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Rationale: Limited pharmacological data are available to guide methadone treatment during pregnancy and postpartum. Objectives: Study goals were to (1) characterize changes in methadone dose across childbearing, (2) determine enantiomer-specific methadone withdrawal kinetics from steady state during late pregnancy, (3) assess enantiomer-specific changes in methadone level/dose (L/D) ratios across childbearing, and (4) explore relationships between CYP2B6, CYP2C19, and CYP3A4 single-nucleotide polymorphisms and maternal dose, plasma concentration, and L/D. Methods: Methadone dose changes and timed plasma samples were obtained for women on methadone ( n = 25) followed prospectively from third trimester of pregnancy to 3 months postpartum. Results: Participants were primarily white, Medicaid insured, and multiparous. All women increased their dose from first to end of second trimester (mean peak increase = 23 mg/day); 71 % of women increased from second trimester to delivery (mean peak increase = 19 mg/day). Half took a higher dose 3 months postpartum than at delivery despite significantly larger clearance during late pregnancy. Third trimester enantiomer-specific methadone half-lives (range R-methadone 14.7-24.9 h; S-methadone, 8.02-18.9 h) were about half of those reported in non-pregnant populations. In three women with weekly 24-h methadone levels after delivery, L/D increased within 1-2 weeks after delivery. Women with the CYP2B6 Q172 variant GT genotype have consistently higher L/D values for S-methadone across both pregnancy and postpartum. Conclusions: Most women require increases in methadone dose across pregnancy. Given the shorter half-life and larger clearances during pregnancy, many pregnant women may benefit from split methadone dosing. L/D increases quickly after delivery and doses should be lowered rapidly after delivery. [ABSTRACT FROM AUTHOR]

Background: Interindividual variation in genetic background may influence the response to chemotherapy and overall survival for patients with advanced-stage non-small cell lung cancer (NSCLC).Methods: To identify genetic variants associated with poor overall survival in these patients, we conducted a genome-wide scan of 307,260 single-nucleotide polymorphisms (SNPs) in 327 advanced-stage NSCLC patients who received platinum-based chemotherapy with or without radiation at the University of Texas MD Anderson Cancer Center (the discovery population). A fast-track replication was performed for 315 patients from the Mayo Clinic followed by a second validation at the University of Pittsburgh in 420 patients enrolled in the Spanish Lung Cancer Group PLATAX clinical trial. A pooled analysis combining the Mayo Clinic and PLATAX populations or all three populations was also used to validate the results. We assessed the association of each SNP with overall survival by multivariable Cox proportional hazard regression analysis. All statistical tests were two-sided.Results: SNP rs1878022 in the chemokine-like receptor 1 (CMKLR1) was statistically significantly associated with poor overall survival in the MD Anderson discovery population (hazard ratio [HR] of death = 1.59, 95% confidence interval [CI] = 1.32 to 1.92, P = 1.42 × 10(-6)), in the PLATAX clinical trial (HR of death = 1.23, 95% CI = 1.00 to 1.51, P = .05), in the pooled Mayo Clinic and PLATAX validation (HR of death = 1.22, 95% CI = 1.06 to 1.40, P = .005), and in pooled analysis of all three populations (HR of death = 1.33, 95% CI = 1.19 to 1.48, P = 5.13 × 10(-7)). Carrying a variant genotype of rs10937823 was associated with decreased overall survival (HR of death = 1.82, 95% CI = 1.42 to 2.33, P = 1.73 × 10(-6)) in the pooled MD Anderson and Mayo Clinic populations but not in the PLATAX trial patient population (HR of death = 0.96, 95% CI = 0.69 to 1.35).Conclusion: These results have the potential to contribute to the future development of personalized chemotherapy treatments for individual NSCLC patients. [ABSTRACT FROM AUTHOR]

A 32-year-old male presented with unilateral orbital-temporal pulsatile headache, followed by fever in the 38°C range and nausea. The patient experienced two episodes of transient dysarthria and tinnitus, each lasting several minutes. MRI revealed swelling of the left cerebral cortex, enhancement of the leptomeninges, dilation of the left middle cerebral artery, and subcortical FLAIR hypointensity. The clinical presentation and MRI findings raised suspicions of myelin oligodendrocyte glycoprotein (MOG) antibody-associated cortical encephalitis. After two courses of steroid pulse therapy, the patient's headache subsided, and there was a significant improvement in the swelling of the left cerebral cortex. Subsequently, serum MOG antibody positivity was confirmed. While unilateral cortical FLAIR hyperintensity and increased blood flow can be observed in various diseases, MOG antibody-associated cortical encephalitis is notably characterized by subcortical FLAIR hypointensity, a finding more frequently observed in this condition compared to other diseases. In this case, the findings were useful for early diagnosis and intervention.

