Marchiafava-Bignami Disease in a Patient With Polysubstance Use Disorder.

Marchiafava-Bignami disease (MBD) is a rare demyelinating disease associated with chronic alcohol use and/or malnutrition leading to vitamin deficiency. Clinical presentation is diverse and can range from mild neurological deficits of dysarthria and confusion to severe symptoms such as coma or even death. Diagnosis is made using imaging modalities including magnetic resonance imaging (MRI) and computed tomography (CT) with the rise in technological advances placing MRI as the most sensitive and specific imaging technology for diagnosis. Classic MBD imaging demonstrates demyelination and necrotic damage of the corpus callosum. While MBD is a well-documented neurologic complication of chronic alcoholism, its occurrence and presentation in the context of concurrent polysubstance abuse remain underexplored. We outline the case of a 27-year-old male with polysubstance use disorder presenting with subacute neurological deterioration and demyelination of the splenium of the corpus callosum.

C-type lectin receptor expression is a hallmark of neutrophils infiltrating the skin in epidermolysis bullosa acquisita.

Introduction: Inflammatory epidermolysis bullosa acquisita (EBA) is characterized by a neutrophilic response to anti-type VII collagen (COL7) antibodies resulting in the development of skin inflammation and blistering. The antibody transfer model of EBA closely mirrors this EBA phenotype. Methods: To better understand the changes induced in neutrophils upon recruitment from peripheral blood into lesional skin in EBA, we performed single-cell RNA-sequencing of whole blood and skin dissociate to capture minimally perturbed neutrophils and characterize their transcriptome. Results: Through this approach, we identified clear distinctions between circulating activated neutrophils and intradermal neutrophils. Most strikingly, the gene expression of multiple C-type lectin receptors, which have previously been reported to orchestrate host defense against fungi and select bacteria, were markedly dysregulated. After confirming the upregulation of Clec4n, Clec4d, and Clec4e in experimental EBA as well as in lesional skin from patients with inflammatory EBA, we performed functional studies in globally deficient Clec4e-/- and Clec4d-/- mice as well as in neutrophil-specific Clec4n-/- mice. Deficiency in these genes did not reduce disease in the EBA model. Discussion: Collectively, our results suggest that while the upregulation of Clec4n, Clec4d, and Clec4e is a hallmark of activated dermal neutrophil populations, their individual contribution to the pathogenesis of EBA is dispensable.

Off-Label Uses of Rituximab in Dermatology.

Purpose of Review: Rituximab has transformed the treatment of B-cell malignancies and rheumatoid arthritis in the past 2 decades. More recently, this anti-CD20 monoclonal antibody has seen increasing usage in the field of dermatology. This review highlights the evidence supporting its use in several important dermatologic conditions. Recent Findings: Key recent findings include the 2018 FDA approval of rituximab for the treatment of moderate-to-severe pemphigus. Summary: Data from randomized controlled trials have demonstrated the efficacy of rituximab in pemphigus, ANCA-associated vasculitis, and cryoglobulinemic vasculitis. More limited data suggests its use in recalcitrant cases of diseases such as pemphigoid, epidermolysis bullosa acquisita, and dermatomyositis. There is scarce evidence and mixed results for rituximab when studied in cutaneous polyarteritis nodosa and cutaneous lupus erythematosus.

Insights Into the Pathogenesis of Bullous Pemphigoid: The Role of Complement-Independent Mechanisms.

Bullous pemphigoid is an autoimmune blistering disease caused by autoantibodies targeting BP180 and BP230. While deposits of IgG and/or complement along the epidermal basement membrane are typically seen suggesting complement -mediated pathogenesis, several recent lines of evidence point towards complement-independent pathways contributing to tissue damage and subepidermal blister formation. Notable pathways include macropinocytosis of IgG-BP180 complexes resulting in depletion of cellular BP180, direct induction of pro-inflammatory cytokines from keratinocytes, as well as IgE autoantibody- and eosinophil-mediated effects. We review these mechanisms which open new perspectives on novel targeted treatment modalities.

