Clinical and Radiological Features of Korean Patients With Anti-HMGCR Myopathy.

BACKGROUND AND PURPOSE: To understand the characteristics of Korean patients with anti-3-hydroxy-3-methylglutaryl-coenxyme A reductase (HMGCR) myopathy, we measured anti-HMGCR antibodies and analyzed the clinical, radiological, and pathological features of patients with anti-HMGCR myopathy. METHODS: We measured titers of anti-HMGCR antibodies in the sera of 99 patients with inflammatory myopathy, 36 patients with genetic myopathy, and 63 healthy subjects using an enzyme-linked immunosorbent assay. We tested 16 myositis-specific autoantibodies (MSAs) in all patients with anti-HMGCR myopathy. RESULTS: Positivity for the anti-HMGCR antibody was observed in 17 (4 males and 13 females) of 99 patients with inflammatory myopathy. The median age at symptom onset was 60 years. Ten (59%) of the patients with anti-HMGCR positivity had taken statins. The titer of anti-HMGCR antibodies was significantly higher in the statin-naïve group (median=230 U/mL, interquartile range=170-443 U/mL) than in the statin-exposed group (median=178 U/mL, interquartile range=105-210 U/mL, p=0.045). The most common symptom was proximal muscle weakness in 15 patients (88%), followed by myalgia in 9 (53%), neck weakness in 4 (24%), dysphagia in 3 (18%), and skin lesions in 2 (12%). The median titer of anti-HMGCR antibody was 202 U/mL. We found eight different MSAs in nine (53%) patients. The median disease duration from symptom onset to diagnosis was significantly shorter in the MSA-positive group than in the MSA-negative group (p=0.027). CONCLUSIONS: Our study was the first to measure anti-HMGCR antibodies in inflammatory myopathy. It has provided new findings, including the suggestion of the coexistence of other MSAs in Korean patients.

Effect of Job Stress on Burnout among Nurses Responding to COVID-19: The Mediating Effect of Resilience.

Background: This study was conducted to evaluate the relationship of job stress, burnout, and resilience of 271 nurses who worked alternately at a university hospital in South Korea Province and a state-designated inpatient ward for COVID-19 in Korea. Methods: The study sample included nurses who worked at a university hospital in South Korea, during the period between February 2020 and May 2021. The participants (n = 271) responded to an online survey between April 2021 and 12 May 2021. The questionnaire included information related to job stress, burn out, and resilience. Results: In phase 1 of regression, job stress had a significant negative effect on resilience of recovery (ß = −0.397, p < 0.001). In phase 2, job stress had a significant positive effect on burnout (ß = 0.513, p < 0.001). In phase 3, resilience had a significant negative effect on burnout (ß = −0.459, p < 0.001). Seventy-five percent of burnout was directly associated with job stress, while 25% of burnout was indirectly associated through mediated effects, through resilience. Conclusions: The promotion of resilience would not only serve as the basis for active coping in situations where burnout and stress are severe, but also serve as a basic driving force for actively overcoming them. Further study to cope with stress and reduce burnout at the organizational level should be conducted.

SOHO State of the Art Updates and Next Questions: Pathology and Pathogenesis of Nodal Peripheral T-Cell Lymphomas.

Peripheral T-cell lymphomas (PTCLs) are a heterogeneous and often clinically aggressive group of neoplasms derived from mature post-thymic T-lymphocytes. These neoplasms are rare and usually diagnostically challenging. Our understanding of the pathogenesis of PTCL is increasing and this improved knowledge is leading us to better molecular characterization, more objective and accurate diagnostic criteria, more effective risk assessment, and potentially better treatments. The focus of this paper is to present a brief overview of the current pathology criteria and molecular and genetic features of nodal peripheral T-cell lymphomas focusing on distinct genetically and molecularly defined subgroups that are being recognized within each major nodal PTCL category. It is expected that the molecular stratification will improve the diagnosis and will provide novel therapeutic opportunities (biomarker-driven and targeted therapies) that might benefit and change the outcomes of patients with these neoplasms.

Presence of concurrent sarcoid-like granulomas indicates better survival in cancer patients: a retrospective cohort study.

