The differing pathophysiologies that underlie COVID-19-associated perniosis and thrombotic retiform purpura: a case series.

BACKGROUND: There are two distinctive acral manifestations of COVID-19 embodying disparate clinical phenotypes. One is perniosis occurring in mildly symptomatic patients, typically children and young adults; the second is the thrombotic retiform purpura of critically ill adults with COVID-19. OBJECTIVES: To compare the clinical and pathological profiles of these two different cutaneous manifestations of COVID-19. METHODS: We compared the light microscopic, phenotypic, cytokine and SARS-CoV-2 protein and RNA profiles of COVID-19-associated perniosis with that of thrombotic retiform purpura in critical patients with COVID-19. RESULTS: Biopsies of COVID-19-associated perniosis exhibited vasocentric and eccrinotropic T-cell- and monocyte-derived CD11c+ , CD14+ and CD123+ dendritic cell infiltrates. Both COVID-associated and idiopathic perniosis showed striking expression of the type I interferon-inducible myxovirus resistance protein A (MXA), an established marker for type I interferon signalling in tissue. SARS-CoV-2 RNA, interleukin-6 and caspase 3 were minimally expressed and confined to mononuclear inflammatory cells. The biopsies from livedo/retiform purpura showed pauci-inflammatory vascular thrombosis without any MXA decoration. Blood vessels exhibited extensive complement deposition with endothelial cell localization of SARS-CoV-2 protein, interleukin-6 and caspase 3; SARS-CoV-2 RNA was not seen. CONCLUSIONS: COVID-19-associated perniosis represents a virally triggered exaggerated immune reaction with significant type I interferon signaling. This is important to SARS-CoV-2 eradication and has implications in regards to a more generalized highly inflammatory response. We hypothesize that in the thrombotic retiform purpura of critically ill patients with COVID-19, the vascular thrombosis in the skin and other organ systems is associated with a minimal interferon response. This allows excessive viral replication with release of viral proteins that localize to extrapulmonary endothelium and trigger extensive complement activation.

Hippocampal subfield pathologic burden in Lewy body diseases vs. Alzheimer's disease.

AIMS: Lewy body diseases (LBD) are characterized by alpha-synuclein (SYN) pathology, but comorbid Alzheimer's disease (AD) pathology is common and the relationship between these pathologies in microanatomic hippocampal subfields is understudied. Here we use digital histological methods to test the association between hippocampal SYN pathology and the distribution of tau and amyloid-beta (Aß) pathology in LBD and contrast with AD subjects. We also correlate pathologic burden with antemortem episodic memory testing. METHODS: Hippocampal sections from 49 autopsy-confirmed LBD cases, 30 with no/low AD copathology (LBD - AD) and 19 with moderate/severe AD copathology (LBD + AD), and 30 AD patients were stained for SYN, tau, and Aß. Sections underwent digital histological analysis of subfield pathological burden which was correlated with antemortem memory testing. RESULTS: LBD - AD and LBD + AD had similar severity and distribution of SYN pathology (P > 0.05), CA2/3 being the most affected subfield (P < 0.02). In LBD, SYN correlated with tau across subfields (R = 0.49, P < 0.001). Tau burden was higher in AD than LBD + AD (P < 0.001), CA1/subiculum and entorhinal cortex (ERC) being most affected regions (P = 0.04 to <0.01). However, tau pathology in LBD - AD was greatest in CA2/3, which was equivalent to LBD + AD. Aß severity and distribution was similar between LBD + AD and AD. Total hippocampal tau and CA2/3 tau was inversely correlated with memory performance in LBD (R = -0.52, -0.69, P = 0.04, 0.009). CONCLUSIONS: Our findings suggest that tau burden in hippocampal subfields may map closely with the distribution of SYN pathology in subfield CA2/3 in LBD diverging from traditional AD and contribute to episodic memory dysfunction in LBD.

Comparison of sporadic and familial behavioral variant frontotemporal dementia (FTD) in a North American cohort.

