A comprehensive multivariate analysis of the center of pressure during quiet standing in patients with Parkinson's disease.

BACKGROUND: We hypothesized that postural instability observed in individuals with Parkinson's disease (PD) can be classified as distinct subtypes based on comprehensive analyses of various evaluated parameters obtained from time-series of center of pressure (CoP) data during quiet standing. The aim of this study was to characterize the postural control patterns in PD patients by performing an exploratory factor analysis and subsequent cluster analysis using CoP time-series data during quiet standing. METHODS: 127 PD patients, 47 aged 65 years or older healthy older adults, and 71 healthy young adults participated in this study. Subjects maintain quiet standing for 30 s on a force platform and 23 variables were calculated from the measured CoP time-series data. Exploratory factor analysis and cluster analysis with a Gaussian mixture model using factors were performed on each variable to classify subgroups based on differences in characteristics of postural instability in PD. RESULTS: The factor analysis identified five factors (magnitude of sway, medio-lateral frequency, anterio-posterior frequency, component of high frequency, and closed-loop control). Based on the five extracted factors, six distinct subtypes were identified, which can be considered as subtypes of distinct manifestations of postural disorders in PD patients. Factor loading scores for the clinical classifications (younger, older, and PD severity) overlapped, but the cluster classification scores were clearly separated. CONCLUSIONS: The cluster categorization clearly identifies symptom-dependent differences in the characteristics of the CoP, suggesting that the detected clusters can be regarded as subtypes of distinct manifestations of postural disorders in patients with PD.

Switching from zonisamide to perampanel improved the frequency of seizures caused by hyperthermia in Dravet syndrome: a case report.

BACKGROUND: Dravet syndrome is a severe epilepsy disorder characterized by drug-resistant seizures and cognitive dysfunction, often caused by SCN1A gene mutations. It leads to neurodevelopmental delays and motor, behavioral, and cognitive impairments, with a high mortality rate. Treatment options include sodium valproate, clobazam, and newer agents such as cannabidiol and fenfluramine. Zonisamide, which is used in some cases, can cause hyperthermia and oligohydrosis. Herein, we present a case of a patient with Dravet syndrome whose seizures were controlled by treating infections and switching from zonisamide to perampanel. CASE PRESENTATION: A 24-year-old Japanese man with Dravet syndrome presented to our department with aspiration pneumonia. The patient had been treated with valproate, sodium bromide, and zonisamide for a long time. His seizures were triggered by hyperthermia. The patient was experiencing a sustained pattern of hyperthermia caused by infection, zonisamide, and persistent convulsions, which caused a vicious cycle of further seizures. In this case, the control of infection and switching from zonisamide to perampanel improved seizure frequency. CONCLUSION: Dravet syndrome usually begins with generalized clonic seizures in its infancy because of fever and progresses to various seizure types, often triggered by fever or seizure-induced heat due to mutations in the SCN1A gene that increases neuronal excitability. Seizures usually diminish with age, but the heat sensitivity remains. In this case, seizures were increased by repeated infections, and hyperthermia was induced by zonisamide, resulting in status epilepticus. Perampanel, an aminomethylphosphonic acid receptor antagonist, decreased seizures but caused psychiatric symptoms. It was effective in suppressing seizures of Dravet syndrome in this patient.

Unveiling the Impact of Outpatient Physiotherapy on Specific Motor Symptoms in Parkinson's Disease: A Prospective Cohort Study.

