Electrogenerated Cationic Reactive Intermediates: The Pool Method and Further Advances.

Electrochemistry serves as a powerful method for generating reactive intermediates, such as organic cations. In general, there are two ways to use reactive intermediates for chemical reactions: (1) generation in the presence of a reaction partner and (2) generation in the absence of a reaction partner with accumulation in solution as a "pool" followed by reaction with a subsequently added reaction partner. The former approach is more popular because reactive intermediates are usually short-lived transient species, but the latter method is more flexible and versatile. This review focuses on the latter approach and provides a concise overview of the current methods for the generation and accumulation of cationic reactive intermediates as a pool using modern techniques of electrochemistry and their reactions with subsequently added nucleophilic reaction partners.

Modified ischaemic nerve block of the forearm: use for the induction of cortical plasticity in distal hand muscles.

KEY POINTS: Ischaemic nerve block (INB) of the forearm rapidly reduces somatosensory input to a part of the body, which leads to the functional reorganization of the temporarily deafferented primary motor cortex (M1). We applied a novel modified INB (mINB) to the forearm, maintaining mean blood pressure, to assess cortical plasticity in the primary somatosensory cortex (S1) and the M1 regions associated with small hand muscles. S1 excitability was measured by median nerve somatosensory-evoked potentials (SEPs), while M1 excitability was evaluated by motor-evoked potentials (MEPS), using transcranial magnetic stimulation. The finding that S1 excitability increased and M1 excitability decreased after the mINB was removed reflects the differential short-term cortical plasticity of the S1 and M1 regions. These opposite effects observed for the S1 and M1 regions following the mINB may indicate a possible intra-hemispheric interaction between the S1 and M1 regions. ABSTRACT: Ischaemic nerve block (INB) causes short-term sensory deprivation, leading to functional reorganization in the deafferented motor cortex (M1). We used a modified INB (mINB) to evaluate cortical plasticity in the somatosensory cortex (S1) and M1 region associated with small hand muscles, because INB strongly inhibits muscles distal to the tourniquet. Thirty-three healthy adults participated in different combinations of four experiments. A pneumatic tourniquet was placed just below the right elbow and inflated to induce a mINB. We recorded the median nerve somatosensory- and motor-evoked potentials (SEPs and MEPs) before, during and after mINB placement and assessed spinal cord excitability using F-wave measurements. SEPs at Erb's point (N9) were abolished during the mINB; those at cortical N20 were suppressed. After removing the mINB, N20 amplitudes increased significantly, while those at N9 did not fully recover. P14 amplitudes after tourniquet deflation immediately recovered to baseline levels. M1-MEP amplitudes decreased during the mINB, and Erb-MEPs were suppressed. After the mINB was removed, M1-MEPs remained suppressed, while Erb-MEPs fully recovered. F-waves were not affected by the intervention. Therefore, sensory, but not motor, nerve function was affected by the mINB. S1 excitability was enhanced after the mINB was removed, indicating that S1 and M1 excitability were modulated in opposing directions after deflation. These after-effects may reflect isolated effects or interactions between the S1 and M1 regions. Our findings may facilitate improved understanding of the sensorimotor modulations that occur distal to the tourniquet due to temporal deafferentation and lead to development of novel neuromodulation protocols.

Metal- and Oxidant-Free Alkenyl C-H/Aromatic C-H Cross-Coupling Using Electrochemically Generated Iodosulfonium Ions.

A three-step transformation consisting of 1) addition of electrochemically generated iodosulfonium ions to vinylarenes to give (1-aryl-2-iodoethoxy)sulfonium ions, 2) nucleophilic substitution by subsequently added aromatic compounds to give 1,1-diaryl-2-iodoethane, and 3) elimination of HI with a base to give 1,1-diarylethenes was developed. The transformation serves as a powerful metal- and chemical-oxidant-free method for alkenyl C-H/aromatic C-H cross-coupling.

Metal-Free Benzylic C-H Amination via Electrochemically Generated Benzylaminosulfonium Ions.

Electrochemical oxidation of toluene derivatives in the presence of N-tosyldiphenylsulfilimine gave the corresponding benzylaminosulfonium ions, which were treated with tetrabutylammonium iodide under non-electrolytic conditions to give N-tosylbenzylamines. The transformation serves as a metal- and chemical-oxidant-free method for benzylic C-H amination. Because of high oxidation potential of N-tosyldiphenylsulfilimine the present method can be applied to synthesis of various benzylamines from functionalized toluene derivatives.