INTRODUCTION: Behavioral variant frontotemporal dementia (bvFTD) may present sporadically or due to an autosomal dominant mutation. Characterization of both forms will improve understanding of the generalizability of assessments and treatments. METHODS: A total of 135 sporadic (s-bvFTD; mean age 63.3 years; 34% female) and 99 familial (f-bvFTD; mean age 59.9; 48% female) bvFTD participants were identified. f-bvFTD cases included 43 with known or presumed chromosome 9 open reading frame 72 (C9orf72) gene expansions, 28 with known or presumed microtubule-associated protein tau (MAPT) mutations, 14 with known progranulin (GRN) mutations, and 14 with a strong family history of FTD but no identified mutation. RESULTS: Participants with f-bvFTD were younger and had earlier age at onset. s-bvFTD had higher total Neuropsychiatric Inventory Questionnaire (NPI-Q) scores due to more frequent endorsement of depression and irritability. DISCUSSION: f-bvFTD and s-bvFTD cases are clinically similar, suggesting the generalizability of novel biomarkers, therapies, and clinical tools developed in either form to the other.

Active lifestyles moderate clinical outcomes in autosomal dominant frontotemporal degeneration.

INTRODUCTION: Leisure activities impact brain aging and may be prevention targets. We characterized how physical and cognitive activities relate to brain health for the first time in autosomal dominant frontotemporal lobar degeneration (FTLD). METHODS: A total of 105 mutation carriers (C9orf72/MAPT/GRN) and 69 non-carriers reported current physical and cognitive activities at baseline, and completed longitudinal neurobehavioral assessments and brain magnetic resonance imaging (MRI) scans. RESULTS: Greater physical and cognitive activities were each associated with an estimated >55% slower clinical decline per year among dominant gene carriers. There was also an interaction between leisure activities and frontotemporal atrophy on cognition in mutation carriers. High-activity carriers with frontotemporal atrophy (-1 standard deviation/year) demonstrated >two-fold better cognitive performances per year compared to their less active peers with comparable atrophy rates. DISCUSSION: Active lifestyles were associated with less functional decline and moderated brain-to-behavior relationships longitudinally. More active carriers "outperformed" brain volume, commensurate with a cognitive reserve hypothesis. Lifestyle may confer clinical resilience, even in autosomal dominant FTLD.

Comparison of In Vivo and Ex Vivo MRI of the Human Hippocampal Formation in the Same Subjects.

Multiple techniques for quantification of hippocampal subfields from in vivo MRI have been proposed. Linking in vivo MRI to the underlying histology can help validate and improve these techniques. High-resolution ex vivo MRI can provide an intermediate modality to map information between these very different imaging modalities. This article evaluates the ability to match information between in vivo and ex vivo MRI in the same subjects. We perform rigid and deformable registration on 10 pairs of in vivo (3 T, 0.4 × 0.4 × 2.6 mm3) and ex vivo (9.4 T, 0.2 × 0.2 × 0.2 mm3) scans, and describe differences in MRI appearance between these modalities qualitatively and quantitatively. The feasibility of using this dataset to validate in vivo segmentation is evaluated by applying an automatic hippocampal subfield segmentation technique (ASHS) to in vivo scans and comparing SRLM (stratum/radiatum/lacunosum/moleculare) surface to manual tracing on corresponding ex vivo scans (and in 2 cases, histology). Regional increases in thickness are detected in ex vivo scans adjacent to the ventricles and were not related to scanner, resolution differences, or susceptibility artefacts. Satisfactory in vivo/ex vivo registration and subvoxel accuracy of ASHS segmentation of hippocampal SRLM demonstrate the feasibility of using this dataset for validation, and potentially, improvement of in vivo segmentation methods.

Complex networks for tracking extreme rainfall during typhoons.

Reconciling the paths of extreme rainfall with those of typhoons remains difficult despite advanced forecasting techniques. We use complex networks defined by a nonlinear synchronization measure termed event synchronization to track extreme rainfall over the Japanese islands. Directed networks objectively record patterns of heavy rain brought by frontal storms and typhoons but mask out contributions of local convective storms. We propose a radial rank method to show that paths of extreme rainfall in the typhoon season (August-November, ASON) follow the overall southwest-northeast motion of typhoons and mean rainfall gradient of Japan. The associated eye-of-the-typhoon tracks deviate notably and may thus distort estimates of heavy typhoon rainfall. We mainly found that the lower spread of rainfall tracks in ASON may enable better hindcasting than for westerly-fed frontal storms in June and July.

Progression of alpha-synuclein pathology in multiple system atrophy of the cerebellar type.