Understanding how outpatient physiotherapy impacts on specific motor symptoms in Parkinson's disease (PD) is important for multidisciplinary care, but these points have not been clarified. We investigated the impact of outpatient physiotherapy on individual motor symptoms in PD patients. Fifty-five PD patients participated in the prospective cohort study, which examined the changes in motor symptoms after 90 min of outpatient physiotherapy program (1×/week for 10 weeks) and at 3 months follow-up. Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) motor score and tremor, rigidity, bradykinesia, and axial scores were assessed and compared pre-intervention, post-intervention, and at follow-up. Significant level was set at 0.05. Their MDS-UPDRS motor score and axial score significantly decreased post-intervention and at the follow-up. In the analysis differentiating effects based on the severity of motor symptoms according to the MDS-UPDRS motor score, only the moderate-severe group showed significant decreases in their MDS-UPDRS motor score, bradykinesia, and axial scores post-intervention, as well as in their MDS-UPDRS motor score, rigidity, bradykinesia, and axial scores at the follow-up. These findings suggest the outpatient physiotherapy might provide benefits, particularly in managing axial symptoms and bradykinesia, for community dwelling PD patients with moderate-severe motor symptoms within a multidisciplinary care framework.

Frailty-Preventing Effect of an Intervention Program Using a Novel Complete Nutritional "COMB-FP Meal": A Pilot Randomized Control Trial.

Frailty is a huge concern for the aging population, and dietary nutrition is considered a key factor in the prevention of aging. To solve the problem of frailty in the aging population, we developed a novel dietary intervention program using a novel COMpletely Balanced for Frailty Prevention (COMB-FP) meal, based on the Dietary Reference Intake for Japanese; in addition, we conducted a pilot randomized control trial comparing an exercise program only (control group) with exercise plus the COMB-FP meal program (test group). We included 110 male and female healthy volunteers with pre-frailty or frailty; the trial lasted for 12 weeks. Two daily meals were replaced with the COMB-FP meals during the trial in the test group. Walking speed and cognitive function were significantly improved in the test group compared with the control group. We observed a similar pattern in other frailty-related outcomes, such as occupancy of the microbiome, World Health Organization well-being index (WHO-5), and oxidative stress. Our study might indicate the importance of a well-balanced intake of nutrients for frailty prevention.

Rituximab Was Effective in Relieving Symptoms of Isaacs Syndrome: A Case Report.

We presented a 23-year-old patient who had experienced neuromyotonia in his left leg. Although he tested negative for anti-LGI1 and anti-CASPR2 antibodies, we diagnosed him with Isaacs syndrome due to myokymic discharges on electromyography and symptoms being relieved by intravenous methylprednisolone (IVMP) and intravenous immunoglobulin (IVIg). IVMP, IVIg, plasma exchange, or cyclosporine treatment did not provide a long-term response; however, rituximab showed long-term improvement. Rituximab should be considered early in the treatment of patients with antibody-negative Isaacs syndrome who are responsive to immunotherapy, including IVMP, IVIg, and plasma exchange, and have long-term symptoms that are hard to control.

Clinical features of anti-mitochondrial M2 antibody-positive myositis: case series of 17 patients.

OBJECTIVE: In 2012, a large number of myositis cases with anti-mitochondrial M2 (AMA-M2) antibody, which had well been known as the serological hallmark for primary biliary cholangitis (PBC), were reported in Japan. Recently, some case series from Japan, France, America, China and India have shown that approximately 2.5% to 19.5% of patients with myositis have AMA-M2 antibody. The objective of this study was to clarify the prevalence, clinical features, treatment outcome, and severity determinants of AMA-M2 positive myositis. METHODS: This study was a multicenter observational study. We enrolled patients who were diagnosed with myositis during a ten-year period between 2012 and 2021. RESULTS: Of the total of 185 patients with inflammatory myopathy, 17 patients were positive for AMA-M2 antibody. The typical symptoms were weakness mainly involving paravertebral muscles, weight loss, respiratory failure, and cardiac complications. Thirteen of the 17 patients had cardiac complications. A strong correlation was found between respiratory failure and modified Rankin Scale (mRS) score. A strong correlation was also found between respiratory failure and body weight, indicating that weight loss can be an indicator of potential progression of respiratory failure. Six of the 17 patients were complicated by malignancy. CONCLUSIONS: This study showed significant correlations between % vital capacity (VC), body mass index (BMI), and mRS score in patients with AMA-M2-positive myositis. Immunotherapy often improved CK level and respiratory dysfunction. We therefore propose that %VC and BMI should be monitored as disease indicators in treatment of AMA-M2-positive myositis.