The Stabilized Cation Pool Method: Metal- and Oxidant-Free Benzylic C-H/Aromatic C-H Cross-Coupling.

Electrochemical oxidation of toluene derivatives in the presence of a sulfilimine gave benzylaminosulfonium ions as stabilized benzyl cation pools, which reacted with subsequently added aromatic nucleophiles to give the corresponding cross-coupling products. The transformation serves as a powerful metal- and chemical-oxidant-free method for benzylic C-H/aromatic C-H cross-coupling. The method has been successfully applied to synthesis of TP27, an inhibitor of PTPase.

Switching the reaction pathways of electrochemically generated ß-haloalkoxysulfonium ions - synthesis of halohydrins and epoxides.

ß-Haloalkoxysulfonium ions generated by the reaction of electrogenerated Br(+) and I(+) ions stabilized by dimethyl sulfoxide (DMSO) reacted with sodium hydroxide and sodium methoxide to give the corresponding halohydrins and epoxides, respectively, whereas the treatment with triethylamine gave α-halocarbonyl compounds.

Trigger medications and patient-related risk factors for Parkinson disease psychosis requiring anti-psychotic drugs: a retrospective cohort study.

BACKGROUND: Psychoses such as hallucinations are a frequent non-motor problem in patients with Parkinson disease (PD) and serious psychosis requires anti-psychotic medications that worsen Parkinsonism. Although psychosis could be associated with patient-related or biological factors such as cognition, age, and severity of PD, it can also be associated with medications.Therefore we aimed to investigate patient-related and medication-related risks of psychosis requiring anti-psychotic medications (serious psychosis). METHODS: A retrospective cohort of 331 PD patients was followed for 2 years. Patient-related factors associated with risk of psychosis were identified by a survival time analysis. In patients who developed psychosis, medications during the hazard period (1-14 days before psychosis) were contrasted with those during the control periods (1 and 3 months before psychosis) using a case-crossover analysis to identify medication-related risks of psychosis. RESULTS: Serious psychosis was detected in 52 patients and the incidence was estimated to be 116 (95% confidence interval [CI], 85-148) per 1,000 person-years. Analyses of baseline characteristics revealed the risk to be higher in patients with a modified Hoehn-Yahr stage of ≥4 (hazard ratio [HR], 2.22; 95% CI, 1.11-4.40), those with a longer duration of PD (HR, 1.25; 95% CI, 1.00-1.55, per 5 years) and those with Mini-Mental State Examination scores of ≤24 (HR, 2.66; 95% CI, 1.37-5.16). The case-crossover analysis revealed that anti-cholinergics use (HR, 19.7; 95% CI, 2.39-162) elevated the risk, while donepezil use reduced it (HR, 0.48; 95% CI, 0.27-0.85). CONCLUSIONS: Risk of psychosis was elevated by increasing severity of PD, cognitive dysfunction and duration of the disease. It was elevated by use of anti-cholinergic drugs and reduced by use of donepezil. The medication-related risk was higher in patients aged ≥ 70 years. In contrast, there was no significant medication-related risk in younger patients, suggesting different pathomechanisms between young and old patients.

Association of Dermatomyositis Sine Dermatitis With Anti-Nuclear Matrix Protein 2 Autoantibodies.

