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[PMID]: 29510721 [Au] Autor: Gill AJ; Garza R; Ambegaokar SS; Gelman BB; Kolson DL [Ad] Address: Department of Neurology, Perelman School of Medicine, University of Pennsylvania, 415 Curie Boulevard, 280C Clinical Research Building, Philadelphia, PA, 19104, USA. [Ti] Title: Heme oxygenase-1 promoter region (GT)n polymorphism associates with increased neuroimmune activation and risk for encephalitis in HIV infection. [So] Source: J Neuroinflammation;15(1):70, 2018 Mar 06. [Is] ISSN: 1742-2094 [Cp] Country of publication: England [La] Language: eng [Ab] Abstract: BACKGROUND: Heme oxygenase-1 (HO-1) is a critical cytoprotective enzyme that limits oxidative stress, inflammation, and cellular injury within the central nervous system (CNS) and other tissues. We previously demonstrated that HO-1 protein expression is decreased within the brains of HIV+ subjects and that this HO-1 reduction correlates with CNS immune activation and neurocognitive dysfunction. To define a potential CNS protective role for HO-1 against HIV, we analyzed a well-characterized HIV autopsy cohort for two common HO-1 promoter region polymorphisms that are implicated in regulating HO-1 promoter transcriptional activity, a (GT)n dinucleotide repeat polymorphism and a single nucleotide polymorphism (A(-413)T). Shorter HO-1 (GT)n repeats and the 'A' SNP allele associate with higher HO-1 promoter activity. METHODS: Brain dorsolateral prefrontal cortex tissue samples from an autopsy cohort of HIV-, HIV+, and HIV encephalitis (HIVE) subjects (n = 554) were analyzed as follows: HO-1 (GT)n polymorphism allele lengths were determined by PCR and capillary electrophoresis, A(-413)T SNP alleles were determined by PCR with allele specific probes, and RNA expression of selected neuroimmune markers was analyzed by quantitative PCR. RESULTS: HIV+ subjects with shorter HO-1 (GT)n alleles had a significantly lower risk of HIVE; however, shorter HO-1 (GT)n alleles did not correlate with CNS or peripheral viral loads. In HIV+ subjects without HIVE, shorter HO-1 (GT)n alleles associated significantly with lower expression of brain type I interferon response markers (MX1, ISG15, and IRF1) and T-lymphocyte activation markers (CD38 and GZMB). No significant correlations were found between the HO-1 (GT)n repeat length and brain expression of macrophage markers (CD163, CD68), endothelial markers (PECAM1, VWF), the T-lymphocyte marker CD8A, or the B-lymphocyte maker CD19. Finally, we found no significant associations between the A(-413)T SNP and HIVE diagnosis, HIV viral loads, or any neuroimmune markers. CONCLUSION: Our data suggest that an individual's HO-1 promoter region (GT)n polymorphism allele repeat length exerts unique modifying risk effects on HIV-induced CNS neuroinflammation and associated neuropathogenesis. Shorter HO-1 (GT)n alleles increase HO-1 promoter activity, which could provide neuroprotection through decreased neuroimmune activation. Therapeutic strategies that induce HO-1 expression could decrease HIV-associated CNS neuroinflammation and decrease the risk for development of HIV neurological disease. [Pt] Publication type: JOURNAL ARTICLE [Em] Entry month: 1803 [Cu] Class update date: 180311 [Lr] Last revision date: 180311 [St] Status: In-Data-Review [do] DOI: 10.1186/s12974-018-1102-z

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[PMID]: 29228201 [Au] Autor: Lowe VJ; Wiste HJ; Senjem ML; Weigand SD; Therneau TM; Boeve BF; Josephs KA; Fang P; Pandey MK; Murray ME; Kantarci K; Jones DT; Vemuri P; Graff-Radford J; Schwarz CG; Machulda MM; Mielke MM; Roberts RO; Knopman DS; Petersen RC; Jack CR [Ad] Address: Department of Radiology, Mayo Clinic, Rochester, MN, USA. [Ti] Title: Widespread brain tau and its association with ageing, Braak stage and Alzheimer's dementia. [So] Source: Brain;141(1):271-287, 2018 Jan 01. [Is] ISSN: 1460-2156 [Cp] Country of publication: England [La] Language: eng [Ab] Abstract: See Herholz (doi:10.1093/brain/awx340) for a scientific commentary on this article.Autopsy data have proposed that a topographical pattern of tauopathy occurs in the brain with the development