A clinicopathological study of low back pain due to middle cluneal nerve entrapment: case series.

PURPOSE: The middle cluneal nerve (MCN) is a pure sensory nerve around the middle buttock. Its entrapment between the iliac crest and the long posterior sacroiliac ligament elicits low back pain (LBP) that can be treated by MCN neurolysis or neurectomy. Because few studies examined the pathology of MCN entrapment (MCN-E) we subjected 7 neurectomized specimens from 6 LBP patients to pathologic study. METHODS: We present 6 consecutive patients (7 sides) with intractable LBP who underwent successful MCN neurectomy. Their symptom duration ranged from 6 to 96 months (average 47.3 months); the follow-up period ranged from 6 to 17 months (average 11.7 months). The surgical outcomes were evaluated using the numerical rating scale (NRS) for LBP and the Roland-Morris Disability Questionnaire (RDQ) score. The resected MCNs underwent neuropathological analysis. RESULTS: Postoperatively, all 6 patients reported immediate LBP amelioration; their NRS and RDQ scores were improved significantly. Pathological study of the 7 resected nerves showed that the myelinated fiber density was decreased in 6 nerves; we observed marked enlargement (n = 5), perineurial thickening and disruption (n = 6), intrafascicular fibrous changes (n = 5), myelinated fibers separated by fibrous cells under the perineurium (n = 4), and Renaut bodies (n = 3). The 7th nerve appeared normal with respect to the density and size of the myelinated fibers, however, the perineurium was slightly thickened. CONCLUSION: We present pathological evidence at the MCN compression site of 7 nerves from 6 patients whose LBP was alleviated by MCN neurectomy, indicating that MCN entrapment can elicit LBP.

Muscle Transcriptomics Shows Overexpression of Cadherin 1 in Inclusion Body Myositis.

OBJECTIVE: This study aimed to elucidate the molecular features of inclusion body myositis (IBM). METHODS: We performed RNA sequencing analysis of muscle biopsy samples from 67 participants, consisting of 58 myositis patients with the pathological finding of CD8-positive T cells invading non-necrotic muscle fibers expressing major histocompatibility complex class I (43 IBM, 6 polymyositis, and 9 unclassifiable myositis), and 9 controls. RESULTS: Cluster analysis, principal component analysis, and pathway analysis showed that differentially expressed genes and pathways identified in IBM and polymyositis were mostly comparable. However, pathways related to cell adhesion molecules were upregulated in IBM as compared with polymyositis and controls (p < 0.01). Notably, CDH1, which encodes the epidermal cell junction protein cadherin 1, was overexpressed in the muscles of IBM, which was validated by another RNA sequencing dataset from previous publications. Western blotting confirmed the presence of mature cadherin 1 protein in the muscles of IBM. Immunohistochemical staining confirmed the positivity for anti-cadherin 1 antibody in the muscles of IBM, whereas there was no muscle fiber positive for anti-cadherin 1 antibody in immune-mediated necrotizing myopathy, antisynthetase syndrome, and controls. The fibers stained with anti-cadherin 1 antibody did not have rimmed vacuoles or abnormal protein accumulation. Experimental skeletal muscle regeneration and differentiation systems showed that CDH1 is expressed during skeletal muscle regeneration and differentiation. INTERPRETATION: CDH1 was detected as a differentially expressed gene, and immunohistochemistry showed that cadherin 1 exists in the muscles of IBM, whereas it was rarely seen in those of other idiopathic inflammatory myopathies. Cadherin 1 upregulation in muscle could provide a valuable clue to the pathological mechanisms of IBM. ANN NEUROL 2022;91:317-328.

Impact of periprocedural bleeding on mid-term outcome in nonagenarians who underwent transcatheter aortic valve implantation: insights from LAPLACE registry.