INTRODUCTION: An increased risk of sarcoidosis and sarcoid-like reactions in subjects with a history of malignancy has been suggested. We assessed the incidence and clinical characteristics of cancer patients with biopsies containing sarcoid-like granulomas on cancer metastasis and patient survival. METHODS: This is a retrospective, multicentre, observational study involving endobronchial ultrasound transbronchial needle aspiration and a melanoma patient dataset at the University of Miami, USA, and a sarcoidosis patient database at Chiba University, Japan. Subjects with a confirmed diagnosis of cancer and who subsequently developed granulomas in different organs were enrolled. The study was registered at Clinicaltrials.gov (NCT03844698). RESULTS: 133 patients met the study's criteria. The most common primary cancer sites were the skin (22.5%), breast (20.3%) and lymph node (12.8%). 24 (18%) patients developed sarcoid-like granulomas within 1 year of cancer diagnosis, 54 (40.6%) between 1 and 5 years and 49 (36.8%) after 5 years. Imaging showed possible sarcoid-like granulomas in lymph nodes in 51 cases (38.3%) and lung tissue and mediastinal lymph nodes in 73 cases (54.9%); some parenchymal reticular opacity and fibrosis was found in 5 (3.7%) and significant parenchymal fibrosis in 2 (1.5%) subjects. According to logistic regression analysis, the frequency of metastatic cancer was significantly lower in patients with sarcoid-like granulomas than in controls. Moreover, multivariate Cox proportional hazard analysis showed a significant survival advantage in those with sarcoid-like granuloma. CONCLUSION: Sarcoid-like granulomas are uncommon pathology findings in cancer patients. There is a significant association between the presence of granulomas and reduced metastasis and increased survival. Further study is warranted to understand the protective mechanism involved.

A case of neuromyelitis optica spectrum disorder following seasonal influenza vaccination.

There have been reports of central nervous systemic inflammatory disease associated with vaccination. We describe a female patient who developed longitudinally extensive transverse myelitis following seasonal influenza vaccination. A 38-year-old woman had severe neck and back pain with urinary retention. She received influenza vaccine 3 days before symptom onset. Examination revealed mild quadriparesis with diffuse hyperreflexia. Magnetic resonance imaging (MRI) of the spine showed a T2 hyperintense lesion with gadolinium enhancement in the spinal cord extending from the cervicomedullary junction to the level of T10. Brain MRI revealed no specific finding for demyelinating lesions. Cerebrospinal fluid had a white blood cell count of 60/L (mononuclear cells 95%) with a protein concentration of 78.2 mg/dL and the blood serum was positive for anti-aquaporin-4 antibodies. She was treated with high-dose methylprednisolone for 5 days followed by tapering of prednisolone. Symptoms improved significantly after treatment. We report a case of neuromyelitis optica spectrum disorder following seasonal influenza vaccination. Neuromyelitis optica spectrum disorder may have been triggered by the recent influenza vaccination, although a pathogenic link has not been established.

Enlarging Bump on the Scrotum.

Extramammary Paget disease is a rare, slow-growing intraepithelial neoplasm of the skin or its underlying appendages. It more commonly affects the apocrine glands of the axilla, vulva, perianal region, scrotum, and/or penis. It often presents as a well-demarcated, thickened, erythematous, or gray-white scaly plaque with indolent growth that may become ulcerated, crusted, papillomatous, or eczematous over time. Pruritus, pain, and burning sensations are common symptoms; however, they are not appreciated by all patients. Many patients are erroneously treated for eczema for months to years before a proper diagnosis is reached. Patients presenting with chronic genital or perineal dermatitis or skin lesions that have been unresponsive to topical therapy should be biopsied for definitive diagnosis.

Thalamo-cortical network underlying deep brain stimulation of centromedian thalamic nuclei in intractable epilepsy: a multimodal imaging analysis.

OBJECTIVE: Deep brain stimulation (DBS) of the centromedian thalamic nucleus (CM) can be an alternative treatment option for intractable epilepsy patients. Since CM may be involved in widespread cortico-subcortical networks, identification of the cortical sub-networks specific to the target stimuli may provide further understanding on the underlying mechanisms of CM DBS. Several brain structures have distinguishing brain connections that may be related to the pivotal propagation and subsequent clinical effect of DBS. METHODS: To explore core structures and their connections relevant to CM DBS, we applied electroencephalogram (EEG) and diffusion tensor imaging (DTI) to 10 medically intractable patients - three generalized epilepsy (GE) and seven multifocal epilepsy (MFE) patients unsuitable for resective surgery. Spatiotemporal activation pattern was mapped from scalp EEG by delivering low-frequency stimuli (5 Hz). Structural connections between the CM and the cortical activation spots were assessed using DTI. RESULTS: We confirmed an average 72% seizure reduction after CM DBS and its clinical efficiency remained consistent during the observation period (mean 21 months). EEG data revealed sequential source propagation from the anterior cingulate, followed by the frontotemporal regions bilaterally. In addition, maximal activation was found in the left cingulate gyrus and the right medial frontal cortex during the right and left CM stimulation, respectively. From DTI data, we confirmed concrete structural connections between CM and those maximal activation spots identified from EEG data. CONCLUSION: These results suggest that the anterior cingulate can be a core cortical structure for the bilateral propagation of CM stimulation. Our DTI findings also indicate that the propagation of CM stimulation may rely upon integrity of structural connections between CM and these key cortical regions. Structures and their connections found in this study may be relevant in the interpretation of the clinical outcomes of CM DBS.