An 83-year-old man with hepatocellular carcinoma developed muscle weakness, ptosis, and dyspnea 3 weeks after receiving atezolizumab. Soon after, mechanical ventilation was initiated, which was followed by marked blood pressure spikes. The levels of creatine kinase and troponin-I were significantly elevated, and acetylcholine receptor antibodies were positive. The patient was diagnosed with immune checkpoint inhibitor (ICI)-induced myositis, myasthenia gravis (MG), myocarditis, and suspected autoimmune autonomic ganglionopathy (AAG). After immunotherapy, the serum markers and blood pressure normalized, and he was weaned from the ventilator after five months. To our knowledge, this is the first reported case of AAG secondary to ICI-induced myositis, MG, and myocarditis.

Background: BRAF mutation has been recognized as a negative prognostic marker for metastatic colorectal cancer (mCRC), but these data are from common BRAF V600E-mutated mCRC. Combination therapy of BRAF inhibitor and anti-epidermal growth factor receptor (EGFR) antibody has been approved for BRAF V600E-mutated mCRC. However, BRAF non-V600 mutations are rare mutations, and their clinical behavior is not understood. Moreover, the BRAF K601E mutation is extremely rare in mCRC, and there have been no reports on its specific treatment., Case Summary: Herein, we report the case of a 59-year-old female with super aggressive mCRC with multiple metastases, which extended to whole body including mediastinal to abdominal lymph nodes, bones, pleura, and peritoneum. The companion diagnostics of tumor tissues showed RAS/BRAF wild-type without microsatellite instability. She received chemotherapy with mFOLFOX6 (oxaliplatin plus infusional 5-fluorouracil [5-FU] and leucovorin) plus panitumumab, following FOLFIRI (irinotecan plus infusional 5-FU and leucovorin) plus ramucirumab. For the next regimen selection, a comprehensive genomic profiling panel was performed and revealed a BRAF K601E mutation, which was not covered in the initial companion diagnostics. After disease progression, a combination of encorafenib, binimetinib, and cetuximab was selected as third-line chemotherapy. The serum levels of tumor markers were immediately decreased accompanied by improvements in pleural effusion and ascites. However, the disease progressed again, and best supportive care was done instead., Conclusion: This case offers novel insights into the clinical behaviors of BRAF non-V600E-mCRC, potentially advancing personalized therapy for rare and aggressive cases., Competing Interests: Conflict-of-interest statement: The authors have no conflicts of interest to declare., (©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.)

Background: Extracellular adenosine 5'-triphosphate (ATP) acts as a signaling molecule in the peripheral nerves, regulating myelination after nerve injury. The present study examined whether the cerebrospinal fluid (CSF) ATP levels in patients with Guillain-Barré syndrome (GBS) and chronic inflammatory demyelinating polyneuropathy (CIDP) are related to disease severity., Methods: CSF ATP levels in 13 patients with GBS and 18 patients with CIDP were compared with those in a control group of 16 patients with other neurological diseases (ONDs). In patients with CIDP, CSF ATP levels were compared before and after treatment. The correlations between CSF ATP levels and other factors, including clinical data and CSF protein levels, were also evaluated., Results: Median CSF ATP levels were significantly higher in patients with GBS and CIDP than in those with ONDs. When patients with CIDP were classified into two groups depending on their responsiveness to immunotherapy, median CSF ATP levels were significantly higher in good responders than in ONDs. CSF ATP levels tended to decrease after treatment in patients with CIDP. In patients with CIDP, there is a negative correlation between CSF ATP and CSF protein levels., Conclusions: CSF ATP levels were increased in patients with GBS and CIDP. In particular, CSF ATP levels tended to decrease following treatment in patients with CIDP. CSF ATP levels may be useful biomarkers for the diagnosis or monitoring of therapeutic effects in patients with GBS and CIDP., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2024 Takamasa Nukui et al.)