Unique Electrical Signature of Phosphate for Specific Single-Molecule Detection of Peptide Phosphorylation.

Single-molecule measurements of biomaterials bring novel insights into cellular events. For almost all of these events, post-translational modifications (PTMs), which alter the properties of proteins through their chemical modifications, constitute essential regulatory mechanisms. However, suitable single-molecule methodology to study PTMs is very limited. Here we show single-molecule detection of peptide phosphorylation, an archetypal PTM, based on electrical measurements. We found that the phosphate group stably bridges a nanogap between metal electrodes and exhibited high electrical conductance, which enables specific single-molecule detection of peptide phosphorylation. The present methodology paves the way to single-molecule studies of PTMs, such as single-molecule kinetics for enzymatic modification of proteins as shown here.

Pembrolizumab-induced Myasthenia Gravis Relapse after Immunosuppressive Therapy.

Myasthenia gravis (MG) is an immune-related adverse event (irAE), and as an irAE, MG (irAE-MG) generally has a monophasic course, with only a few case reports of irAE-MG flare-ups during the course of the disease. We herein report a case of pembrolizumab-induced MG with relapsing symptoms. irAE-MG is a rare disease that has not yet been fully characterized, and our case shows that MG symptoms may relapse. Therefore, regular follow-up is necessary, even after the symptoms improve with immunosuppressive therapy.

Structural Asymmetry of Metallic Single-Atom Contacts Detected by Current-Voltage Characteristics.

The complex behavior of the simplest atomic-scale conductors indicates that the electrode structure itself is significant in the design of future nanoscale devices. In this study, the structural asymmetry of metallic atomic contacts formed between two macroscopic Au electrodes at room temperature was investigated. Characteristic signatures of the structural asymmetries were detected by fast current-voltage (I-V) measurements with a time resolution of approximately 100 µs. Statistical analysis of more than 300,000 I-V curves obtained from more than 1000 contact-stretching processes demonstrates that the current rectification properties are correlated with the conductance of the nanocontacts. A substantial suppression of the variation in current rectification was observed for the atomic contacts with integer multiples of the conductance quantum. Statistical analysis of the time-resolved I-V curves revealed that the current rectification variations increased significantly from 500 µs onward before the breakage of the atomic contacts. Ab initio atomistic simulations of the stretching processes and corresponding I-V characteristics confirmed the magnitude of the rectification and related it to the structural asymmetries in the breakdown process of the junctions. Overall, we provide a better understanding of the interplay between geometric and electronic structures at atomically defined metal-metal interfaces by probing charge transport properties in extremely sensitive nanocontacts.

Visualization of Thermal Transport Properties of Self-Assembled Monolayers on Au(111) by Contact and Noncontact Scanning Thermal Microscopy.

Thermal transport properties of patterned binary self-assembled monolayers (SAMs) on Au(111) were examined using scanning thermal microscopy (SThM) with both contact and noncontact methods. We fabricated two-dimensional (2D) patterns with two separate domains of n-hexadecanethiol/benzenethiol, benzenethiol/n-butanethiol, or n-hexadecanethiol/n-butanethiol. In the experimental setup, the efficiency of thermal transport from a SThM tip to the SAM surface can be evaluated in terms of the temperature change at the SThM tip. In the contact regime, where a SThM tip physically contacts the SAM surface, direct thermal transport through the SAM and radiation-based thermal transport through the space where SAMs exist may contribute to a drop in temperature at the tip. In the noncontact regime, thermal transport relies on radiation-based heat dissipation from the heated tip to the SAMs. 2D mapping of the spatial temperature distribution on SAMs reflects the difference in thermal transport properties of the two SAM domains. We found that the contact method is effective for visualizing the temperature contrast, which reflects the thermal transport properties of the constituent molecules when the domains of the SAMs have a similar height, while the noncontact method allows visualization of the temperature distribution, which is related to the height of each domain of the SAMs, rather than the chemical structures of the constituent molecules. Combination of contact and noncontact SThM enables 2D imaging of thermal transport properties and topographic imaging simultaneously and represents a new technique for investigating the thermal properties of materials surfaces, which is essential for nanoscale thermal management.