AIMS: The aim of this study was to identify early foci of α-synuclein (α-syn pathology) accumulation, subsequent progression and neurodegeneration in multiple system atrophy of the cerebellar type (MSA-C). METHODS: We analysed 70-µm-thick sections of 10 cases with MSA-C and 24 normal controls. RESULTS: MSA-C cases with the lowest burden of pathology showed α-syn glial cytoplasmic inclusions (GCIs) in the cerebellum as well as in medullary and pontine cerebellar projections. Cerebellar pathology was highly selective and severely involved subcortical white matter, whereas deep white matter and granular layer were only mildly affected and the molecular layer was spared. Loss of Purkinje cells increased with disease duration and was associated with neuronal and axonal abnormalities. Neocortex, basal ganglia and spinal cord became consecutively involved with the increasing burden of α-syn pathology, followed by hippocampus, amygdala, and, finally, the visual cortex. GCIs were associated with myelinated axons, and the severity of GCIs correlated with demyelination. CONCLUSIONS: Our findings indicate that cerebellar subcortical white matter and cerebellar brainstem projections are likely the earliest foci of α-syn pathology in MSA-C, followed by involvement of more widespread regions of the central nervous system and neurodegeneration with disease progression.

Novel conformation-selective alpha-synuclein antibodies raised against different in vitro fibril forms show distinct patterns of Lewy pathology in Parkinson's disease.

AIMS: The aim of this study was to test the hypothesis that different conformations of misfolded α-synuclein (α-syn) are present in Parkinson's disease (PD) brain. METHODS: Using two previously characterized conformations of α-syn fibrils, we generated new conformation-selective α-syn monoclonal antibodies (mAbs). We then interrogated multiple brain regions in a well-characterized autopsy cohort of PD patients (n = 49) with these mAbs, Syn7015 and Syn9029. RESULTS: Syn7015 detects Lewy bodies (LBs) and Lewy neurites (LNs) formed by pathological α-syn in all brain regions tested, and is particularly sensitive to LNs and small Lewy dots, inclusions believed to form early in the disease. Further, we observed colocalization between Syn7015 and an early marker of α-syn pathology formation, phospho-Ser129-α-syn, and a lack of extensive colocalization with markers of more mature pathology. In comparison, Syn9029 detects Lewy pathology in all regions examined, but indicates significantly fewer LNs than Syn7015. In addition, colocalization of Syn9029 with later markers of α-syn pathology maturation (ubiquitin and P62) suggests that the pathology detected by Syn9029 is older. Semiquantitative scoring of both LN and LB pathology in nine brain regions further established this trend, with Syn7015 LN scores consistently higher than Syn9029 LN scores. CONCLUSIONS: Our data indicate that different conformations of α-syn pathology are present in PD brain and correspond to different stages of maturity for Lewy pathology. Regional analysis of Syn7015 and Syn9029 immunostaining also provides support for the Braak hypothesis that α-syn pathology advances through the brain.

Staphylococcus aureus sporotrichoid lymphangitis without bacteremia in a transplant recipient.

Pyogenic sporotrichoid infections are rare. There are only 4 reports in the literature of Staphylococcus aureus presenting as sporotrichoid lymphangitis (also known as lymphocutaneous syndrome or nodular lymphangitis). We report the first case, to our knowledge, of S. aureus sporotrichoid infection without bacteremia in an immunocompromised organ transplant recipient.

Generalized verrucosis in a patient with GATA2 deficiency.

Generalized verrucosis is a characteristic of several genetic and immunodeficiency disorders including epidermodysplasia verruciformis; warts, hypogammaglobulinaemia, infections and myelokathexis (WHIM) syndrome; warts, immunodeficiency, lymphoedema and anogenital dysplasia (WILD) syndrome; severe combined immune deficiency and HIV, among others. In recent years, it has been consistently recognized in patients with GATA2 deficiency, a novel immunodeficiency syndrome characterized by monocytopenia, B-cell and natural killer-cell lymphopenia, and a tendency to develop myeloid leukaemias and disseminated mycobacterial, human papillomavirus (HPV) and opportunistic fungal infections. Mutations in GATA2 cause haploinsufficiency and track in families as an autosomal dominant immunodeficiency. GATA2 is a transcription factor involved in early haematopoietic differentiation and lymphatic and vascular development. We describe a case of generalized verrucosis with HPV type 57 presenting in a young man with GATA2 deficiency. GATA2 deficiency is a novel dominant immunodeficiency that is often recognized later in life and should be considered in the differential diagnosis of patients with generalized verrucosis.