Parkinson's disease (PD) is a neurodegenerative movement disorder associated with a loss of dopamine neurons in the substantia nigra. The diagnosis of PD is sensitive since it shows clinical features that are common with other neurodegenerative diseases. In addition, most symptoms arise at the late stage of the disease, where most dopaminergic neurons are already damaged. Several studies reported that oxidative stress is a key modulator in the development of PD. This condition occurs due to excess reactive oxygen species (ROS) production in the cellular system and the incapability of antioxidants to neutralize it. In this study, we focused on the pathology of PD by measuring serum xanthine oxidase (XO) activity, which is an enzyme that generates ROS. Interestingly, the serum XO activity of patients with PD was markedly upregulated compared to patients with other neurological diseases (ONDs) as a control. Moreover, serum XO activity in patients with PD showed a significant correlation with the disease severity based on the Hoehn and Yahr (HY) stages. The investigation of antioxidant status also revealed that serum uric acid levels were significantly lower in the severe group (HY ≥ 3) than in the ONDs group. Together, these results suggest that XO activity may contribute to the development of PD and might potentially be a biomarker for determining disease severity in patients with PD.

Introduction: Immune checkpoint inhibitors are sometimes associated with immune-related adverse events during or after treatment. Among these, aseptic meningitis is a rare and serious complication. We report the first case of atezolizumab-induced aseptic meningitis, which occurred during treatment for advanced hepatocellular carcinoma (HCC)., Case Presentation: A 74-year-old woman diagnosed with advanced HCC and treated with first-line atezolizumab plus bevacizumab developed anorexia, fatigue, and fever, after three treatment cycles. Cerebrospinal fluid examination showed slightly increased cell count and protein level but no infection or malignancy. Contrast enhancement along the cerebral sulcus was evident in contrast-enhanced magnetic resonance imaging, and the patient was diagnosed with aseptic meningitis associated with atezolizumab. Steroid therapy soon improved her clinical symptoms, and the contrast enhancement along the cerebral sulcus disappeared., Conclusion: Clinicians should monitor to avoid serious immune-related adverse events, such as aseptic meningitis, in patients during treatment of HCC with immune checkpoint inhibitors and make the diagnosis as soon as possible., Competing Interests: All authors declare that they have no conflict of interest., (© 2024 The Author(s). Published by S. Karger AG, Basel.)

A female patient in her 50s who underwent chemotherapy for left primary breast cancer presented with cancerous pleurisy and disseminated intravascular coagulation. Esophagogastroduodenoscopy and liver biopsy revealed gastric and liver cancer. Distinguishing between primary and metastatic cancer by pathological findings is difficult using hematoxylin and eosin staining. We diagnosed and treated simultaneous primary breast cancer (ER-positive) and gastric cancer with liver metastasis (ER-negative), based on differences in estrogen receptor expression. The patient lived for 10 months with chemotherapy. After death, an autopsy was performed because the endoscopic results were atypical for primary gastric cancer, and additional immunohistochemical studies indicated gastric metastasis of breast cancer.