Data from several recent studies have demonstrated the safety and efficacy of transcatheter aortic valve implantation (TAVI) for severe aortic stenosis (AS) even in nonagenarians. However, the impact of periprocedural bleeding following TAVI on their outcome remains unclear. In the aLliAnce for exPloring cLinical prospects of AortiC valvE disease (LAPLACE) registry, we compared outcomes between the bleeding and no-bleeding groups among 1953 patients < 90 years old (mean age, 83.0 ± 4.6 years old) and 316 nonagenarians (mean age, 91.7 ± 1.9 years old) who underwent TAVI with a median follow-up period of 628 days. The group with any periprocedural bleeding showed a higher 30-day mortality than the no-bleeding group in patients < 90 years old (3.3% vs. 0.5%, p = 0.001) and nonagenarians (7.9% vs. 0.7%, p = 0.001). In patients < 90 years old, severe periprocedural bleeding (n = 85) was associated with a higher mid-term all-cause mortality rate than no severe bleeding (n = 1,868), even after adjusting for covariates (hazard ratio [HR], 1.994; 95% confidence interval [CI] 1.287-2.937; p = 0.002). On the other hand, in nonagenarians, any periprocedural bleeding (n = 38) was associated with a higher mid-term cardiovascular (CV) mortality rate (21.1% vs. 4.3%, log-rank p = 0.014) than no bleeding (n = 278), even after adjusting for covariates (HR, 3.104; 95% CI 1.140-8.449; p = 0.027). In conclusion, any periprocedural bleeding after TAVI was associated with mid-term CV mortality in nonagenarians, whereas severe bleeding was associated with mid-term all-cause mortality in patients < 90 years old.

Effect of cerebrospinal fluid drainage pressure in descending and thoracoabdominal aortic repair: a prospective multicenter observational study.

PURPOSE: Cerebrospinal fluid drainage (CSFD) is recommended during open or endovascular thoracic aortic repair. However, the incidence of CSFD complications is still high. Recently, CSF pressure has been kept high to avoid complications, but the efficacy of CSFD at higher pressures has not been confirmed. We hypothesize that CSFD at higher pressures is effective for preventing motor deficits. METHODS: This prospective observational study included 14 hospitals that are members of the Japanese Society of Cardiovascular Anesthesiologists. Patients who underwent thoracic and thoracoabdominal aortic repair were divided into four groups: Group 1, CSF pressure around 10 mmHg; Group 2, CSF pressure around 15 mmHg; Group 3, CSFD initiated when motor evoked potential amplitudes decreased; and Group 4, no CSFD. We assessed the association between the CSFD group and motor deficits using mixed-effects logistic regression with a random intercept for the institution. RESULTS: Of 1072 patients in the study, 84 patients (open surgery, 51; thoracic endovascular aortic repair, 33) had motor deficits at discharge. Groups 1 and 2 were not associated with motor deficits (Group 1, odds ratio (OR): 1.53, 95% confidence interval (95% CI): 0.71-3.29, p = 0.276; Group 2, OR: 1.73, 95% CI: 0.62-4.82) when compared with Group 4. Group 3 was significantly more prone to motor deficits than Group 4 (OR: 2.56, 95% CI: 1.27-5.17, p = 0.009). CONCLUSION: CSFD is not associated with motor deficits in thoracic and thoracoabdominal aortic repair with CSF pressure around 10 or 15 mmHg.

Expanded clinical spectrum of oculopharyngodistal myopathy type 1.