Cerebrospinal Biomarker Cut-off Methods Defined Only by Alzheimer's Disease Predict More Precisely Conversions of Mild Cognitive Impairment.

BACKGROUND AND PURPOSE: The cerebrospinal fluid (CSF) biomarkers play an important supportive role as diagnostic and predictive indicators of Alzheimer's disease (AD). About 30% of controls in old age show abnormal values of CSF biomarkers and display a higher risk for AD compared with those showing normal values. The cut-off values are determined by their diagnostic accuracy. However, the current cut-off values may be less accurate, because controls include high-risk groups of AD. We sought to develop models of patients with AD, who are homogenous for CSF biomarkers. METHODS: We included participants who had CSF biomarker data in the Alzheimer's Disease Neuroimaging Initiative database. We investigated the factors related to CSF biomarkers in patients with AD using linear mixed models. Using the factors, we developed models corresponding to CSF biomarkers to classify patients with mild cognitive impairment (MCI) into high risk and low risk and analyzed the conversion from MCI to AD using the Cox proportional hazards model. RESULTS: APOE ε4 status and age were significantly related to CSF Aß1-42. CSF t-tau, APOE ε2 status and sex were significant factors. The CSF p-tau181 was associated with age and frequency of diagnosis. Accordingly, we modeled the three CSF biomarkers of AD. In MCI without APOE ε4, our models were better predictors of conversion. CONCLUSIONS: We can interpret CSF biomarkers based on the models derived from the data obtained from patients with AD.

Distal hereditary motor neuropathy type 7B with Dynactin 1 mutation.

Mutations in the Dynactin 1 (DCTN1) gene have been demonstrated to result in various neurodegenerative diseases, including distal hereditary motor neuropathy type 7B (dHMN7B), Perry syndrome, amyotrophic lateral sclerosis and amyotrophic lateral sclerosis­frontotemporal dementia. However, since the first dHMN7B patient with a DCTN1 mutation was described in 2003, to the best of our knowledge no further cases have been reported. In the present study, the DCTN1 p.G59S mutation was identified in two unrelated families from a total of 24 Korean families with dHMN, by whole exome sequencing. Codon 59 appears to be the mutational hot spot in the DCTN1 gene, as all described dHMN7B patients to date have harbored an identical p.G59S mutation. The families of the present study with the DCTN1 mutation had a milder disease with a later onset compared with the previously described patients. No affected family members exhibited facial muscle weakness or bulbar involvement. One family member demonstrated vocal cord palsy as the initial sign of disease; however, in the other family hand muscle weakness was the first major symptom. No affected patients demonstrated sensory loss or upper motor neuron involvements. Although this is only the second report of dHMN7B resulting from a DCTN1 mutation, the frequency of the DCTN1 mutation was not low in the Korean population examined, and clinical heterogeneities were observed in patients with the DCTN1 mutation. Therefore, it may be beneficial to screen all dHMN patients for the DCTN1 mutation.

Mild cognitive impairment due to alzheimer disease is less likely under the age of 65.

Patients with amnestic mild cognitive impairment (aMCI) are considered to have a high risk for Alzheimer dementia (AD). Even high positive predictive values, however, cannot be guaranteed even by tests with high sensitivity and specificity when disease prevalence is low. If we regard the clinical criteria for aMCI as a test for predicting aMCI due to AD, the positive predictive value of the criteria will be low by definition in young patients with aMCI (age below 65 years) because of the low prevalence of AD in this age group. To test this hypothesis, we compared CSF biomarkers for AD between young (age below 65 years) and old (age 65 years or older) age groups of normal cognition, aMCI, and AD of the Alzheimer's Disease Neuroimaging Initiative database. Using these biomarkers, we observed that the prevalence of aMCI due to AD differed significantly between the young and the old. For example, only 28.2% young aMCI, but 63.2% old aMCI, had abnormal CSF amyloid measures consistent with AD pathology. As posited, the presence of aMCI due to AD was lower in young aMCI than in old aMCI. Given that the likelihood of aMCI due to AD is reduced in younger subjects, more attention to and evaluation of alternative diagnoses need to be considered in this group.