Background: Despite the suggestion that direct compression by granuloma and ischemia resulting from vasculitis can cause nerve fiber damage, the mechanisms underlying sarcoid neuropathy have not yet been fully clarified., Methods: We examined the clinicopathological features of sarcoid neuropathy by focusing on electrophysiological and histopathological findings of sural nerve biopsy specimens. We included 18 patients with sarcoid neuropathy who had non-caseating epithelioid cell granuloma in their sural nerve biopsy specimens., Results: Although electrophysiological findings suggestive of axonal neuropathy were observed, particularly in the lower limbs, all but three patients showed ≥1 abnormalities in nerve conduction velocity or distal motor latency. Additionally, a conduction block was observed in 11 of the 16 patients for whom waveforms were assessed; five of them fulfilled motor nerve conduction criteria strongly supportive of demyelination as defined in the European Academy of Neurology/Peripheral Nerve Society (EAN/PNS) guideline for chronic inflammatory demyelinating polyneuropathy (CIDP). In most patients, sural nerve biopsy specimens revealed a mild to moderate degree of myelinated fiber loss. Fibrinoid necrosis was observed in one patient, and electron microscopy analysis revealed demyelinated axons close to granulomas in six patients., Conclusions: Patients with sarcoid neuropathy may meet the EAN/PNS electrophysiological criteria for CIDP due to the frequent presence of conduction blocks. Based on our results, in addition to the ischemic damage resulting from granulomatous inflammation, demyelination may play an important role in the mechanism underlying sarcoid neuropathy., (© 2023 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Introduction: Endoscopic diagnosis is essential for predicting the curability of early gastric cancer (EGC; R0 resection) before treatment, but the relationship between ulcerative lesions and clinical outcomes remains unclear. We aimed to investigate the effect of proton pump inhibitor (PPI) or potassium-competitive acid blocker (P-CAB) on the morphological changes of ulcerative EGCs and its relevance to the clinical outcomes., Methods: Altogether, 143 patients with differentiated ulcerative EGC that were resected by endoscopic submucosal dissection were retrospectively identified and divided into the following two cohorts depending on their PPI/P-CAB administration status: PPI/P-CAB (n = 76) and non-PPI/P-CAB (n = 67) cohorts. Furthermore, in each cohort, the patients were further divided into the improved and unimproved subgroups based on the ulcerative changes., Results: In the PPI/P-CAB cohort, the deep submucosal invasion and lymphovascular invasion rates were significantly higher in the unimproved subgroup than in the improved subgroup, resulting in a significantly lower R0 resection rate. Contrarily, no significant differences were found between the two subgroups in the non-PPI/P-CAB cohort. The significance of PPI/P-CAB administration was observed only in the ulcerative EGCs with open-type atrophy (R0 resection rate; improved vs. unimproved, 90.9% vs. 48.0%, p = 0.001). When the finding of improved ulcer with PPI/P-CAB administration was used as the indication of endoscopic resection in ulcerative EGCs with open-type atrophy, high sensitivity (78.9%) and accuracy (76.3%) rates for the curability were observed, which were higher than those of conventional endoscopic diagnosis alone (p = 0.021)., Conclusion: PPI or P-CAB administration might contribute to the potential selection of ulcerative EGCs, enabling endoscopic curative resection., (© 2024 S. Karger AG, Basel.)

Summary: Supervised learning is widely used in biology for prediction, and ensemble learning, including stacking, is a promising technique for increasing and stabilizing the prediction accuracy. In this study, we developed an R package for stacking. This package depends on the R package caret and can handle models supported by caret. Stacking involves cross-validation of training data with multiple base learners, and the predicted values are used as explanatory variables for the meta-learner. In the prediction, the testing data were fed into the base models, and the returned values were averaged for each base learner. The averaged values were then fed into the meta-model, and the final predictions were returned. Using this package, the training and prediction procedures for stacking can be conducted using one-row scripts., Availability and Implementation: The R package stacking is available at the Comprehensive R Archive Network (CRAN) (https://cran.r-project.org/) and GitHub (https://github.com/Onogi/stacking). R scripts to reproduce the presented results are also reposited at GitHub., Competing Interests: The authors declare no conflicts of interest associated with this manuscript., (© The Author(s) 2023. Published by Oxford University Press.)

Background: Self-expanding metallic stent (SEMS) and trans-anal colorectal tube (TCT) are alternative treatments to conventional emergency surgery for non-right-sided obstructive colon cancer (NROCC). However, the one with better short- and long-term outcomes remains controversial. Thus, this multicenter case-control study aimed to analyze and compare SEMS and TCT for NROCC., Methods: Patients with stage II/III NROCC who underwent surgery between January 2010 and December 2019 at either of the eight selected Japanese affiliate hospitals were, retrospectively, reviewed. Baseline characteristics between the SEMS and TCT groups were adjusted by propensity score (PS) matching., Results: Among 239 reviewed patients (SEMS: 76, TCT: 163), 180 were finally included in two well-balanced cohorts through PS: SEMS group (65 patients) and TCT group (115 patients). Technical success, clinical success, morbidity, and short-term mortality were not significantly different between the two groups. SEMS placement achieved significantly higher rates for primary resection/anastomosis without stoma (SEMS: 90.8% vs. TCT: 77.4%, p < 0.001) and laparoscopic surgery (SEMS: 64.6% vs. TCT: 43.5%, p < 0.001) than TCT placement. However, 5-year overall survival (SEMS: 83.7% vs. TCT: 86.4%; p = 0.822) and 5-year relapse-free survival (SEMS: 64.7% vs. TCT: 66.4%; p = 0.854) showed no significant differences between these groups., Conclusions: Both SEMS and TCT revealed similar long-term outcomes, but SEMS placement was better in achieving primary resection/anastomosis and laparoscopic surgery in patients with stage II/III NROCC., (© 2023. Japanese Society of Gastroenterology.)