INTRODUCTION/AIMS: Heterozygous CGG repeat expansions in low-density lipoprotein receptor-related protein 12 (LRP12) have recently been identified as a cause of oculopharyngodistal myopathy (OPDM), and the disease is designated as OPDM type 1 (OPDM1). In contrast to broadening of our knowledge on the genetic background of OPDM, what we know of the clinical phenotype of genetically confirmed OPDM1 remains limited. METHODS: This investigation was a single-center case series study of OPDM consisting of ten patients from seven families. Repeat-primed polymerase chain reaction and Southern blot analyses were performed to confirm the CGG repeat expansions in LRP12. Clinical findings were retrospectively reviewed. RESULTS: Seven patients from five families were identified as having CGG repeat expansions in LRP12. We found a high prevalence of axial muscle involvement, such as neck muscle weakness (6/7) and fatty infiltration in the rectus abdominis muscle, as revealed by computed tomography (5/5). We identified patients with very subtle oculopharyngeal symptoms, mimicking isolated distal myopathy. Muscle specimens were collected from the biceps brachii and tibialis anterior muscles of three patients. Myopathic changes were more severe with more atrophic fibers forming clusters in the tibialis anterior than the biceps brachii muscles of these three patients. No rimmed vacuoles were observed in the biceps brachii muscles in two of the three patients. DISCUSSION: This study shows the expanded clinical spectrum of OPDM1, highlighting the importance of axial muscle evaluation in OPDM1. Considering patients with very subtle oculopharyngeal symptoms, genetic analysis of LRP12 should be considered in patients with isolated distal myopathy.

Defective Reelin/Dab1 signaling pathways associated with disturbed hippocampus development of homozygous yotari mice.

Homozygous Dab1 yotari mutant mice, Dab1yot (yot/yot) mice, have an autosomal recessive mutation of Dab1 and show reeler-like phenotype including histological abnormality of the cerebellum, hippocampus, and cerebral cortex. We here show abnormal hippocampal development of yot/yot mice where granule cells and pyramidal cells fail to form orderly rows but are dispersed diffusely in vague multiplicative layers. Possibly due to the positioning failure of granule cells and pyramidal cells and insufficient synaptogenesis, axons of the granule cells did not extend purposefully to connect with neighboring regions in yot/yot mice. We found that both hippocampal granule cells and pyramidal cells of yot/yot mice expressed proteins reactive with the anti-Dab1 antibody. We found that Y198- phosphorylated Dab1 of yot/yot mice was greatly decreased. Accordingly the downstream molecule, Akt was hardly phosphorylated. Especially, synapse formation was defective and the distribution of neurons was scattered in hippocampus of yot/yot mice. Some of neural cell adhesion molecules and hippocampus associated transcription factors of the neurons were expressed aberrantly, suggesting that the Reelin-Dab1 signaling pathway seemed to be importantly involved in not only neural migration as having been shown previously but also neural maturation and/or synaptogenesis of the mice. It is interesting to clarify whether the defective neural maturation is a direct consequence of the dysfunctional Dab1, or alternatively secondarily due to the Reelin-Dab1 intracellular signaling pathways.

Combination Use of Inoue-Balloon and Self-Expandable Transcatheter Valves in Managing Aortic Stenosis Not Amenable to Balloon-Expandable Valves.

Data on the combined use of aortic Inoue-Balloon catheter and self-expandable transcatheter valve for patients undergoing transcatheter aortic valve replacement (TAVR) are lacking. This study aimed to assess the feasibility and safety of this combination, particularly in patients who cannot be safely managed with balloon-expandable valves.Between 2018 and 2021, 140 consecutive patients who had Inoue-Balloon catheters with self-expandable valves were retrospectively examined. Self-expandable transcatheter valves were deployed using the heart team approach in patients with calcification on the left ventricular outflow tract, which could not be safely addressed with the current-generation balloon-expandable valves.The 20- and 22 mm Inoue-Balloon catheters were used with the 26- and 29 mm Evolut valves, respectively. According to the Valve Academic Research Consortium-2 criteria, the procedural success rate was 95.0%, with an early safety at 30 days rate of 6.5%. A total of 27 patients required post-dilation with the same Inoue-Balloon catheter used for pre-dilation after adjustment to appropriate sizes. Post-dilation, with balloon size adjusted to be 1.4 ± 0.9 mm larger than that in pre-dilation, was effective in 19 out of 27 patients (70.3%) for decreasing paravalvular leak after transcatheter valve deployment. The procedural complication rates between patients with and without post-dilation were not different.The combined use of the size-adjustable Inoue-Balloon catheter and self-expandable valve is safe, particularly in patients who cannot be safely managed with balloon-expandable valves. However, further studies are warranted to elucidate concerns regarding the durability of self-expandable transcatheter valves after post-dilation using the Inoue-Balloon catheter.