Subcortical vascular dementia (SVaD) without hypertension (HTN) may be a unique subtype of vascular dementia (VaD).

Although HTN is the most important factor in the pathogenesis of SVaD, about 20% of patients with SVaD do not have HTN. We hypothesize that SVaD without HTN may have strong risk factors other than HTN, and the study on this group can elucidate the risk factors for SVaD. We included 332 patients with SVaD from the database of the Clinical Research Center for Dementia of South Korea (CREDOS) study. Among them, 26.2% of patients (87 out of 332) had no history of HTN. We analyzed the differences in risk factors, clinical features, and survival time of SVaD according to HTN. Contrary to our expectations, SVaD without HTN had less known vascular risk factors such as diabetes mellitus (DM), dyslipidemia, and obesity. In addition, SVaD without HTN had different clinical features including less depression, focal neurological signs or symptoms and more features of disinhibition. However, although SVaD without HTN had less known vascular risk factors that can shorten survival times, the survival times did not differ according to the presence of HTN. SVaD without HTN may be a unique subtype of SVaD and can be a target group for studies of unknown risk factors for SVaD.

Distribution of the corticobulbar tract in the internal capsule.

It is generally thought that the corticobulbar tract descends through the genu of the internal capsule (IC). There have been several reports that genu lesions cause bulbar symptoms such as facial palsies, dysarthria, and dysphagia. However, the precise location of the corticobulbar tract in the IC remains controversial. The purpose of our study is to assess whether the corticobulbar tract passes through the IC genu. We reviewed 26 patients with selective IC infarction and located the sites related to bulbar symptoms. In addition, using diffusion tensor imaging, we reconstructed tracts passing through the IC in ten subjects without cerebral infarction. Patients with genu infarction, which extended to more than half of the posterior limb of the IC, showed bulbar symptoms. However, patients with genu infarction, which was limited to the genu, did not have bulbar symptoms. In contrast, patients with lesions limited to the posterior limb may show bulbar symptoms. According to statistical maps of the region of interest, the lesions related to bulbar symptoms were localized to areas that were beyond the midpoint of the posterior limb of the IC. In diffusion tensor imaging of subjects without cerebral infarctions, the corticobulbar and corticospinal tracts did not pass through the IC genu. Our data provide evidence that the corticobulbar tract does not pass through the IC genu. The proposed location of the corticobulbar tract in the level of the IC lies beyond the midpoint of the posterior limb.

A case of isolated middle cerebral artery stenosis with hemichorea and moyamoya pattern collateralization.

Isolated middle cerebral artery (MCA) stenosis in young patients with no other medical condition may be a unique pathologic entity with a benign long-term course. Generally, moyamoya disease shows a progression of stenosis from internal cerebral artery (ICA) to other intracranial vessel. A 26-year-old woman was admitted for choreic movements of the right arm and leg. Brain magnetic resonance imaging showed no stroke. Conventional angiography revealed 48% stenosis of the left M1 without ICA stenosis. Single photon emission computed tomography revealed perfusion asymmetry after acetazolamide injection, suggesting decreased uptake in the left basal ganglia and the cerebral cortex. Her hemichorea was mildly decreased with risperidone. One year later, follow-up angiography showed complete occlusion of the left M1 with neovascularization suggestive of moyamoya disease. The patient underwent bypass surgery and her hemichorea disappeared. This may be an atypical presentation of moyamoya disease. The bypass surgery was an effective measure for restoring the vascular insufficiency and, resultantly, controlling her hemichorea.

The application of molecular techniques to solid tumors.

Recent developments in the field of molecular biology including the sequencing of the human genome and related high throughput methodologies are presenting the diagnostic pathologist with new opportunities to expand our understanding of human disease. These techniques enable the comprehensive assessment of molecular alterations with cell populations of interest, including cancer. It will be necessary for the diagnostic pathologist to become familiar with these techniques to effectively translate their potential into the clinical environment.