Apolipoprotein E ε4/4 genotype limits response to dietary induction of hyperhomocysteinemia and resulting inflammatory signaling

Vascular contributions to cognitive impairment and dementia (VCID) are the second leading cause of dementia behind Alzheimer’s disease. Apolipoprotein E (ApoE) is a lipid transporting lipoprotein found within the brain and periphery. The APOE ε4 allele is the strongest genetic risk factor for late onset Alzheimer’s disease and is a risk factor for VCID. Our lab has previously utilized a dietary model of hyperhomocysteinemia (HHcy) to induce VCID pathology and cognitive deficits in mice. This diet induces perivascular inflammation through cumulative oxidative damage leading to glial mediated inflammation and blood brain barrier breakdown. Here, we examine the impact of ApoE ε4 compared to ε3 alleles on the progression of VCID pathology and inflammation in our dietary model of HHcy. We report a significant resistance to HHcy induction in ε4 mice, accompanied by a number of related differences related to homocysteine (Hcy) metabolism and methylation cycle, or 1-C, metabolites. There were also significant differences in inflammatory profiles between ε3 and ε4 mice, as well as significant reduction in Serpina3n, a serine protease inhibitor associated with ApoE ε4, expression in ε4 HHcy mice relative to ε4 controls. Finally, we find evidence of pervasive sex differences within both genotypes in response to HHcy induction.

Epidemiological, Clinical, Trichoscopic, and Histopathological Features of Lupus Erythematous Mimicking Alopecia Areata: A Multicenter Retrospective Study

<b><i>Introduction:</i></b> All types of lupus erythematosus (LE) may cause hair loss. Nonscarring alopecia was correlated with systemic LE, based on its high specificity. Discoid LE can also appear as nonscarring patches in early stages. Patchy alopecia LE-specific may also mimic alopecia areata (AA) – which can co-occur with LE. The distinction is fundamental to early diagnosis and effective treatment. This study aims to analyze clinical, epidemiological, trichoscopic, and histopathological features of patients with patchy LE-specific alopecia, nonscarring type, mimicking AA. <b><i>Methods:</i></b> This is a multicentric retrospective study. We reviewed the medical records of patients with a confirmed diagnosis of LE mimicking AA. <b><i>Results:</i></b> Ten patients were included (90% female) with a mean age of 45.9 years. Clinically, 60% showed erythema and 70% presented incomplete hair loss. The most common trichoscopic findings were interfollicular arborizing vessels (90%) and scattered brown discoloration (80%). On histopathology, perivascular inflammation (85.7%), peribulbar lymphocytes (85.7%), and dermal pigment incontinence (71.4%) were present in most cases. <b><i>Discussion/Conclusion:</i></b> Trichoscopy was found as an essential first step for the patchy alopecia diagnosis, enabling to differentiate LE from AA. Putting it mildly, trichoscopy raises the suspicion that leads to a biopsy, increasing the diagnostic accuracy with better outcome for patients.

The “Target Sign” in a 46-Year-Old Patient with COVID-19 Pneumonia

COVID-19 has various imaging manifestations, most commonly peripheral ground-glass opacities with a basilar posterior predominance. Less common imaging manifestations include consolidations, findings typical of organizing pneumonia, such as “halo” or a “reverse halo” sign, and vascular enlargement. Our case describes a “target sign” on CT, which is uncommon but is increasingly being recognized. The target sign consists of a central nodular opacity with surrounding ground-glass opacity, then a surrounding relatively lucent ring, and a more peripheral ring of consolidation or ground-glass opacification. This may be the sequela of focal vascular enlargement, endothelial injury, microangiopathy, and perivascular inflammation. The case described involves a 46-year-old male who presented with subjective fevers, nonproductive cough, and hypoxia, subsequently diagnosed with COVID-19. CT imaging performed as part of initial work-up revealed multifocal ground-glass opacities scattered throughout the lung parenchyma, as well as multiple target sign lesions. Although it is a rare finding, the target sign, when present, may suggest the diagnosis of COVID-19.