Cerebrospinal fluid drainage to prevent postoperative spinal cord injury in thoracic aortic repair.

BACKGROUND: Cerebrospinal fluid drainage (CSFD) is recommended as a spinal cord protective strategy in open and endovascular thoracic aortic repair. Although small studies support the use of CSFD, systematic reviews have not suggested definite conclusion and a large-scale study is needed. Therefore, we reviewed medical records of patients who had undergone descending and thoracoabdominal aortic repair (both open and endovascular repair) at multiple institutions to assess the association between CSFD and postoperative motor deficits. METHODS: Patients included in this study underwent descending or thoracoabdominal aortic repair between 2000 and 2013 at 12 hospitals belonging to the Japanese Association of Spinal Cord Protection in Aortic Surgery. We conducted a retrospective study to investigate whether motor-evoked potential monitoring is effective in reducing motor deficits in thoracic aortic aneurysm repair. We use the same dataset to examine whether CSFD reduces motor deficits after propensity score matching. RESULTS: We reviewed data from 1214 patients [open surgery, 601 (49.5%); endovascular repair, 613 (50.5%)]. CSFD was performed in 417 patients and not performed in the remaining 797 patients. Postoperative motor deficits were observed in 75 (6.2%) patients at discharge. After propensity score matching (n = 700), mixed-effects logistic regression performed revealed that CSFD is associated with postoperative motor deficits at discharge [adjusted odds ratio (OR), 3.87; 95% confidence interval (CI), 2.30-6.51]. CONCLUSION: CSFD may not be effective for postoperative motor deficits at discharge.

First external validation of sensitivity and specificity of the European League Against Rheumatism (EULAR)/American College of Rheumatology (ACR) classification criteria for idiopathic inflammatory myopathies with a Japanese cohort.

OBJECTIVE: To externally validate the performance of the new European League Against Rheumatism (EULAR)/American College of Rheumatology (ACR) classification criteria set for idiopathic inflammatory myopathies (IIM) with a Japanese cohort. METHODS: This study included 420 IIM and 402 non-IIM cases. Probability of having IIM in each patient was calculated using the collected data set. The cut-off probability was set at 55%, as recommended by EULAR/ACR. Patients classified as IIM by the criteria were further subclassified with classification trees. RESULTS: When the probability cut-off was set at 55%, the sensitivity/specificity of the new criteria to diagnose IIM were 89.3%/91.0% in the total cohort, 88.1%/95.1% without muscle biopsy data and 90.4%/65.5% with biopsy data. The cohort included 12 overlap syndrome patients with biopsy data, who were included as non-IIM cases in accordance with traditional Japanese methods. When they were included in the IIM cases, the specificity in patients with biopsy increased to 74.4%. The sensitivity/specificity of the new criteria to diagnose polymyositis/dermatomyositis (PM/DM) plus juvenile and amyopathic DM in the Japanese cohort was 87.4%/92.4%, which were greater than those of the Tanimoto's criteria revised to enable classification of amyopathic DM (ADM) (71.2%/87.8%) and were comparable with those of Bohan & Peter's criteria to diagnose those diseases except for ADM (88.4%/88.3%). CONCLUSIONS: Our study externally validated high specificity of the new criteria for the first time, although with several limitations, including low percentage of child patients. The new criteria have higher sensitivity and/or specificity in classification of PM/DM than the previously reported criteria, demonstrating its usefulness for interethnic patients.

Prolonged Intensive Care Unit Stay Following Transcatheter Aortic Valve Replacement.