Single-molecule junction spontaneously restored by DNA zipper.

The electrical properties of DNA have been extensively investigated within the field of molecular electronics. Previous studies on this topic primarily focused on the transport phenomena in the static structure at thermodynamic equilibria. Consequently, the properties of higher-order structures of DNA and their structural changes associated with the design of single-molecule electronic devices have not been fully studied so far. This stems from the limitation that only extremely short DNA is available for electrical measurements, since the single-molecule conductance decreases sharply with the increase in the molecular length. Here, we report a DNA zipper configuration to form a single-molecule junction. The duplex is accommodated in a nanogap between metal electrodes in a configuration where the duplex is perpendicular to the nanogap axis. Electrical measurements reveal that the single-molecule junction of the 90-mer DNA zipper exhibits high conductance due to the delocalized π system. Moreover, we find an attractive self-restoring capability that the single-molecule junction can be repeatedly formed without full structural breakdown even after electrical failure. The DNA zipping strategy presented here provides a basis for novel designs of single-molecule junctions.

Control of dominant conduction orbitals by peripheral substituents in paddle-wheel diruthenium alkynyl molecular junctions.

Control of charge carriers that transport through the molecular junctions is essential for thermoelectric materials. In general, the charge carrier depends on the dominant conduction orbitals and is dominantly determined by the terminal anchor groups. The present study discloses the synthesis, physical properties in solution, and single-molecule conductance of paddle-wheel diruthenium complexes 1R having diarylformamidinato supporting ligands (DArF: p-R-C6H4-NCHN-C6H4-R-p) and two axial thioanisylethynyl conducting anchor groups, revealing unique substituent effects with respect to the conduction orbitals. The complexes 1R with a few different aryl substituents (R = OMe, H, Cl, and CF3) were fully characterized by spectroscopic and crystallographic analyses. The single-molecule conductance determined by the scanning tunneling microscope break junction (STM-BJ) technique was in the 10-5 to 10-4 G 0 region, and the order of conductance was 1OMe > 1CF3 ≫ 1H ∼ 1Cl, which was not consistent with the Hammett substituent constants σ of R. Cyclic voltammetry revealed the narrow HOMO-LUMO gaps of 1R originating from the diruthenium motif, as further supported by the DFT study. The DFT-NEGF analysis of this unique result revealed that the dominant conductance routes changed from HOMO conductance (for 1OMe) to LUMO conductance (for 1CF3). The drastic change in the conductance properties originates from the intrinsic narrow HOMO-LUMO gaps.

Inflammatory Myopathy Associated with Anti-mitochondrial Antibody Presenting Only with Respiratory Failure.

A 56-year-old woman presenting with type II respiratory failure was transferred to our hospital. She did not exhibit muscle weakness or elevated serum myogenic enzymes, but needle electromyography revealed myogenic changes in the limb muscles, and her blood tests were positive for anti-mitochondrial antibodies (AMA). Muscle histopathological findings included immune-mediated necrotizing myopathy, so she was diagnosed with inflammatory myopathy associated with AMA. After treatment with corticosteroids and noninvasive positive pressure ventilation, her symptoms improved. If a diagnosis of type II respiratory failure is difficult, inflammatory myopathy associated with AMA should be considered as a differential diagnosis.

Water Splitting Induced by Visible Light at a Copper-Based Single-Molecule Junction.