Deciphering the Contribution of BP230 Autoantibodies in Bullous Pemphigoid.

Bullous pemphigoid (BP) is a subepidermal autoimmune blistering disease predominantly affecting elderly patients and carries significant morbidity and mortality. Patients typically suffer from severe itch with eczematous lesions, urticarial plaques, and/or tense blisters. BP is characterized by the presence of circulating autoantibodies against two components of the hemidesmosome, BP180 and BP230. The transmembrane BP180, also known as type XVII collagen or BPAG2, represents the primary pathogenic autoantigen in BP, whereas the intracellular BP230 autoantigen is thought to play a minor role in disease pathogenesis. Although experimental data exist suggesting that anti-BP230 antibodies are secondarily formed following initial tissue damage mediated by antibodies targeting extracellular antigenic regions of BP180, there is emerging evidence that anti-BP230 IgG autoantibodies alone directly contribute to tissue damage. It has been further claimed that a subset of patients has a milder variant of BP driven solely by anti-BP230 autoantibodies. Furthermore, the presence of anti-BP230 autoantibodies might correlate with distinct clinical features. This review summarizes the current understanding of the role of BP230 and anti-BP230 antibodies in BP pathogenesis.

Unmet Medical Needs in Chronic, Non-communicable Inflammatory Skin Diseases.

An estimated 20-25% of the population is affected by chronic, non-communicable inflammatory skin diseases. Chronic skin inflammation has many causes. Among the most frequent chronic inflammatory skin diseases are atopic dermatitis, psoriasis, urticaria, lichen planus, and hidradenitis suppurativa, driven by a complex interplay of genetics and environmental factors. Autoimmunity is another important cause of chronic skin inflammation. The autoimmune response may be mainly T cell driven, such as in alopecia areata or vitiligo, or B cell driven in chronic spontaneous urticaria, pemphigus and pemphigoid diseases. Rare causes of chronic skin inflammation are autoinflammatory diseases, or rheumatic diseases, such as cutaneous lupus erythematosus or dermatomyositis. Whilst we have seen a significant improvement in diagnosis and treatment, several challenges remain. Especially for rarer causes of chronic skin inflammation, early diagnosis is often missed because of low awareness and lack of diagnostics. Systemic immunosuppression is the treatment of choice for almost all of these diseases. Adverse events due to immunosuppression, insufficient therapeutic responses and relapses remain a challenge. For atopic dermatitis and psoriasis, a broad spectrum of innovative treatments has been developed. However, treatment responses cannot be predicted so far. Hence, development of (bio)markers allowing selection of specific medications for individual patients is needed. Given the encouraging developments during the past years, we envision that many of these challenges in the diagnosis and treatment of chronic inflammatory skin diseases will be thoroughly addressed in the future.

Simple Strategies for Improving Inference with Linked Data: A Case Study of the 1850-1930 IPUMS Linked Representative Historical Samples.

New large-scale linked data are revolutionizing quantitative history and demography. This paper proposes two complementary strategies for improving inference with linked historical data: the use of validation variables to identify higher quality links and a simple, regression-based weighting procedure to increase the representativeness of custom research samples. We demonstrate the potential value of these strategies using the 1850-1930 Integrated Public Use Microdata Series Linked Representative Samples (IPUMS-LRS)-a high quality, publicly available linked historical dataset. We show that, while incorrect linking rates appear low in the IPUMS-LRS, researchers can reduce error rates further using validation variables. We also show how researchers can reweight linked samples to balance observed characteristics in the linked sample with those in a reference population using a simple regression-based procedure.

Free fatty acid receptor 3 differentially contributes to ß-cell compensation under high-fat diet and streptozotocin stress.