Successful ex vivo gene therapy directed to liver in a patient with familial hypercholesterolaemia.

An ex vivo approach to gene therapy for familial hypercholesterolaemia (FH) has been developed in which the recipient is transplanted with autologous hepatocytes that are genetically corrected with recombinant retroviruses carrying the LDL receptor. We describe the treatment of a 29 year old woman with homozygous FH by ex vivo gene therapy directed to liver. She tolerated the procedures well and in situ hybridization of liver tissue four months after therapy revealed evidence for engraftment of transgene expressing cells. The patient's LDL/HDL ratio declined from 10-13 before gene therapy to 5-8 following gene therapy, improvements which have remained stable for the duration of the treatment (18 months). This represents the first report of human gene therapy in which stable correction of a therapeutic endpoint has been achieved.

The potential role for acupuncture in treating symptoms in patients with lung cancer: an observational longitudinal study.

BACKGROUND: Most lung cancer patients experience multiple symptoms related either to the disease or its treatment. The commonly reported symptoms are pain, depression, anxiety, nausea, and poor well-being. The aim of the present study was to evaluate the effect of acupuncture as a potential treatment modality in symptomatic lung cancer patients. METHODS: This prospective observational study enrolled 33 lung cancer patients from the Peter Brojde Lung Cancer Centre between August 2010 and May 2012. All patients received 45-minute sessions of acupuncture, 1-2 times weekly for a minimum of 4 sessions. Symptom severity was assessed using the Edmonton Symptom Assessment System (esas) before and after completion of acupuncture. RESULTS: The study cohort included 30 patients with non-small- cell lung cancer and 3 with small-cell lung cancer. Mean age was 62 years (range: 36-88 years); 17 of the patients were women. Most of the patients had advanced-stage cancer (73%) and good performance status (Eastern Cooperative Oncology Group 0-1: 88%). Of these patients, 67% received anticancer treatment (chemotherapy or radiotherapy, or both) with acupuncture. Of the remaining 10 patients, 8 received acupuncture after a complete surgical resection of their tumour, and because of their advanced age, 2 received acupuncture and best supportive care. The median number of acupuncture sessions was 7 (interquartile range: 4-13 sessions). Statistically significant improvements in pain, appetite, nausea, nervousness, and well-being were observed. A clinically important improvement (2 points on the esas) was reported by 61% of patients for pain and by 33% for well-being. A significant positive correlation between improved well-being and the number of acupuncture sessions was observed. This correlation remained significant even after controlling for treatment and narcotic use. Receiver operating characteristic analysis demonstrated that a minimum of 6 acupuncture sessions are required for a 70% chance of a clinically important improvement in well-being. CONCLUSIONS: The present study is the first to demonstrate that acupuncture may be an effective approach for improving symptoms-in particular, pain and well-being-in lung cancer patients. Acupuncture is a safe and minimally invasive procedure, and it is potentially useful even in patients undergoing anticancer treatment.

Periumbilical parasitic thumbprint purpura: strongyloides hyperinfection syndrome acquired from a cadaveric renal transplant.

Periumbilical parasitic thumbprint purpura may be a presenting sign of hyperinfection strongyloidiasis in the immunocompromised host. We report a case of fatal hyperinfection strongyloidiasis acquired from a cadaveric renal allograft, diagnosed by the pathognomonic periumbilical thumbprint purpuric eruption, confirmed by skin biopsy and laboratory testing.

A pilot study of ex vivo gene therapy for homozygous familial hypercholesterolaemia.

The outcome of the first pilot study of liver-directed gene therapy is reported here. Five patients with homozygous familial hypercholesterolaemia (FH) ranging in age from 7 to 41 years were enrolled; each patient tolerated the procedure well without significant complications. Transgene expression was detected in a limited number of hepatocytes of liver tissue harvested four months after gene transfer from all five patients. Significant and prolonged reductions in low density lipoprotein (LDL) cholesterol were demonstrated in three of five patients; in vivo LDL catabolism was increased 53% following gene therapy in a receptor negative patient, who realized a reduction in serum LDL equal to approximately 150 mg dl-1. This study demonstrates the feasibility of engrafting limited numbers of retrovirus-transduced hepatocytes without morbidity and achieving persistent gene expression lasting at least four months after gene therapy. The variable metabolic responses observed following low-level genetic reconstitution in the five patients studied precludes a broader application of liver-directed gene therapy without modifications that consistently effect substantially greater gene transfer.