of dementia due to Alzheimer's disease. We evaluated the findings of tau-PET to better understand neurofibrillary tangle development as it is seen in cognitively unimpaired and impaired individuals. The evolution of Alzheimer's disease tauopathy in cognitively unimpaired individuals needs to be examined to better understand disease pathogenesis. Tau-PET was performed in 86 cognitively impaired individuals who all had abnormal amyloid levels and 601 cognitively unimpaired individuals. Tau-PET findings were assessed for relationships with clinical diagnosis, age, and regional uptake patterns relative to Braak stage. Regional and voxel-wise analyses were performed. Topographical findings from tau-PET were characterized using hierarchical clustering and clinical characteristic-based subcategorization. In older cognitively unimpaired individuals (≥50 years), widespread, age-related elevated tau signal was seen among those with normal or abnormal amyloid status as compared to younger cognitively unimpaired individuals (30-49 years). More frequent regional tau signal elevation throughout the brain was seen in cognitively unimpaired individuals with abnormal versus normal amyloid. Elevated tau signal was seen in regions that are considered high Braak Stage in cognitively unimpaired and cognitively impaired individuals. Hierarchical clustering and clinical characteristic-based categorizations both showed different patterns of tau signal between groups such as greater tau signal in frontal regions in younger onset Alzheimer's disease dementia participants (most of whom had a dysexecutive clinical presentation). Tau-PET signal increases modestly with age throughout the brain in cognitively unimpaired individuals and elevated tau is seen more often when amyloid brain accumulation is present. Tau signal patterns in cognitively unimpaired correspond to early Braak stage but also suggest tangle involvement in extra-medial temporal and extra-temporal regions that are considered more advanced in the Braak scheme even when amyloid negative. Our findings also suggest the possibility of widespread development of early tangle pathology rather than a pattern defined exclusively by adjacent, region-to-region spread, prior to onset of clinical symptoms. Distinct patterns of neurofibrillary tangle deposition in younger-onset Alzheimer's disease dementia versus older-onset Alzheimer's disease dementia provide evidence for variability in regional tangle deposition patterns and demonstrate that different disease phenotypes have different patterns of tauopathy. Pathological correlation with imaging is needed to assess the implications of these observations. [Pt] Publication type: JOURNAL ARTICLE [Em] Entry month: 1712 [Cu] Class update date: 180311 [Lr] Last revision date: 180311 [St] Status: In-Data-Review [do] DOI: 10.1093/brain/awx320

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[PMID]: 29523700 [Au] Autor: Gogliotti R; Fisher N; Stansley B; Jones C; Lindsley C; Conn J; Niswender C [Ad] Address: Vanderbilt University. [Ti] Title: Total RNA-sequencing of Rett Syndrome Autopsy Samples Identifies the M4 Muscarinic Receptor as a Novel Therapeutic Target. [So] Source: J Pharmacol Exp Ther;, 2018 Mar 09. [Is] ISSN: 1521-0103 [Cp] Country of publication: United States [La] Language: eng [Ab] Abstract: Mutations in the Methyl CpG Binding Protein 2 (MECP2) gene are responsible for the neurodevelopmental disorder Rett syndrome (RTT). MeCP2 is a DNA-binding protein whose abundance and ability to complex with HDAC3 is linked to the regulation of chromatin structure. Consequently, loss-of-function mutations in MeCP2 are predicted to have broad effects on gene expression. However, to date, studies in mouse models of RTT have identified a limited number of gene or pathway-level disruptions, and even fewer genes have been identified that could be considered amenable to classical drug discovery approaches. Here, we performed RNA-sequencing (seq) on 9 motor cortex and 6 cerebellar autopsy samples from RTT patients and controls. This approach identified 1,883 significantly affected genes in the motor cortex and 2,110 genes in the cerebellum, with