The free fatty acid receptor 3 (FFA3) is a nutrient sensor of gut microbiota-generated nutrients, the short-chain fatty acids. Previously, we have shown that FFA3 is expressed in ß-cells and inhibits islet insulin secretion ex vivo. Here, we determined the physiological relevance of the above observation by challenging wild-type (WT) and FFA3 knockout (KO) male mice with 1) hyperglycemia and monitoring insulin response via highly sensitive hyperglycemic clamps, 2) dietary high fat (HF), and 3) chemical-induced diabetes. As expected, FFA3 KO mice exhibited significantly higher insulin secretion and glucose infusion rate in hyperglycemic clamps. Predictably, under metabolic stress induced by HF-diet feeding, FFA3 KO mice exhibited less glucose intolerance compared with the WT mice. Moreover, similar islet architecture and ß-cell area in HF diet-fed FFA3 KO and WT mice was observed. Upon challenge with streptozotocin (STZ), FFA3 KO mice initially exhibited a tendency for an accelerated incidence of diabetes compared with the WT mice. However, this difference was not maintained. Similar glycemia and ß-cell mass loss was observed in both genotypes 10 days post-STZ challenge. Higher resistance to STZ-induced diabetes in WT mice could be due to higher basal islet autophagy. However, this difference was not protective because in response to STZ, similar autophagy induction was observed in both WT and FFA3 KO islets. These data demonstrate that FFA3 plays a role in modulating insulin secretion and ß-cell response to stressors. The ß-cell FFA3 and autophagy link warrant further research.

How Well Do Automated Linking Methods Perform? Lessons from U.S. Historical Data.

This paper reviews the literature in historical record linkage in the U.S. and examines the performance of widely-used record linking algorithms and common variations in their assumptions. We use two high-quality, hand-linked datasets and one synthetic ground truth to examine the direct effects of linking algorithms on data quality. We find that (1) no algorithm (including hand-linking) consistently produces representative samples; (2) 15 to 37 percent of links chosen by widely-used algorithms are classified as errors by trained human reviewers; and (3) false links are systematically related to baseline sample characteristics, showing that some algorithms may induce systematic measurement error into analyses. A case study shows that the combined effects of (1)-(3) attenuate estimates of the intergenerational income elasticity by up to 20 percent, and common variations in algorithm assumptions result in greater attenuation. As current practice moves to automate linking and increase link rates, these results highlight the important potential consequences of linking errors on inferences with linked data. We conclude with constructive suggestions for reducing linking errors and directions for future research.

Sub-Trochanteric Hip Fracture Following Core Decompression for Osteonecrosis in a Patient with a Pre-Existing Contralateral Occult Femoral Neck Fracture.

We present a unique case of a 62-year-old patient with bilateral osteonecrosis of the femoral heads secondary to corticosteroid use. She presented with an occult right femoral neck fracture and was treated with percutaneous pinning of the right femoral neck and a left-sided percutaneous drilling. Despite apparent appropriate technique, the patient sustained a left sub-trochanteric hip fracture while shifting in bed in the postoperative care unit and was taken back for cephalo-medullary nail fixation. Femoral head osteonecrosis may be an under-reported risk factor for development of pathological neck fractures. We present an overview of this topic along with suggestions for joint preservation treatment of similar patients at higher risk for perioperative fracture.

Acute septic arthritis of the knee: A rare case report of infection with Parvimonas micra after an intra-articular corticosteroid injection for osteoarthritis.

Acute bacterial mono-articular septic arthritis affects most commonly the lower extremity joints in adult population and most commonly caused by Staphylococcus aureus. Various risk factors determine susceptibility to infection including host immunity, medical co-morbidity and joint structural abnormality and other organisms may be involved. Parvimonas micra (P. micra) is among the rare organisms that may be associated with atypical septic arthritis and primarily affects the native knee joint. Only 3 case reports in the literature have reported on pyogenic pyogenic joint infection caused by this organism. We hereby present our experience with a case of knee septic arthritis caused by P. micra in a patient with knee osteoarthritis following a recent intra-articular injection with corticosteroids. In susceptible patients, Intra-articular corticosteroid injection and crystal induced arthritis may propose a potential risk of contracting infection with P. micra.