Clinical uses of the medicinal leech: a practical review.

The medicinal leech, Hirudo medicinalis, is an excellent example of the use of invertebrates in the treatment of human disease. Utilized for various medical indications since the ancient times, the medicinal leech is currently being used in a narrow range of well-defined and scientifically-grounded clinical applications. Hirudotherapy is most commonly used in the setting of venous congestion associated with soft tissue replantations and free flap-based reconstructive surgery. This is a comprehensive review of current clinical applications of hirudotherapy, featuring a comprehensive search of all major medical search engines (i.e. PubMed, Google Scholar, ScientificCommons) and other cross-referenced sources. The authors focus on indications, contraindications, practical application/handling of the leech, and therapy-related complications.

Marginal warming associated with a COVID-19 quarantine and the implications for disease transmission.

During January-February 2020, parts of China faced restricted mobility under COVID-19 quarantines, which have been associated with improved air quality. Because particulate pollutants scatter, diffuse, and absorb incoming solar radiation, a net negative radiative forcing, decreased air pollution can yield surface warming. As such, this study (1) documents the evolution of China's January-February 2020 air temperature and concurrent particulate changes; (2) determines the temperature response related to reduced particulates during the COVID-19 quarantine (C19Q); and (3) discusses the conceptual implications for temperature-dependent disease transmission. C19Q particulate evolution is monitored using satellite analyses, and concurrent temperature anomalies are diagnosed using surface stations and Aqua AIRS imagery. Meanwhile, two WRF-Chem simulations are forced by normal emissions and the satellite-based urban aerosol changes, respectively. Urban aerosols decreased from 27.1% of pre-C19Q aerosols to only 17.5% during C19Q. WRF-Chem resolved ~0.2 °C warming across east-central China, that represented a minor, though statistically significant contribution to C19Q temperature anomalies. The largest area of warming is concentrated south of Chengdu and Wuhan where temperatures increased between +0.2-0.3 °C. The results of this study are important for understanding the anthropogenic forcing on regional meteorology. Epidemiologically, the marginal, yet persistent, warming during C19Q may retard temperature-dependent disease transmission, possibly including SARS-CoV-2.

Pathological drivers of neurodegeneration in suspected non-Alzheimer's disease pathophysiology.

BACKGROUND: Little is known about the heterogeneous etiology of suspected non-Alzheimer's pathophysiology (SNAP), a group of subjects with neurodegeneration in the absence of ß-amyloid. Using antemortem MRI and pathological data, we investigated the etiology of SNAP and the association of neurodegenerative pathologies with structural medial temporal lobe (MTL) measures in ß-amyloid-negative subjects. METHODS: Subjects with antemortem MRI and autopsy data were selected from ADNI (n=63) and the University of Pennsylvania (n=156). Pathological diagnoses and semi-quantitative scores of MTL tau, neuritic plaques, α-synuclein, and TDP-43 pathology and MTL structural MRI measures from antemortem T1-weighted MRI scans were obtained. ß-amyloid status (A+/A-) was determined by CERAD score and neurodegeneration status (N+/N-) by hippocampal volume. RESULTS: SNAP reflects a heterogeneous group of pathological diagnoses. In ADNI, SNAP (A-N+) had significantly more neuropathological diagnoses than A+N+. In the A- group, tau pathology was associated with hippocampal, entorhinal cortex, and Brodmann area 35 volume/thickness and TDP-43 pathology with hippocampal volume. CONCLUSION: SNAP had a heterogeneous profile with more mixed pathologies than A+N+. Moreover, a role for TDP-43 and tau pathology in driving MTL neurodegeneration in the absence of ß-amyloid was supported.

Downstream effects of polypathology on neurodegeneration of medial temporal lobe subregions.

