed albuminocytologic dissociation and he was diagnosed with pure motor Guillain-Barré syndrome (GBS). Thin-layer chromatography immunostaining and an enzyme-linked immunosorbent assay revealed an immunoglobulin G antibody to the ganglioside complex GM1/GalNAc-GD1a in his acute phase serum. A serial nerve conduction study revealed conduction block in the median and ulnar nerve trunks and temporal dispersion in the tibial nerve, without an evident remyelination pattern during the course of the disease. A sensory nerve conduction study was normal. According to Hadden's criteria, the electrodiagnostic findings were judged as a primary demyelinating pattern. Weakness and abnormal motor nerve conduction recovered rapidly after intravenous immunoglobulin therapy. In view of the localization of GM1 and GalNAc-GD1a on the axolemma of the motor nerves, the clinical course and electrophysiological features may have resulted from functional conduction failure at the nodes of Ranvier of the motor nerves, rather than primary demyelination or axonal degeneration. The illness resembled acute motor conduction block neuropathy characterized by preserved sensory function, an early conduction block at intermediate nerve segments, and good recovery. GM1 and GalNAc-GD1a may form a complex in the axolemma at the nodes of Ranvier or paranodes of the motor nerves, and may be a target antigen in pure motor GBS; especially in the form with acute motor conduction block neuropathy. The present case is the first description of a GBS patient with an IgG anti-GM1/GalNAc-GD1a antibody.

Isolation and identification of dibutyl phthalate-degrading bacteria from hydrospheres in Tokyo.

Dibutyl phthalate (DBP) is used widely as a plasticizer and is thought to negatively affect various organisms. To isolate and investigate DBP-degrading bacteria from hydrospheres in Tokyo, strains were selected on YNB medium containing DBP as the sole carbon source, and candidate strains were identified by zones of clearing around the colonies. Degradation of DBP by the strains was subsequently measured with HPLC, and bacterial identification was accomplished using 16S rDNA sequences. Nineteen strains of DBP degraders were isolated from activated sludge in a sewage treatment plant, from Tokyo Bay, and from the Takahama Canal. These strains degraded 16.8%-88.0% of DBP (0.1%, v/v) for 2 weeks and were identified as several species of Acinetobacter, as well as Tsukamurella tyrosinosolvens, Ochrobactrum anthropi, and Staphylococcus saprophyticus. Commercially available strains of Acinetobacter were also found to degrade DBP.

Antibodies to ganglioside complexes consisting of asialo-GM1 and GQ1b or GT1a in Fisher and Guillain-Barré syndromes.

To determine the epitopes of ganglioside complexes (GSCs) containing GQ1b or GT1a, we investigated their reactivity to GSCs consisting of asialo-GM1 (GA1) and GQ1b or GT1a using IgG anti-GQ1b- or anti-GT1a-positive sera. Nine anti-GQ1b-positive sera had higher activity to GA1/GQ1b than to GQ1b, only five of which reacted with GM1/GQ1b and GD1b/GQ1b. Five of 14 sera positive for GA1/GT1a and GM1/GT1a were negative for GA1/GQ1b and GM1/GQ1b. Sialic acids attached to the internal galactose of gangliotetraose can influence the reactivity of anti-GSC antibodies. Screening for antibodies to GSCs containing GA1 is useful for elucidation of the antibody-mediated pathophysiology.

Clinical features of opticospinal multiple sclerosis with anti-aquaporin 4 antibody.

BACKGROUND: We have followed 9 Japanese patients with opticospinal multiple sclerosis (OSMS), some of whom showed longitudinally extensive spinal cord lesions, deep sensory disturbances and resistance to treatment. We investigated the patients for anti-aquaporin 4 (AQP4) antibodies and related this to their neuroimaging, clinical and laboratory features. METHODS: We studied the clinical course, neurological findings, cerebrospinal fluid (CSF), and electrophysiological findings, and determined the presence of anti-AQP4 antibody and human leukocyte antigen DPB1 and DRB1 alleles. RESULTS: Five patients (56.6%) had anti-AQP4 antibody. Antibody-positive patients displayed female predominance, longitudinally extensive spinal cord lesions, higher frequency of exacerbations, severe disability, and higher cell counts and total protein content without IgG oligoclonal bands in the CSF. They also showed poor steroid responsiveness and poor therapeutic response to interferon beta(1b). CONCLUSIONS: The presence of anti-AQP4 antibodies correlates with clinical severity and poor prognosis in OSMS.