Neuromyelitis optica spectrum disorder (NMOSD) is an inflammatory disease of the central nervous system (CNS) characterized by severe myelitis and optic neuritis. Double-stranded DNA (dsDNA) is involved in the pathogenesis of various autoimmune diseases, such as systemic lupus erythematosus. However, its role in NMOSD remains unclear. In this study, the concentration of dsDNA in the cerebrospinal fluid (CSF) was quantified in 23 patients with NMOSD and 16 patients with other neurological diseases (ONDs). CSF dsDNA levels in patients with NMOSD (median: 0.03 ng/µL) were significantly higher than those in patients with ONDs (median: 0.01 ng/μl). CSF dsDNA levels showed no significant difference before and after treatment. Elevation of CSF dsDNA levels may suggest its essential role in the augmentation of CNS inflammation in patients with NMOSD., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

A female patient in her 60s, treated with oral corticosteroids for scleroderma diagnosed 11 years ago, visited our hospital complaining of a persistent fever and liver dysfunction. She was treated with antibiotics, but her fever continued. Abdominal ultrasonography revealed multiple hypoechoic splenic masses. Splenic masses revealed multiple masses with no contrast effect in arterial and portal phases and nuclear in equilibrium phase by contrast computed tomography study, as well as hyperintensity masses with low signal areas in magnetic resonance imaging T2-weighted images. Liver tissue was obtained by percutaneous liver biopsy, and histological findings showed epithelioid cell granulomas without tumor cells. Further interview and physical examination revealed scratch scars from domestic cats and left axillary lymph node swelling. Hence, a cat scratch disease was suspected. She was diagnosed with cat scratch disease by serum indirect immunofluorescence. Her fever was resolved with minocycline administration. Therefore, persistent fever with splenic masses should be suspected of hepatosplenic cat scratch disease.

A 47-year-old woman was admitted to our hospital for scrutiny of limb weakness and orthostatic hypotension that had progressed from childhood. She had been treated for alacrima and esophageal achalasia from childhood. On admission, she had hyperreflexia of upper and lower extremities, distal predominant muscle atrophy in the lower extremities, decreased sensation of the distal extremities, and autonomic neuropathy. Her blood test results ruled out adrenal insufficiency, but Schirmer's test was positive. Given the lacrimation symptoms, esophageal achalasia, and neuropathy, the patient was diagnosed with triple A syndrome in whom a c.463C>T mutation (p.R155C) was found in the AAAS gene by genetic testing. Triple A syndrome is an autosomal recessive inherited disease caused by mutations in the AAAS gene. Genetic testing of the AAAS gene should be considered in patients with one or two of main symptoms of triple A syndrome.

A 62-year-old woman with coronavirus disease (COVID-19) developed coma on day 19 after her pneumonia was ameliorated. Brain magnetic resonance imaging with gadolinium showed radial linear perivascular enhancement, typically seen in glial fibrillary acidic protein (GFAP) astrocytopathy, although anti-GFAP antibody results were negative. Her consciousness recovered with high-dose steroid administration. We diagnosed the patient with COVID-19-associated acute disseminated encephalomyelopathy (ADEM) with radial linear perivascular emphasis., Competing Interests: The authors declare no conflict of interest., (© 2021 Japanese Society for Neuroimmunology.)

Previous studies have reported that transcranial direct current stimulation (tDCS) of the frontal polar area (FPA) ameliorated motor disability in patients with Parkinson's disease (PD). Here we report changes in neuromelanin (NM) imaging of dopaminergic neurons before and after rehabilitation combined with anodal tDCS over the FPA for 2 weeks in a PD patient. After the intervention, the patient showed clinically meaningful improvements while the NM-sensitive area in the SN increased by 18.8%. This case study is the first report of NM imaging of the SN in a PD patient who received tDCS. Abbreviations FPA: front polar area; PD: Parkinson's disease; NM: neuromelanin; DCI: DOPA decarboxylase inhibitor; STEF: simple test for evaluating hand function; TUG: timed up and go test; TMT: trail-making test; SN: substantia nigra; NM-MRI: neuromelanin magnetic resonance imaging; MCID: the minimal clinically important difference; SNpc: substantia nigra pars compacta; VTA: ventral tegmental area; LC: locus coeruleus; PFC: prefrontal cortex; M1: primary motor cortex; MDS: Movement Disorder Society; MIBG: 123 I-metaiodobenzylguanidine; SBR: specific binding ratio; SPECT: single-photon emission computed tomography; DAT: dopamine transporter; NIBS: noninvasive brain stimulation; tDCS: transcranial direct current stimulation; MAOB: monoamine oxidase B; DCI: decarboxylase inhibitor; repetitive transcranial magnetic stimulation: rTMS; diffusion tensor imaging: DTI; arterial spin labeling: ASL.