The medial temporal lobe (MTL) is a nidus for neurodegenerative pathologies and therefore an important region in which to study polypathology. We investigated associations between neurodegenerative pathologies and the thickness of different MTL subregions measured using high-resolution post-mortem MRI. Tau, TAR DNA-binding protein 43 (TDP-43), amyloid-ß and α-synuclein pathology were rated on a scale of 0 (absent)-3 (severe) in the hippocampus and entorhinal cortex (ERC) of 58 individuals with and without neurodegenerative diseases (median age 75.0 years, 60.3% male). Thickness measurements in ERC, Brodmann Area (BA) 35 and 36, parahippocampal cortex, subiculum, cornu ammonis (CA)1 and the stratum radiatum lacunosum moleculare (SRLM) were derived from 0.2 × 0.2 × 0.2 mm3 post-mortem MRI scans of excised MTL specimens from the contralateral hemisphere using a semi-automated approach. Spearman's rank correlations were performed between neurodegenerative pathologies and thickness, correcting for age, sex and hemisphere, including all four proteinopathies in the model. We found significant associations of (1) TDP-43 with thickness in all subregions (r = - 0.27 to r = - 0.46), and (2) tau with BA35 (r = - 0.31) and SRLM thickness (r = - 0.33). In amyloid-ß and TDP-43 negative cases, we found strong significant associations of tau with ERC (r = - 0.40), BA35 (r = - 0.55), subiculum (r = - 0.42) and CA1 thickness (r = - 0.47). This unique dataset shows widespread MTL atrophy in relation to TDP-43 pathology and atrophy in regions affected early in Braak stageing and tau pathology. Moreover, the strong association of tau with thickness in early Braak regions in the absence of amyloid-ß suggests a role of Primary Age-Related Tauopathy in neurodegeneration.

Fatal disseminated Acanthamoeba infection in a liver transplant recipient immunocompromised by combination therapies for graft-versus-host disease.

Immunosuppressed solid organ transplant recipients are at increased risk for acquisition of opportunistic pathogens, with potentially fatal consequences. With the introduction of novel immunosuppressive agents used to prevent organ rejection and to treat the sequelae of transplantation, severity and rates of infection with unusual opportunistic pathogens may increase. Various monoclonal antibodies are now being used in the treatment of severe, acute graft-versus-host disease (GVHD), including rituximab, daclizumab, and alemtuzumab. These therapies, particularly when used in combination and with other traditional forms of immunosuppression, may have profound effects on the immune system. Acanthamoeba species are ubiquitous, free-living protozoa that rarely cause disseminated disease in the immunocompromised host. We report a fatal case of disseminated Acanthamoeba infection with a dramatic cutaneous presentation in a liver transplant recipient severely immunocompromised by sequential standard and novel therapies used to successfully treat life-threatening acute GVHD. This case illustrates the current major limitation of these therapies, discusses the cutaneous findings in disseminated acanthamoebiasis, and highlights the need to maintain vigilance for the presence of unusual infection in patients receiving similar therapeutic regimens.

Identification of alpha-beta unsaturated aldehydes as sources of toxicity to activated sludge biomass in polyester manufacturing wastewater.

Wastewater generated in industrial production processes are often contaminated by hazardous chemicals. Characterization by means of toxicity-directed analysis is useful for identifying which fractions of a waste stream possess the most toxicity. We applied this approach to evaluate toxic components of a polyester manufacturing wastewater. Using the reduction in oxygen uptake rate of activated sludge as an indicator of toxicity, it was determined that increasing the pH from 3 to 11 followed by air stripping significantly reduced the toxicity of the wastewater. Comparative headspace GC/MS analysis of wastewater at different pHs selected a group of Volatile Organic Compounds (VOCs) associated with the observed effect of air stripping at pH 11. Ten of these compounds were identified as alpha,beta unsaturated aldehydes (acrolein (2-propenal) congeners); these compounds are known to be toxic as well as mutagenic. Confirmation that these compounds were a cause of toxicity was achieved by demonstrating that removal of these compounds by air stripping significantly reduced the wastewater mutagenic potency in a Salmonella mutagenicity assay. Formation of these volatile compounds by base catalyzed aldol condensation at pH 11 may account for the effectiveness of air stripping in reducing toxicity. To date there is no record in the literature about the toxicity and presence of acrolein congeners in polyester manufacturing wastewater.