Infection of Brain Pericytes Underlying Neuropathology of COVID-19 Patients

A wide range of neurological manifestations have been associated with the development of COVID-19 following SARS-CoV-2 infection. However, the etiology of the neurological symptomatology is still largely unexplored. Here, we used state-of-the-art multiplexed immunostaining of human brains (n = 6 COVID-19, median age = 69.5 years; n = 7 control, median age = 68 years) and demonstrated that expression of the SARS-CoV-2 receptor ACE2 is restricted to a subset of neurovascular pericytes. Strikingly, neurological symptoms were exclusive to, and ubiquitous in, patients that exhibited moderate to high ACE2 expression in perivascular cells. Viral dsRNA was identified in the vascular wall and paralleled by perivascular inflammation, as signified by T cell and macrophage infiltration. Furthermore, fibrinogen leakage indicated compromised integrity of the blood–brain barrier. Notably, cerebrospinal fluid from additional 16 individuals (n = 8 COVID-19, median age = 67 years; n = 8 control, median age = 69.5 years) exhibited significantly lower levels of the pericyte marker PDGFRβ in SARS-CoV-2-infected cases, indicative of disrupted pericyte homeostasis. We conclude that pericyte infection by SARS-CoV-2 underlies virus entry into the privileged central nervous system space, as well as neurological symptomatology due to perivascular inflammation and a locally compromised blood–brain barrier.

Survey the Immuno-pharmacology Effect of Botulinum Toxin in Cell Signaling of Bronchial Smooth Muscle Cells of the Allergic Asthma

BackgroundAsthma is the lung disease that influenced more than 350 million people in worldwide. ASM spasm leads to AHR and bronchial obstruction that are acute symptoms of asthma attack. BTX is bacteria toxin that acts as muscle relaxant and may have therapeutic effect on AHR and asthma. Therefore, the effect of BTX on the AHR and related gene expression was evaluated.MethodsAfter producing of asthma mice model, which were treated with BTX in two ways; IN and N (0.01, 0.1, 1 and 10 U/ml). AHR was measured on day 24, 26, 28, 30 and gene expression of TrkA, TrkB, M1-M5, α7nAChR, TNF-α and ERK2 were evaluated. At least, in lung histopathology, perivascular and peribronchial inflammation, mucus production and goblet cell hyperplasia were studied. ResultsOn day 24, treatment with BTX for all dosages had no significant effect on AHR but, on day 26 and 28, AHR was decreased and it was continued on day 30 for all treated groups. Treatment with BTX had no significant effect on the expressions of TrkA, TrkB, M1, M2, M3, M4, M5, α7nAChR, TNF-α and ERK2 genes, perivascular inflammation, peribronchial inflammation, hyperplasia of the goblet cell and production of mucus. Also, the mice have been received BTX 10 mg/ml, were died. ConclusionsBTX therapy controlled asthma attacks via decreasing of AHR and induction of relaxation in the ASMs. But, it has no significant effect on inflammation and mucus production. In using of BTX, attention to the safe dose and prevention of dangerous side effects are necessary.

Neuropathology and Inflammatory Cell Characterization in 10 Autoptic COVID-19 Brains

COVID-19 presents with a wide range of clinical neurological manifestations. It has been recognized that SARS-CoV-2 infection affects both the central and peripheral nervous system, leading to smell and taste disturbances; acute ischemic and hemorrhagic cerebrovascular disease; encephalopathies and seizures; and causes most surviving patients to have long lasting neurological symptoms. Despite this, typical neuropathological features associated with the infection have still not been identified. Studies of post-mortem examinations of the cerebral cortex are obtained with difficulty due to laboratory safety concerns. In addition, they represent cases with different neurological symptoms, age or comorbidities, thus a larger number of brain autoptic data from multiple institutions would be crucial. Histopathological findings described here are aimed to increase the current knowledge on neuropathology of COVID-19 patients. We report post-mortem neuropathological findings of ten COVID-19 patients. A wide range of neuropathological lesions were seen. The cerebral cortex of all patients showed vascular changes, hyperemia of the meninges and perivascular inflammation in the cerebral parenchyma with hypoxic neuronal injury. Perivascular lymphocytic inflammation of predominantly CD8-positive T cells mixed with CD68-positive macrophages, targeting the disrupted vascular wall in the cerebral cortex, cerebellum and pons were seen. Our findings support recent reports highlighting a role of microvascular injury in COVID-19 neurological manifestations.