Background: Extracellular adenosine 5'-triphosphate (ATP) has been suggested to cause neuroinflammation and motor neuron degeneration by activating microglia and astrocytes in amyotrophic lateral sclerosis (ALS). Since we have developed a highly sensitive ATP assay system, we examined cerebrospinal fluid (CSF) ATP levels in patients with ALS whether it can be a useful biomarker in ALS., Methods: Forty-eight CSF samples from 44 patients with ALS were assayed for ATP with a newly established, highly sensitive assay system using luciferase luminous reaction. CSF samples from patients with idiopathic normal pressure hydrocephalus (iNPH) were assayed as a control. Patients were divided into two groups depending on their disease severity, as evaluated using the Medical Research Council (MRC) sum score. Correlations between the CSF ATP levels and other factors, including clinical data and serum creatinine levels, were evaluated., Results: CSF ATP levels were significantly higher in patients with ALS than in the iNPH (716 ± 411 vs. 3635 ± 5465 pmol/L, p < 0.01). CSF ATP levels were significantly higher in the more severe group than in the iNPH group (6860 ± 8312 vs. 716 ± 411 pmol/L, p < 0.05) and mild group (6860 ± 8312 vs. 2676 ± 3959 pmol/L, p < 0.05) respectively. ALS functional rating scale-revised (ALSFRS-R) (37.9 ± 5.7 vs. 42.4 ± 2.8, p < 0.01) and serum creatinine levels (0.51 ± 0.13 vs. 0.68 ± 0.23 mg/dL, p < 0.05) were significantly lower in the severe group than in the mild group respectively. A negative correlation of CSF ATP levels with MRC sum score was demonstrated in the correlation analysis adjusted for age and sex (r = -0.3, p = 0.08)., Conclusions: Extracellular ATP is particularly increased in the CSF of patients with advanced ALS. CSF ATP levels may be a useful biomarker for evaluating disease severity in patients with ALS.

Objectives: Neurofilament light chain (NfL) levels have been suggested as reflecting axonal damage in various inflammatory and neurodegenerative disorders, including acquired peripheral neuropathies. We aimed to investigate if serum NfL (sNfL) levels can be a biomarker of disease activity and treatment response in patients with chronic inflammatory demyelinating polyneuropathy (CIDP)., Materials and Methods: The sNfL levels of eleven newly diagnosed patients with CIDP were retrospectively assayed and compared with seven healthy volunteers. The levels were assayed before and after intravenous immunoglobulin treatment in patients with CIDP and were also assayed in the remission period., Results: Baseline sNfL levels in patients with CIDP before treatment were significantly higher than those in healthy controls. The levels significantly decreased overtime after one month of treatment and in remission period. There were significant negative correlations between the sNfL levels and the disease duration (the interval between the onset of the disease and the time of sampling), and weak correlations between the sNfL levels and overall neuropathy limitations scale., Conclusions: sNfL may be a potential biomarker reflecting the disease activity in patients with CIDP., (© 2021 The Authors. Brain and Behavior published by Wiley Periodicals LLC.)

Mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) is caused by defective oxidative phosphorylation in the cerebral parenchyma, cerebral blood vessels, and leptomeningeal tissue. Although increased blood and cerebrospinal fluid (CSF) lactate level has been used as a diagnostic biomarker in patients with MELAS, no biomarkers reflecting disease activity exist. Since we have developed a highly sensitive ATP assay system using luciferase luminous reaction, we examined CSF ATP in patients with MELAS and found that it negatively correlates with disease activity and that it reflects the efficacy of the treatment. CSF ATP might be a novel disease monitoring marker for MELAS., (Copyright © 2019 Elsevier B.V. and Mitochondria Research Society. All rights reserved.)