a global trend towards increased expression. Pathway-level analysis identified enrichment in genes associated with MAPK-signaling, long-term potentiation, and axon guidance. A survey of our RNA-seq results also identified a significant decrease in expression of the muscarinic acetylcholine receptor 4 (CHRM4) gene, which encodes a receptor (M4) that is the subject of multiple large drug discovery efforts for schizophrenia and Alzheimer's disease. We confirmed that CHRM4 expression was decreased in RTT patients, and, excitingly, we demonstrated that M4 potentiation normalizes social and cognitive phenotypes in Mecp2+/- mice. This work provides an experimental paradigm in which translationally relevant targets can be identified using transcriptomics in RTT autopsy samples, back-modeled in Mecp2+/- mice, and assessed for preclinical efficacy using existing pharmacological tool compounds. [Pt] Publication type: JOURNAL ARTICLE [Em] Entry month: 1803 [Cu] Class update date: 180310 [Lr] Last revision date: 180310 [St] Status: Publisher

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[PMID]: 29384690 [Au] Autor: Hanna MG; Ahmed I; Nine J; Prajapati S; Pantanowitz L [Ad] Address: From the Department of Pathology, University of Pittsburgh Medical Center (UPMC), Pittsburgh, Pennsylvania (Drs Hanna, Nine, and Pantanowitz and Mr Ahmed); Icahn School of Medicine at Mount Sinai, The Mount Sinai Hospital, New York, New York (Dr Prajapati). [Ti] Title: Augmented Reality Technology Using Microsoft HoloLens in Anatomic Pathology. [So] Source: Arch Pathol Lab Med;, 2018 Jan 31. [Is] ISSN: 1543-2165 [Cp] Country of publication: United States [La] Language: eng [Ab] Abstract: CONTEXT: - Augmented reality (AR) devices such as the Microsoft HoloLens have not been well used in the medical field. OBJECTIVE: - To test the HoloLens for clinical and nonclinical applications in pathology. DESIGN: - A Microsoft HoloLens was tested for virtual annotation during autopsy, viewing 3D gross and microscopic pathology specimens, navigating whole slide images, telepathology, as well as real-time pathology-radiology correlation. RESULTS: - Pathology residents performing an autopsy wearing the HoloLens were remotely instructed with real-time diagrams, annotations, and voice instruction. 3D-scanned gross pathology specimens could be viewed as holograms and easily manipulated. Telepathology was supported during gross examination and at the time of intraoperative consultation, allowing users to remotely access a pathologist for guidance and to virtually annotate areas of interest on specimens in real-time. The HoloLens permitted radiographs to be coregistered on gross specimens and thereby enhanced locating important pathologic findings. The HoloLens also allowed easy viewing and navigation of whole slide images, using an AR workstation, including multiple coregistered tissue sections facilitating volumetric pathology evaluation. CONCLUSIONS: - The HoloLens is a novel AR tool with multiple clinical and nonclinical applications in pathology. The device was comfortable to wear, easy to use, provided sufficient computing power, and supported high-resolution imaging. It was useful for autopsy, gross and microscopic examination, and ideally suited for digital pathology. Unique applications include remote supervision and annotation, 3D image viewing and manipulation, telepathology in a mixed-reality environment, and real-time pathology-radiology correlation. [Pt] Publication type: JOURNAL ARTICLE [Em] Entry month: 1802 [Cu] Class update date: 180309 [Lr] Last revision date: 180309 [St] Status: Publisher [do] DOI: 10.5858/arpa.2017-0189-OA