Importance: Reports on dermatomyositis (DM) sine dermatitis (DMSD) are scarce, and the concept of the disease has not been widely accepted. Objective: To confirm the existence of DMSD, determine its prevalence, and characterize its serologic features. Design, Setting, and Participants: This is a cohort study that reviewed clinical information, laboratory data, and muscle pathology slides from January 2009 to August 2019. We further assessed the follow-up data of 14 patients with DMSD. The median (interquartile range) follow-up period was 34 (16-64) months. Muscle biopsy samples, along with clinical information and laboratory data, were sent to a referral center for muscle diseases in Japan for diagnosis. Of patients whose myopathologic diagnosis was made at the National Center of Neurology and Psychiatry between January 2009 and August 2019, 199 patients were eligible for inclusion. These patients underwent full investigation for DM-specific autoantibodies (against transcriptional intermediary factor γ, Mi-2, melanoma differentiation-associated gene 5, nuclear matrix protein 2 [NXP-2], and small ubiquitin-like modifier activating enzyme ); however, 17 patients were excluded because their muscle fibers did not express myxovirus resistance protein A, a sensitive and specific marker of DM muscle pathology. Main Outcomes and Measures: Diagnosis of DMSD was based on the absence of a skin rash at the time of muscle biopsy. Results: Of the 182 patients, 93 were women (51%) and 46 were children (25%) (<18 years). Fourteen patients (8%) had DMSD and none were clinically diagnosed with DM. Among the 14 patients with DMSD, 12 (86%) were positive for anti-NXP-2 autoantibodies, while the remaining 2 were positive for anti-transcriptional intermediary factor γ and anti-Mi-2 autoantibodies, respectively. Only 28% of patients (47 of 168) with a skin rash were positive for anti-NXP-2 autoantibodies, indicating a significant association between anti-NXP-2 autoantibodies and DMSD (86% [12 of 14] vs 28% [47 of 168]; P < .001). This association was also supported by multivariable models adjusted for disease duration (odds ratio, 126.47; 95% CI, 11.42-1400.64; P < .001). Conclusions and Relevance: Dermatomyositis sine dermatitis does exist and accounts for 8% of patients with DM confirmed with muscle biopsy. Dermatomyositis sine dermatitis is significantly associated with anti-NXP-2 autoantibodies, which contrasts with anti-MDA5 DM, which is typically clinically amyopathic in presentation. It is essential to distinguish DMSD from other types of myositis because DM-specific therapies that are currently under development, including Janus kinase inhibitors, may be effective for DMSD.

A case of hearing loss and quadriplegia after a pontine hemorrhage.

We herein describe the case of a 50-year-old female who developed a pontine hemorrhage with consciousness disturbance and quadriplegia. Her respiratory condition was so bad that she needed to be intubated and put on artificial respiration. After her consciousness and respiratory condition gradually recovered, we noticed that she had developed a bilateral hearing loss. The auditory brain stem response test revealed only I waves on both sides, thus suggesting that her hearing loss had been caused by an injury to the hearing-conducting pathway including the cochlear nuclei. In this case, the hematoma extended from the lower to the upper part of pons and, furthermore, it was also located broadly in the dorsal part of the pons. As a result, the cochlear nuclei and corpus trapezoideum appeared to have been destroyed by the hematoma. However, since most cases with a brain stem hemorrhage showing bilateral hearing loss tend to be in a severe condition, this condition is often easy to overlook. We should therefore carefully evaluate patients' reaction to hearing stimulation to avoid overlooking any hearing loss in such patients.

[A case of refractory generalized myasthenia gravis with anti-acetylcholine receptor antibodies treated with rituximab].

We report a case of a 57-year-old woman with thymoma-associated generalized myasthenia gravis (MG) showing severe bulbar and respiratory symptoms, moderate weakness of the neck muscles, and mild weakness of extremity muscles. Corticosteroid treatment with various types of immunosuppressive agents, such as cyclosporine, tacrolimus, and azathioprine, did not improve her symptoms. Plasma exchange transiently improved her symptoms, and she was required to undergo plasmapheresis every 4 weeks. At first, cyclophosphamide pulse therapy was administered, which improved her symptoms transiently. Thereafter, rituximab (RTX) was administered. Six months after RTX administration, respiratory distress and dysphagia improved gradually, and reduction in the dosage of corticosteroids from 30 mg/day to 10 mg/day did not result in symptom deterioration. Therefore, the interval between successive plasmapheresis treatments was increased from 4 to 9 weeks 19 months after the first RTX administration. During a 26-month period from the first administration of RTX, the number of CD20+ B cells in peripheral blood decreased and remained at 0% to 26% of that before RTX treatment. The titer of anti-acetylcholine receptor antibodies did not change during the first course of treatment (0.6-0.9 nmol/l). The clinical symptom worsened with the increase of the number of CD20+ B cells in peripheral blood in the 27 month after 1st RTX administration. Therefore, RTX was administered a second time, after which the patient's clinical symptoms again improved gradually. The titer of anti-acetylcholine receptor antibodies came to be stable with 0.5-0.7 nmol and low level during the 2nd course. Corticosteroids could be discontinued in the 16th month. The findings suggest that RTX can be one of the choices for pharmacological therapy in patients with intractable MG accompanied by the presence of anti-acetylcholine receptor antibodies.

Automated electrochemical assembly of the protected potential TMG-chitotriomycin precursor based on rational optimization of the carbohydrate building block.

The anomeric arylthio group and the hydroxyl-protecting groups of thioglycosides were optimized to construct carbohydrate building blocks for automated electrochemical solution-phase synthesis of oligoglucosamines having 1,4-ß-glycosidic linkages. The optimization study included density functional theory calculations, measurements of the oxidation potentials, and the trial synthesis of the chitotriose trisaccharide. The automated synthesis of the protected potential N,N,N-trimethyl-d-glucosaminylchitotriomycin precursor was accomplished by using the optimized building block.