A 17-year-old woman was admitted to our hospital because of a high fever, consciousness disturbance, and delirious behavior. Methicillin susceptible Staphylococcus aureus (MSSA) infection was confirmed by blood culture. Transthoracic echocardiogram showed no abnormality at first. Diffusion-weighted brain MRI showed a high intensity lesion in the middle portion of the splenium, which was shown as low intensity on apparent diffusion coefficient map. Then, antibiotics therapy was started against suspected bacterial meningitis, while the lumbar puncture was not performed because of the decreased number of platelets. Since the systolic murmur appeared at the apex on day 12, the diagnosis with infectious endocarditis was made by transthoracic echocardiogram. The MRI abnormalities disappeared on day 16 and we diagnosed her with clinically mild encephalitis/encephalopathy with a reversible splenial lesion (MERS) associated with infectious endocarditis. This case suggests that MERS can occur associated with infectious endocarditis caused by Staphylococcus aureus.

Personalized cancer therapy relies on identifying patient subsets that benefit from a therapeutic intervention and suggest alternative regimens for those who don't. A new data integrative approach, based on graphical models, was applied on our multi-modal -omics, and clinical data cohort of metastatic melanoma patients. We found that response to chemotherapy is directly linked to ten gene expression, four methylation variables and PARP1 SNP rs1805407. PARP1 is a DNA repair gene critical for chemotherapy response and for which FDA-approved inhibitors are clinically available (olaparib). We demonstrated that two PARP inhibitors (ABT-888 and olaparib) make SNP carrier cancer cells of various histologic subtypes more sensitive to alkylating agents, but they have no effect in wild-type cells. Furthermore, PARP1 inhibitors act synergistically with chemotherapy in SNP carrier cells (especially in ovarian cancer for which olaparib is FDA-approved), but they are additive at best in wild-type cancer cells. Taken together, our results suggest that the combination of chemotherapy and PARP1 inhibition may benefit the carriers of rs1805407 in the future and may be used in personalized therapy strategies to select patients that are more likely to respond to PARP inhibitors.

Parkinson's disease (PD) is a neurodegenerative disorder with motor and non-motor symptoms due to degeneration of dopaminergic neurons. The current pharmacological treatments induce complications associated with long-term use. However, current stimulation techniques for PD treatment, such as deep brain stimulation (DBS), are too invasive. In this context, non-invasive brain stimulation including transcranial direct current stimulation (tDCS) may be a safe and effective alternative treatment for PD. We previously reported that anodal tDCS over the frontal polar area (FPA) improved motor functions in heathy subjects. Therefore, in the present study, effects of tDCS over the FPA on motor and cognitive functions of PD patients were analyzed. Nine PD patients (3 men and 6 women) participated in this cross over study with three tDCS protocols; anodal, cathodal or sham tDCS over the FPA. Each tDCS protocol was applied for 1 week (5 times/week). Before and after each protocol, motor and cognitive functions of the patients were assessed using Unified PD Rating Scale [UPDRS (part III: motor examination)], Fugl Meyer Assessment set (FMA), Simple Test for Evaluating hand Function (STEF) and Trail Making Test A (TMT-A). The results indicated that anodal stimulation significantly decreased scores of motor disability in UPDRS-III compared with sham and cathodal stimulation, and significantly increased scores of motor functions in FMA compared with sham stimulation. Furthermore, anodal stimulation significantly decreased time to complete a motor task requiring high dexterity in STEF compared with those requiring low and medium levels of dexterity. In addition, anodal stimulation significantly decreased time to complete the TMT-A task, which requires executive functions, compared with sham stimulation. To the best of our knowledge, this is the first clinical research reporting that tDCS over the FPA successfully improved the motor and non-motor functions in PD patients. These findings suggest that tDCS over the FPA might be a useful alternative for the treatment of PD patients.

We report a case of acute disseminated encephalomyelitis (ADEM) concomitant with polyneuropathy associated with anti-lactosylceramide antibody. A 68-year-old man was admitted to our hospital with ophthalmoparesis, bulbar palsy, tetraplegia after suffering from upper respiratory infection and headache. Subsequently, he developed respiratory failure requiring mechanical ventilation. Fluid-attenuated inversion recovery (FLAIR) MRI showed high intensities in the pons and medulla, and a nerve conduction study revealed motor-dominant axonal polyneuropathy. Although the laboratory tests revealed the presence of anti-lactosylceramide antibody in his serum, he was diagnosed with acute disseminated encephalomyelitis concomitant with polyneuropathy. Whereas the intensive treatment with corticosteroids, plasmapharesis, and high-dose intravenous immunoglobulin (IVIg) brought a moderate improvement, his tetraparesis continued to exist.