PURPOSE: Postoperative intensive care unit (ICU) stay after cardiac surgeries has been extensively studied, but little attention has been given to ICU stay following transcatheter aortic valve replacement (TAVR). This study examined ICU stay after TAVR. METHODS: Two hundred and forty-five patients who underwent TAVR between April 2010 and October 2016 were studied retrospectively. We investigated the status of ICU stay, the predictors of prolonged ICU stay (PICUS), and its impact on short- and long-term outcomes. Prolonged ICU stay was defined as post-TAVR ICU stay longer than 2 days (day of TAVR + 1 day). RESULTS: Length of ICU stay was 2.6 ± 4.9 days, and PICUS was identified in 14.7% of the patients. The predominant reason for PICUS was congestive heart failure or circulatory failure (41.7%). Pulmonary dysfunction and nontransfemoral approach were independent predictors of PICUS (pulmonary dysfunction: odds ratio = 2.64, 95% confidence interval [CI]: 1.05-7.35; nontransfemoral approach: odds ratio = 2.81, 95% CI: 1.15-6.89). Prolonged ICU stay was associated with higher rate of 30-day combined end point (PICUS vs non-PICUS: 44.4% vs 3.3%, P < .0001), longer postoperative hospital stay (49.9 ± 141.9 days vs 12.0 ± 6.0 days, P < .0001), and lower rate of discharge home (77.8% vs 95.2%, P = .0002). Patients with PICUS had worse long-term survival (P < .0001), and PICUS was a predictor of mortality (hazard ratio: 4.21, 95% CI: 2.09-8.22). CONCLUSION: Prolonged ICU stay following TAVR was found in 14.7%, and pulmonary dysfunction and nontransfemoral approach were associated with PICUS. Short- and long-term prognoses were worse in patients with PICUS than those without.

Transcatheter aortic valve implantation-related futility: prevalence, predictors, and clinical risk model.

Futility denotes failure to achieve the projected outcome. We investigated the prevalence, predictors, and clinical risk model of transcatheter aortic valve implantation (TAVI)-related futility. We included 464 consecutive patients undergoing TAVI from 2010 to 2017. Futility was defined as death and/or hospitalization for heart failure (HFH) within 1 year after TAVI. Of 464 patients (mean age: 84.4 years), 69% were females (EuroSCOREII: 6.3%; Society of Thoracic Surgeons [STS] score: 6.9%). Forty-six patients (9.9%) experienced TAVI-related futility, and 36 of 46 patients (69.6%) died within 1 year due to cardiac (37.5%) and non-cardiac (62.5%) causes. Previous HFH (hazard ratio [HR], 2.20; 95% confidence interval [CI]: 1.13-4.35, p = 0.020), chronic obstructive pulmonary disease (COPD) (HR, 3.39; 95% CI: 1.12-8.42, p = 0.033), and moderate/severe mitral or tricuspid regurgitation (HR, 2.98; 95% CI: 1.32-6.27, p = 0.010) were independent predictors of futility. With 1 point assigned to each predictor (total 0 point, futility low-risk; total 1 point, futility intermediate-risk; total 2-3 points, futility high-risk), the futility risk model clearly stratified individual futility risk into three groups (the freedom from futility at 1 year: 96.2%, 82.1%, and 67.9% each). Our futility risk model presented better discrimination than EuroSCOREII, and STS score (c-statistic: 0.73 vs. 0.68 vs. 0.67). Medical futility was recognized in 9.9% of patients undergoing TAVI. Previous HFH, COPD, and concomitant atrioventricular regurgitation were associated with futility. The risk model derived from three predictors showed good performance in predicting futility risk.

Interaction between SDF1 and CXCR4 Promotes Photoreceptor Differentiation via Upregulation of NFκB Pathway Signaling Activity in Pax6 Gene-Transfected Photoreceptor Precursors.