Delirium and high fever are associated with subacute motor deterioration in Parkinson disease: a nested case-control study.

BACKGROUND: In Parkinson disease (PD), systemic inflammation caused by respiratory infections such as pneumonia frequently occurs, often resulting in delirium in the advanced stages of this disease. Delirium can lead to cognitive and functional decline, institutionalization, and mortality, especially in the elderly. Inflammation causes rapid worsening of PD motor symptoms and signs, sometimes irreversibly in some, but not all, patients. PURPOSE: To identify factors associated with subacute motor deterioration in PD patients with systemic inflammation. METHODS: The association of clinical factors with subacute motor deterioration was analyzed by a case-control study. Subacute motor deterioration was defined as sustained worsening by one or more modified Hoehn and Yahr (H-Y) stages. Using multivariable logistic regression incorporating baseline characteristics (age, sex, PD duration, modified H-Y stage, dementia, and psychosis history) and statistically selected possible predictors (peak body temperature, duration of leukocytosis, and presence of delirium), the odds ratios for these factors were estimated as relative risks. RESULTS: Of 80 PD patients with systemic inflammation, 26 with associated subacute motor deterioration were designated as cases and the remainder as controls. In the 26 cases, 6 months after its onset the motor deterioration had persisted in 19 patients and resolved in four (three were lost for follow-up). Multivariable logistic regression analysis showed that delirium and body temperature are significantly associated with motor deterioration after systemic inflammation (P = 0.001 for delirium and P = 0.026 for body temperature), the adjusted odds ratios being 15.89 (95% confidence interval [CI]: 3.23-78.14) and 2.78 (95% CI: 1.13-6.83), respectively. CONCLUSIONS: In patients with PD and systemic inflammation, delirium and high body temperature are strong risk factors for subsequent subacute motor deterioration and such deterioration can persist for over 6 months.

Subclinical elevation of plasma C-reactive protein and illusions/hallucinations in subjects with Parkinson's disease: case-control study.

BACKGROUND: Though infections are associated with psychotic symptoms, whether or not subclinical inflammation is associated with hallucinations is not known in Parkinson's disease (PD). PURPOSE: To investigate the association of illusions/hallucinations and plasma CRP levels in PD patients without symptomatic infections. METHODS: PD patients not diagnosed as having infections were assessed for illusions and hallucinations using the Parkinson Psychosis Questionnaire (PPQ). It comprises four-domain questions: PPQ-A for sleep problems, PPQ-B for hallucinations/illusions, PPQ-C for delusions, and PPQ-D for disorientation. Assigning patients with ≥1 points in the PPQ-B score to be cases and others as controls, the association of hallucinations/illusions and clinical features (age, sex, duration of PD, Unified Parkinson's Disease Rating Scale part 3 (UPDRS-3), Mini-Mental State Examination (MMSE) score, sleep disturbance (PPQ-A score) as well as daily doses of L-Dopa, dopamine agonists, amantadine, and selegiline) were analyzed using a case-control design. RESULTS: A total of 111 patients were examined and plasma CRP levels were <0.1-6.0 mg/L. Hallucinations or illusions were detected in 28 (25.2%). There were significant differences in age, UPDRS-3 score, MMSE score, PPQ-A, daily doses of L-Dopa and dopamine agonists and plasma CRP levels between cases and controls. A multivariate logistic regression model revealed that UPDRS-3 scores and plasma CRP levels were significantly associated with hallucinations/illusions with an adjusted odds ratio of 1.96 (95% confidence interval (CI) 1.20-3.20) per 10 points and 1.57 (95% confidence interval 1.13-2.16) per two-fold, respectively. Dividing patients into thirds by CRP levels (≤0.2, 0.3-0.6, ≥0.7 mg/L), the prevalence of hallucinations/illusions was 13.2%, 21.6%, and 41.7%, in the bottom-, middle-, and top-thirds, respectively (for trend p = 0.012). CONCLUSIONS: Subclinical elevation of plasma CRP levels was associated with hallucinations or illusions after adjustment for motor disability, suggesting that subclinical elevations of CRP levels might be an independent risk for hallucinations/illusions.

Diagnostic accuracy of apparent diffusion coefficient and 123I-metaiodobenzylguanidine for differentiation of multiple system atrophy and Parkinson's disease.