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[PMID]: 29377868 [Au] Autor: Shiroky JS; Lerner-Ellis JP; Govindarajan A; Urbach DR; Devon KM [Ad] Address: Department of Surgery, University of Toronto, Toronto, Canada. [Ti] Title: Characteristics of Adrenal Masses in Familial Adenomatous Polyposis. [So] Source: Dis Colon Rectum;, 2018 Jan 24. [Is] ISSN: 1530-0358 [Cp] Country of publication: United States [La] Language: eng [Ab] Abstract: BACKGROUND: Adrenal masses are a known extraintestinal manifestation of familial adenomatous polyposis. However, the literature on this association is largely confined to case reports. OBJECTIVE: This study aimed to determine the characteristics of adrenal masses in familial adenomatous polyposis and their clinical significance, as well as to estimate their prevalence. Mutational analysis was conducted to determine if any potential genotype-phenotype correlations exist. DESIGN: This is a retrospective cohort study. SETTING: Analysis included all patients meeting the criteria of classic familial adenomatous polyposis who were registered with the Familial Gastrointestinal Cancer Registry, a national Canadian database. PATIENTS: Appropriate imaging or autopsy reports were available in 311 registry patients. Patients with adrenal metastases were excluded. OUTCOME MEASURES: Data collection included demographic data, mutation genotype, adrenal mass characteristics, surgical interventions and mortality. RESULTS: The prevalence of adrenal masses was 16% (n = 48/311). The median age at diagnosis of adrenal mass was 45 years. The median diameter of adrenal mass at diagnosis was 1.7 cm (interquartile range, 1.4-3.0) with a median maximal diameter of 2.5 cm (interquartile range, 1.7-4.1) with median imaging follow-up of 48 months. The majority of adrenal masses were benign (97%, n = 61/63). Surgery was performed on 7 patients because of concerns for size, malignancy, or hormonal secretion. One adrenal-related death was due to an adrenocortical carcinoma. Mutation analysis did not identify any specific genotype-phenotype correlations. LIMITATIONS: There were incomplete or insufficient endocrinology data available in the registry to allow for the analysis of hormone secretion patterns. CONCLUSIONS: Adrenal masses are approximately twice as prevalent in the familial adenomatous polyposis population as in previous studies of the general population. Nearly all mutations led to truncation of the APC gene; however, there was no genetic signature to help predict those at increased risk. The majority of adrenal lesions identified were of benign etiology; thus, an intensive management or surveillance strategy with imaging screening is likely unwarranted. See Video Abstract at http://links.lww.com/DCR/A507. [Pt] Publication type: JOURNAL ARTICLE [Em] Entry month: 1801 [Cu] Class update date: 180309 [Lr] Last revision date: 180309 [St] Status: Publisher [do] DOI: 10.1097/DCR.0000000000001008

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[PMID]: 29320549 [Au] Autor: Heikkilä HM; Jokinen TS; Syrjä P; Junnila J; Hielm-Björkman A; Laitinen-Vapaavuori O [Ad] Address: Department of Equine and Small Animal Medicine, Faculty of Veterinary Medicine, University of Helsinki, Helsinki, Finland. [Ti] Title: Assessing adverse effects of intra-articular botulinum toxin A in healthy Beagle dogs: A placebo-controlled, blinded, randomized trial. [So] Source: PLoS One;13(1):e0191043, 2018. [Is] ISSN: 1932-6203 [Cp] Country of publication: United States [La] Language: eng [Ab] Abstract: OBJECTIVE: To investigate the clinical, cytological, and histopathological adverse effects of intra-articularly injected botulinum toxin A in dogs and to study whether the toxin spreads from the joint after the injection. METHODS: A longitudinal, placebo-controlled, randomized clinical trial was conducted with six healthy laboratory Beagle dogs. Stifle joints were randomized to receive either 30 IU of onabotulinum toxin A or placebo in a 1:1 ratio. Adverse effects and spread of the toxin were examined by evaluating dynamic and static weight-bearing of the injected limbs, by assessing painless range of motion and pain on palpation of joints, and by performing synovial fluid analysis, neurological examination, and electrophysiological recordings at different examination time-points in a 12-week period after the injections. The dogs were then euthanized and autopsy and histopathological examination of joint structures and adjacent muscles and nerves were performed. RESULTS: Intra-articular botulinum toxin A did not cause local weakness or injection site pain. Instead, static weight-bearing and painless range of motion of stifle