BACKGROUND: CCL2 (also known as monocyte chemoattractant protein 1) and CX3CR1 (also known as Fractalkine receptor)-deficient mice have damaged photoreceptors. OBJECTIVES: We examined the interaction of SDF1 and CXCR4 on the differentiation of retinal progenitors into rhodopsin-positive photoreceptors. METHODS: Cloned retinal progenitors were obtained by Pax6 gene transfection of mouse iPS cells followed by serial dilution. Clones were selected by expression of nestin, Musashi1, Six3, and Chx10 mRNA. Cell surface protein expression was analyzed by flow cytometry. The levels of mRNA and intracellular protein were examined by real-time PCR and immunochemistry, respectively. Transient transfection experiments of retinal progenitors were conducted using a human rhodopsin promoter luciferase plasmid. RESULTS: We selected 10 clones that expressed Six3, Chx10, Crx, Rx1, Nrl, CD73, and rhodopsin mRNA, which, except for rhodopsin, are photoreceptor precursor markers. Clones expressed both CD73 and CXCR4 on the cell surface and differentiated into rhodopsin-positive photoreceptors, which was reinforced by the addition of exogenous SDF1. A CXCR4 inhibitor AMD3100 blocked SDF1-mediated differentiation of progenitors into photoreceptors. SDF1 enhanced human rhodopsin promoter transcription activity, possibly via the NFκB pathway. Addition of SDF1 to the cell culture induced nuclear translocation of NFκB on retinal progenitor cell clones. Neonatal and newborn mouse retinas expressed SDF1 and CXCR4. Cells in the outer nuclear layer where photoreceptors are located expressed CXCR4 at P14 and P56. Cells in the inner nuclear layer expressed SDF1. CONCLUSIONS: These findings suggest that retinal progenitor cell differentiation was at least partly regulated by SDF1 and CXCR4 via upregulation of NFκB activity.

Collagen-derived dipeptide prolyl hydroxyproline directly binds to Foxg1 to change its conformation and inhibit the interaction with Runx2.

Collagen-derived dipeptide prolyl hydroxyproline (Pro-Hyp) is involved in the proliferation and differentiation of various types of cultured cells. To elucidate the mechanism underlying Pro-Hyp actions during osteoblast differentiation, we hypothesized that proteins binding to Pro-Hyp serve to mediate cellular signaling, affecting Runx2 expression. Recently, we performed the characterization of Foxg1, that it enhances Runx2 expression in the presence of Pro-Hyp. Our findings indicate that Pro-Hyp directly binds to the Foxg1 recombinant protein, which leads to the structural alteration of the Foxg1 protein. In addition, Foxg1 appears to interact with Runx2 in the absence of Pro-Hyp, with Pro-Hyp disrupting the interaction between Foxg1 and Runx2. Collectively, our results indicate that the Pro-Hyp bound Foxg1 alters the structured conformation of Foxg1, resulting in conformational changes that lead to dissociation from Runx2. These novel findings suggest that during osteoblast differentiation, Pro-Hyp mediates Runx2 activity though directly binding to Foxg1 and increases Runx2 expression. Abbreviations: CPT: collagen peptide; GST: Glutathione S-transferase; PAGE: Polyacrylamide gel electrophoresis; PCR: Polymerase chain reaction; prolyl hydroxyproline: Pro-Hyp.

Outcomes of Transcatheter Aortic Valve Implantation in Patients with Cirrhosis.

Cirrhosis is a significant adverse factor of cardiac surgeries. Transcatheter aortic valve implantation (TAVI) has evolved as a less invasive therapy for aortic stenosis, whereas detailed case analysis of TAVI in cirrhotic patients is limited.Among 444 consecutive patients who underwent TAVI in the Sakakibara Heart Institute between October 2013 and January 2018, we retrospectively reviewed 11 patients (2.5%) with cirrhosis. All outcomes were defined according to the Valve Academic Research Consortium-2 criteria.The median age of the patients was 82 years, and eight (73%) were female. Seven patients (64%) were Child-Turcotte-Pugh class A, and four patients (36%) were class B. The Model for End-Stage Liver Disease score was 10 (7.0-13). TAVI was performed using Edwards SAPIEN XT/SAPIEN3 in nine patients (82%), and Medtronic CoreValve/Evolut R in two patients (18%), via transfemoral (n = 8, 73%) or transapical (n = 3, 27%) approach. The device success rate was 100% and no extracorporeal circulation had been inducted. No death, stroke, life-threatening bleeding, and acute kidney injury stage 2 or 3 occurred within 30 days, but three major bleeding events (27%) were documented (two access-site bleeding in transapical approach, and one pulmonary hemorrhage caused by transient mitral regurgitation). During a median follow-up of 493 days, four deaths had occurred, and the mid-term survival rate was 81% and 65% at one and two years each.TAVI is a promising therapeutic option for patients with cirrhosis. Further study should be needed regarding optimal patient selection and procedures in patients with cirrhosis.