Water splitting is an essential process for converting light energy into easily storable energy in the form of hydrogen. As environmentally preferable catalysts, Cu-based materials have attracted attention as water-splitting catalysts. To enhance the efficiency of water splitting, a reaction process should be developed. Single-molecule junctions (SMJs) are attractive structures for developing these reactions because the molecule electronic state is significantly modulated, and characteristic electromagnetic effects can be expected. Here, water splitting is induced at Cu-based SMJ and the produced hydrogen is characterized at a single-molecule scale by employing electron transport measurements. After visible light irradiation, the conductance states originate from Cu/hydrogen molecule/Cu junctions, while before irradiation, only Cu/water molecule/Cu junctions were observed. The vibration spectra obtained from inelastic electron tunneling spectroscopy combined with the first-principles calculations reveal that the water molecule trapped between the Cu electrodes is decomposed and that hydrogen is produced. Time-dependent and wavelength-dependent measurements show that localized-surface plasmon decomposes the water molecule in the vicinity of the junction. These findings indicate the potential ability of Cu-based materials for photocatalysis.

Single-molecule junctions of multinuclear organometallic wires: long-range carrier transport brought about by metal-metal interaction.

Here, we report multinuclear organometallic molecular wires having (2,5-diethynylthiophene)diyl-Ru(dppe)2 repeating units. Despite the molecular dimensions of 2-4 nm the multinuclear wires show high conductance (up to 10-2 to 10-3 G 0) at the single-molecule level with small attenuation factors (ß) as revealed by STM-break junction measurements. The high performance can be attributed to the efficient energy alignment between the Fermi level of the metal electrodes and the HOMO levels of the multinuclear molecular wires as revealed by DFT-NEGF calculations. Electrochemical and DFT studies reveal that the strong Ru-Ru interaction through the bridging ligands raises the HOMO levels to access the Fermi level, leading to high conductance and small ß values.

Interaction between spatial neglect and attention deficit in patients with right hemisphere damage.

Unilateral spatial neglect (USN) was originally regarded as a parietal syndrome, but it has become evident that USN is a disturbance in the widespread attention network. Here, we focused on an interaction between spatial neglect and non-spatial aspect of attention deficit, and aimed to establish a novel evaluation approach based on the characteristics of the spatial distribution of reaction times. We tested 174 patients with right hemisphere damage and divided them based on their prescreening scores on the Behavioral Inattention Test (BIT): (1) USN++ (n = 79: BIT<131), (2) USN+ (n = 47: BIT≥131 with history of USN), and (3) RHD (n = 48: without neglect symptom). The patients were asked to conduct a touch panel-based pointing task toward 2D-arranged (seven columns × five rows) circular targets on a PC monitor, and the reaction time to each object was recorded. To evaluate aspects of attention deficit and neglect symptoms, we calculated the total average of the reaction time for all objects (RTmean) and the ratios of the right and left space (L/Rratio), respectively. The results revealed that RTmean and L/Rratio can be regarded as independent evaluation parameters for attention deficit and neglect symptoms, respectively. Voxel-based lesion-symptom mapping based on RTmean and L/Rratio values revealed relevant lesions with attention-related brain areas (middle temporal gyrus, angular gyrus, and inferior frontal gyrus), and neglect-related brain areas (superior temporal gyrus and superior longitudinal fascicules). A cluster analysis with Gaussian mixture model detected six different states of USN with an interaction between neglect symptoms and attention deficit. Interestingly, the recovery process after USN can be properly explained by the transition pattern from one cluster to another. Our results suggest that a novel evaluation approach to distinguish between neglect symptoms and attention deficit, namely the characterization of the interaction between RTmean and L/Rratio, provides useful information for understanding pathological features of USN.

Single-molecule determination of chemical equilibrium of DNA intercalation by electrical conductance.

We investigated a single-molecule reaction of DNA intercalation as an example of a bimolecular association reaction. Single-molecule conductance values of the product and reactant molecules adsorbed on an Au surface were measured to identify and quantify these molecules. The binding isotherm was constructed, and the association constant of the reaction was determined on a single-molecule basis.