joints decreased in the placebo limbs. No clinically significant abnormalities associated with intra-articular botulinum toxin A were detected in the neurological examinations. Electrophysiological recordings showed low compound muscle action potentials in two dogs in the botulinum toxin A-injected limb. No significant changes were detected in the synovial fluid. Autopsy and histopathological examination of the joint and adjacent muscles and nerves did not reveal histopathological adverse effects of the toxin. CONCLUSION: Intra-articular botulinum toxin A does not produce significant clinical, cytological, or histopathological adverse effects in healthy dogs. Based on the electrophysiological recordings, the toxin may spread from the joint, but its clinical impact seems to be low. [Mh] MeSH terms primary: Botulinum Toxins, Type A/adverse effects Cartilage, Articular/metabolism [Mh] MeSH terms secundary: Animals Botulinum Toxins, Type A/administration & dosage Cartilage, Articular/pathology Dogs Female Placebos [Pt] Publication type: JOURNAL ARTICLE; RANDOMIZED CONTROLLED TRIAL; RESEARCH SUPPORT, NON-U.S. GOV'T [Nm] Name of substance: 0 (Placebos); EC 3.4.24.69 (Botulinum Toxins, Type A) [Em] Entry month: 1803 [Cu] Class update date: 180309 [Lr] Last revision date: 180309 [Js] Journal subset: IM [Da] Date of entry for processing: 180111 [St] Status: MEDLINE [do] DOI: 10.1371/journal.pone.0191043

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[PMID]: 29521044 [Au] Autor: Waszczuk-Gajda A; Kaminski MF; Koperski L; Kaminska A; Drozd-Sokolowska J; Lewandowski Z; Wasiutynski A; Górnicka B; Jedrzejczak WW [Ad] Address: Department of Hematology, Oncology and Internal Diseases, Medical University of Warsaw, Poland. [Ti] Title: Heart infarct as the major cause of death of hematological patients as identified by autopsy. [So] Source: Adv Clin Exp Med;27(1):63-70, 2018 Jan. [Is] ISSN: 1899-5276 [Cp] Country of publication: Poland [La] Language: eng [Ab] Abstract: BACKGROUND: Despite progress in diagnostic procedures, clinical diagnosis is not always confirmed by an autopsy. An autopsy is a valuable tool in evaluating diagnostic accuracy. OBJECTIVES: The aim of the study was to compare clinical diagnoses of immediate causes of death with autopsy findings in patients with hematological malignancies or aplastic anemia. MATERIAL AND METHODS: In this study, the results of 154 autopsies (1993-2004) of patients with hematological diseases were reviewed and compared with clinical data. The most probable causes of death in the case of particular hematological diseases as well as the discordances between clinical and autopsy diagnoses and their relation to the clinical characteristic were identified in the studied cohort, which primarily included patients whose death at that particular time was not explained by the clinical course, and in 50% of cases was sudden. RESULTS: Although various combined infections have been found to be responsible for the largest number of deaths (26.6%), the most common single cause was myocardial infarction (29 patients, 18.8%). The discordance between clinical and post-mortem diagnoses of immediate causes of death was found in 55 patients (35.7%; 95% CI 28.2-42.8%), with 50.9% of cases considered class I discrepancies according to Goldman's criteria. The myocardial infarction was found to be clinically undiagnosed in 69% of cases. In 41% of cases, it was a class I discrepant diagnosis. CONCLUSIONS: This data suggests that hematological patients require special attention and probably preventive measures concerning coronary heart disease, particularly during the initiation of antineoplastic therapy. [Pt] Publication type: JOURNAL ARTICLE [Em] Entry month: 1803 [Cu] Class update date: 180309 [Lr] Last revision date: 180309 [St] Status: In-Data-Review [do] DOI: 10.17219/acem/65866