Treatment consensus for management of polymyositis and dermatomyositis among rheumatologists, neurologists and dermatologists.

Although rheumatologists, neurologists and dermatologists see patients with polymyositis (PM) and dermatomyositis (DM), their management appears to vary depending on the physician's specialty. The aim of the present study was to establish the treatment consensus among specialists of the three fields to standardize the patient care. We formed a research team supported by a grant from the Ministry of Health, Labor and Welfare, Japan. Clinical questions (CQ) on the management of PM and DM were raised. A published work search on CQ was performed primarily using PubMed. Using the nominal group technique, qualified studies and results in the published work were evaluated and discussed to reach consensus recommendations. They were sent out to the Japan College of Rheumatology, Japanese Society of Neurology and Japanese Dermatological Association for their approval. We reached a consensus in 23 CQ and made recommendations and a decision tree for management was proposed. They were officially approved by the three scientific societies. In conclusion, a multidisciplinary treatment consensus for the management of PM and DM was established for the first time.

Splicing variant of WDFY4 augments MDA5 signalling and the risk of clinically amyopathic dermatomyositis.

OBJECTIVES: Idiopathic inflammatory myopathies (IIMs) are a heterogeneous group of rare autoimmune diseases in which both genetic and environmental factors play important roles. To identify genetic factors of IIM including polymyositis, dermatomyositis (DM) and clinically amyopathic DM (CADM), we performed the first genome-wide association study for IIM in an Asian population. METHODS: We genotyped and tested 496 819 single nucleotide polymorphism for association using 576 patients with IIM and 6270 control subjects. We also examined the causal mechanism of disease-associated variants by in silico analyses using publicly available data sets as well as by in in vitro analyses using reporter assays and apoptosis assays. RESULTS: We identified a variant in WDFY4 that was significantly associated with CADM (rs7919656; OR=3.87; P=1.5×10-8). This variant had a cis-splicing quantitative trait locus (QTL) effect for a truncated WDFY4isoform (tr-WDFY4), with higher expression in the risk allele. Transexpression QTL analysis of this variant showed a positive correlation with the expression of NF-κB associated genes. Furthermore, we demonstrated that both WDFY4 and tr-WDFY4 interacted with pattern recognition receptors such as TLR3, TLR4, TLR9 and MDA5 and augmented the NF-κB activation by these receptors. WDFY4 isoforms also enhanced MDA5-induced apoptosis to a greater extent in the tr-WDFY4-transfected cells. CONCLUSIONS: As CADM is characterised by the appearance of anti-MDA5 autoantibodies and severe lung inflammation, the WDFY4 variant may play a critical role in the pathogenesis of CADM.

Novel De Novo KCND3 Mutation in a Japanese Patient with Intellectual Disability, Cerebellar Ataxia, Myoclonus, and Dystonia.

Spinocerebellar ataxia 19/22 (SCA19/22) is a rare type of autosomal dominant SCA that was previously described in 11 families. We report the case of a 30-year-old Japanese man presenting with intellectual disability, early onset cerebellar ataxia, myoclonus, and dystonia without a family history. MRI showed cerebellar atrophy, and electroencephalograms showed paroxysmal sharp waves during hyperventilation and photic stimulation. Trio whole-exome sequencing analysis of DNA samples from the patient and his parents revealed a de novo novel missense mutation (c.1150G>A, p.G384S) in KCND3, the causative gene of SCA19/22, substituting for evolutionally conserved glycine. The mutation was predicted to be functionally deleterious by bioinformatic analysis. Although pure cerebellar ataxia is the most common clinical feature in SCA19/22 families, extracerebellar symptoms including intellectual disability and myoclonus are reported in a limited number of families, suggesting a genotype-phenotype correlation for particular mutations. Although autosomal recessive diseases are more common in patients with early onset sporadic cerebellar ataxia, the present study emphasizes that such a possibility of de novo mutation should be considered.