BACKGROUND: It is often hard to differentiate Parkinson's disease (PD) and parkinsonian variant of multiple system atrophy (MSA-P), especially in the early stages. Cardiac sympathetic denervation and putaminal rarefaction are specific findings for PD and MSA-P, respectively. PURPOSE: We investigated diagnostic accuracy of putaminal apparent diffusion coefficient (ADC) test for MSA-P and (123)I-metaiodobenzylguanidine (MIBG) scintigram for PD, especially in early-stage patients. METHODS: The referral standard diagnosis of PD and MSA-P were the diagnostic criteria of the United Kingdom Parkinson's Disease Society Brain Bank Criteria and the second consensus criteria, respectively. Based on the referral standard criteria, diagnostic accuracy [area under the receiver-operator characteristic curve (AUC), sensitivity and specificity] of the ADC and MIBG tests was estimated retrospectively. Diagnostic accuracy of these tests performed within 3 years of symptom onset was also investigated. RESULTS: ADC and MIBG tests were performed on 138 patients (20 MSA and 118 PD). AUC was 0.95 and 0.83 for the ADC and MIBG tests, respectively. Sensitivity and specificity were 85.0% and 89.0% for MSA-P diagnosis by ADC test and 67.0% and 80.0% for PD diagnosis by MIBG test. When these tests were restricted to patients with disease duration ≤ 3 years, the sensitivity and specificity were 75.0% and 91.4% for the ADC test (MSA-P diagnosis) and 47.7% and 92.3% for the MIBG test (PD diagnosis). CONCLUSIONS: Both tests were useful in differentiating between PD and MSA-P, even in the early stages. In early-stage patients, elevated putaminal ADC was a diagnostic marker for MSA-P. Despite high specificity of the MIBG test, careful neurological history and examinations were required for PD diagnosis because of possible false-negative results.

Clinical factors associated with abnormal postures in Parkinson's disease.

BACKGROUND: Abnormal posture (AP) is often seen in Parkinson's disease (PD), and marked forms known as dropped head syndrome and camptocormia encumber daily living activities. Unlike other motor disabilities such as bradykinesia or muscular rigidity, AP is not always improved but rather deteriorated by PD medication. PURPOSE: To clarify factors associated with neck and thoracolumbar AP. METHODS: Neck flexion (NF) and thoracolumbar (TL) angles were measured in 216 consecutive PD patients and 175 elderly healthy controls. The differences in NF and TL angles between PD patients and controls were designated as ΔNFA and ΔTLA, respectively. The association of ΔNFA or ΔTLA and predictable factors such as age, sex, duration of PD, Hoehn Yahr (H-Y) stage, Unified Parkinson's Disease Rating Scale Part 3 (UPDRS-3), daily dose of dopamine agonists, and comorbid orthopedic spinal lesions was investigated in PD patients. Patients were divided into quartiles according to ΔNFA or ΔTLA. The association between predictable factors and ΔNFA or ΔTLA was estimated as odds ratio (OR), comparing with the lowest quartile as the reference by multivariate regression analysis. RESULTS: Compared with controls, distributions of all three posture angles were significantly shifted rightward in PD patients. Although there were no difference in UPDRS-3 scores in the quartiles of ΔNFA, the highest quartile was associated with H-Y stage ≥3 [OR 2.99, 95% confidence interval (CI) 1.33-6.70, p = 0.008] after adjustment for age, sex and comorbid orthopedic spinal lesions. The highest quartile of ΔTLA was associated with comorbid orthopedic spinal lesions [OR 5.83 (1.42-23.8), p = 0.014], and UPDRS-3 score [OR 3.04 (1.80-5.15)/10 points, p<0.0001]. CONCLUSION: Thoraco-lumbar AP was associated with UPDRS-3 scores and orthopedic spinal lesions, and in contrast, neck AP was not associated with these factors, suggesting that they had different pathomechanisms.

Automated solution-phase synthesis of oligosaccharides via iterative electrochemical assembly of thioglycosides.

A new iterative one-pot sequential method for the solution-phase synthesis of oligosaccharides has been devised on the basis of the electrochemical oxidation of a propagating thioglycoside terminus to generate the corresponding triflate, followed by the reaction with a thioglycoside building block having a free hydroxyl group. A practical automated synthesizer was developed for the method and was effectively used for assembling up to six thioglycoside building blocks to synthesize partial structures of poly-ß-D-(1-6)-N-acetylglucosamine.