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[PMID]: 29520562 [Au] Autor: Zivkovic V; Nikolic S [Ad] Address: Institute of Forensic Medicine, University of Belgrade - School of Medicine, 31a Deligradska str., Belgrade, 11000, Serbia. [Ti] Title: Regarding the editorial "The autopsy evaluation of 'straightforward' fire deaths". [So] Source: Forensic Sci Med Pathol;, 2018 Mar 08. [Is] ISSN: 1556-2891 [Cp] Country of publication: United States [La] Language: eng [Pt] Publication type: LETTER [Em] Entry month: 1803 [Cu] Class update date: 180309 [Lr] Last revision date: 180309 [St] Status: Publisher [do] DOI: 10.1007/s12024-018-9966-x

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[PMID]: 29519969 [Au] Autor: Yamashiro N; Nagasaka T; Ooishi N; Tsuchiya M; Takaki R; Kobayashi F; Shindo K; Takiyama Y [Ad] Address: Department of Neurology, Faculty of Medicine, University of Yamanashi. [Ti] Title: [An Autopsy Case of Meningoencephalitis and Cerebral Infarction that Developed with Ramsay Hunt Syndrome and Disseminated Herpes Zoster]. [So] Source: Brain Nerve;70(3):253-258, 2018 Mar. [Is] ISSN: 1881-6096 [Cp] Country of publication: Japan [La] Language: jpn [Ab] Abstract: We report here the clinical presentation and subsequent autopsy of a 90-year-old man who developed small papules with pain and swelling in his right ear. On admission, he exhibited right facial nerve paralysis, neck stiffness and Kernig's sign. The cell count was elevated and the varicella-zoster virus-PCR was positive in the CSF. Brain magnetic resonance imaging showed hyperintense lesions in the left pons and left temporal lobe, in FLAIR images. We diagnosed the patient with Ramsay Hunt syndrome and meningoencephalitis due to varicella-zoster virus. Although the symptoms of meningitis improved following treatment with intravenous acyclovir (750 mg/day initially, raised to 1,125 mg/day), 16 days after admission, he died suddenly due to gastrointestinal hemorrhage. The autopsy findings included lymphocytic infiltration of the leptomeninges and perivascular space of the cerebrum, and slight parenchyma in the left temporal lobe and insula, as the main histological features. Encephalitis due to varicella zoster virus has been recognized as a vasculopathy affecting large and small vessels. Pathological confirmation is rare in varicella zoster virus meningoencephalitis. [Pt] Publication type: ENGLISH ABSTRACT; JOURNAL ARTICLE [Em] Entry month: 1803 [Cu] Class update date: 180309 [Lr] Last revision date: 180309 [St] Status: In-Data-Review [do] DOI: 10.11477/mf.1416200990

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[PMID]: 29518653 [Au] Autor: Mishima-Kimura S; Yonemitsu K; Ohtsu Y; Sasao A; Tsutsumi H; Furukawa S; Nishitani Y [Ad] Address: Department of Forensic Medicine, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan. [Ti] Title: Liquid chromatography-tandem mass spectrometry detection of benzalkonium chloride (BZK) in a forensic autopsy case with survival for 18 days post BZK ingestion. [So] Source: Leg Med (Tokyo);32:48-51, 2018 Mar 02. [Is] ISSN: 1873-4162 [Cp] Country of publication: Ireland [La] Language: eng [Ab] Abstract: We report a forensic autopsy case of an elderly man who ingested unknown amount of germicidal disinfectant containing 50% benzalkonium chloride (BZK). He survived for 18 days after BZK ingestion and then died because of pneumonia. A liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was used to detect three BZK compounds (C -BZK, C -BZK and C -BZK) in the blood. Extraction of BZK was carried out according to a modified QuEChERS method. Chromatographic separation was achieved on an ODS column and detection was performed in selected reaction monitoring mode. The accuracy and the precision were acceptable for quantitative analysis in the concentration range of 10-200 ng/mL for the three BZK compounds. BZK was detected in heart and femoral vein blood samples even 18 days after BZK ingestion. Taking into consideration clinical information during 18 days hospitalization and the autopsy findings, the cause of death was attributed to BZK poisoning. Several toxico-kinetic factors regarding absorption and excretion of BZK in the body were also discussed to elucidate the detection of BZK such a long time after ingestion. [Pt] Publication type: JOURNAL ARTICLE [Em] Entry month: 1803 [Cu] Class update date: 180308 [Lr] Last revision date: 180308 [St] Status: Publisher

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