Low back pain due to superior cluneal nerve entrapment: A clinicopathologic study.

INTRODUCTION: We studied the clinical and nerve pathologic features in 6 patients whose low back pain (LBP) was relieved by superior cluneal nerve (SCN) neurectomy to determine whether nerve compression was the mechanism underlying this type of LBP. METHODS: All 6 patients (7 nerves) underwent SCN neurectomy for intractable LBP. Their clinical outcomes and the pathologic features of 7 nerves were reviewed. RESULTS: All patients reported LBP relief immediately after SCN neurectomy. Pathologic study of the 7 resected nerves showed marked enlargement, decreased myelinated fiber density, an increase in thinly myelinated fibers (n = 2), perineurial thickening (n = 5), subperineurial edema (n = 4), and Renaut bodies (n = 4). At the distal end of 1 enlarged nerve, we observed a moderate reduction in the density and marked reduction in the number of large myelinated fibers. DISCUSSION: The pathologic findings and effectiveness of neurectomy suggest that, in our patients, SCN neuropathy likely elicited LBP via nerve compression. Muscle Nerve 57: 777-783, 2018.

Outcomes of patients requiring extracorporeal membrane oxygenation in transcatheter aortic valve implantation: a clinical case series.

Transcatheter aortic valve implantation (TAVI) has been established as a low-invasive therapy for aortic stenosis, but circulatory collapse necessitating mechanical circulatory support could occur during TAVI due to procedure itself or procedural complications. The purpose of this study is to describe the outcomes of patients requiring extracorporeal membrane oxygenation (ECMO) in TAVI. Among 384 consecutive patients undergoing TAVI from April 2010 to July 2017 in Sakakibara Heart Institute, we evaluated seven patients (1.8%) who required ECMO during procedure. The definitions of outcome were derived from Valve Academic Research Consortium-2 criteria. The indication of ECMO included bridge to emergent surgery due to mechanical complication (n = 3) [aortic root rupture (n = 2), and left-ventricle rupture (n = 1); emergent use], bridge to recovery from cardiac stunning (n = 3; emergent use), and circulatory support for cardiogenic shock (n = 1; prophylactic use). All patients were cannulated from femoral artery and vein, and there was no ECMO-related complication. Six out of seven patients were weaned from ECMO during the TAVI procedure, whereas the other patient with annulus rupture died the following day after TAVI. Five patients survived to discharge [postoperative hospital stay: 27.6 ± 24.3 (23) days]. During mean follow-up of 253 days, a total of three patients died due to annulus rupture, refractory heart failure, and pneumonia, respectively. ECMO is effective and a safe mechanical support device during TAVI. The mid-term outcomes of patients who needed ECMO were unfavorable. Further evolution of transcatheter heart valve is essential, and prophylactic ECMO may contribute to better prognosis in selected patients.

Renoprotective Transcatheter Aortic Valve Implantation Without Contrast Media.

The therapeutic role of transcatheter aortic valve implantation (TAVI) in high surgical risk or inoperable cases has been established. Most of the candidates for TAVI are elderly and have multiple comorbidities including chronic kidney disease. However, contrast-enhanced computed tomography and coronary angiography, both of which require iodine contrast media, are essential for pre-procedural planning. In addition, TAVI could have adverse effects on kidney function including contrast media-induced nephrotoxicity. Acute kidney injury following TAVI has been reported to be related to poor prognosis. In a case with advanced renal dysfunction, we successfully avoided post-procedural acute kidney injury by performing pre-procedural evaluation using minimal contrast and TAVI without contrast media. If anatomical conditions and experiences of the heart team are adequate, renoprotective TAVI should be a favorable therapy for patients with aortic stenosis complicated by renal dysfunction.