Pathological structure of visuospatial neglect: A comprehensive multivariate analysis of spatial and non-spatial aspects.

Visuospatial neglect (VSN) is a neurological syndrome of higher brain functions in which an individual fails to detect stimuli on a space that is contralateral to a hemispheric lesion. We performed a comprehensive multivariate analysis based on the principal component analysis (PCA) and cluster analysis in patients with right hemisphere stroke and then performed a determination of different elements of VSN. PCA-based cluster analysis detected distinct aspects of VSN as follows: cluster 1: low arousal and attention state, cluster 2: exogenous neglect, cluster 3: spatial working memory (SWM) deficit. Lesion analysis revealed neural correlates for each cluster and highlighted "disturbance of the ventral attention network" for the stagnation of exogenous attention and "parietal damage" for SWM deficit. Our results reveal a pathological structure of VSN as multiple components of an attention network deficit, and they contribute to the understanding of the mechanisms underlying VSN.

Organometallic Molecular Wires with Thioacetylene Backbones, trans-{RS-(C≡C)n }2 Ru(phosphine)4 : High Conductance through Non-Aromatic Bridging Linkers.

In this work, the design, synthesis, and single-molecule conductance of ethynyl- and butadiynyl-ruthenium molecular wires with thioether anchor groups [RS=n-C6 H13 S, p-tert-Bu-C6 H4 S), trans-{RS-(C≡C)n }2 Ru(dppe)2 (n=1 (1R ), 2 (2R ); dppe: 1,2-bis(diphenylphosphino)ethane) and trans-(n-C6 H13 S-C≡C)2 Ru{P(OMe)3 }4 3hex ] are reported. Scanning tunneling microscope break-junction study has revealed conductance of the organometallic molecular wires with the thioacetylene backbones higher than that of the related organometallic wires having arylethynylruthenium linkages with the sulfur anchor groups, trans-{p-MeS-C6 H4 -(C≡C)n }2 Ru(phosphine)4 4n (n=1, 2) and trans-(Th-C≡C)2 Ru(phosphine)4 5 (Th=3-thienyl). It should be noted that the molecular junctions constructed from the butadiynyl wire 2R , trans-{Au-RS-(C≡C)2 }2 Ru(dppe)2 (Au: gold metal electrode), show conductance comparable to that of the covalently linked polyynyl wire with the similar molecular length, trans-{Au-(C≡C)3 }2 Ru(dppe)2 63 . The DFT non-equilibrium Green's function (NEGF) study supports the highly conducting nature of the thioacetylene molecular wires through HOMO orbitals.

Single-Molecule Junction of a Cationic Rh(III) Polyyne Molecular Wire.

Single-molecule conductance studies on metal-containing inorganic and organometallic molecular wires are relatively less explored compared to those on organic molecular wires. Furthermore, conductance and transmission profiles of the metal-containing wires insensitive to the metal centers often hinder rational design for high performance wires. Here, synthesis and single-molecule conductance measurements of the bis(butadiynyl)rhodium wires with tetracarbene ligands 1H and 1Au are reported as rare examples for Rh(III) diacetylide molecular wires. The rhodium wires derived from the terminal acetylene and gold-functionalized precursors show comparable, high single-molecule conductance ((6-7) × 10-3 G0) as determined by the STM break-junction measurements, suggesting formation of virtually the same covalently linked metal electrode-molecule-metal electrode junctions. The values for the metallapolyynes are larger than those of the organic polyyne wires having the similar molecular lengths. The hybrid DFT-NEGF calculations of the model systems suggest that profiles of transmission spectra are highly sensitive to the presence and species of the metal fragments doped into the polyyne molecular wire because the conductance orbitals of the metallapolyynes molecular junctions carry significant metal fragment characters. Thus, the metallapolyyne junctions turn out to be suitable platforms for rationally designed molecular wires.