APOE4 impairs the microglial response in Alzheimer's disease by inducing TGFß-mediated checkpoints.

The APOE4 allele is the strongest genetic risk factor for late-onset Alzheimer's disease (AD). The contribution of microglial APOE4 to AD pathogenesis is unknown, although APOE has the most enriched gene expression in neurodegenerative microglia (MGnD). Here, we show in mice and humans a negative role of microglial APOE4 in the induction of the MGnD response to neurodegeneration. Deletion of microglial APOE4 restores the MGnD phenotype associated with neuroprotection in P301S tau transgenic mice and decreases pathology in APP/PS1 mice. MGnD-astrocyte cross-talk associated with ß-amyloid (Aß) plaque encapsulation and clearance are mediated via LGALS3 signaling following microglial APOE4 deletion. In the brains of AD donors carrying the APOE4 allele, we found a sex-dependent reciprocal induction of AD risk factors associated with suppression of MGnD genes in females, including LGALS3, compared to individuals homozygous for the APOE3 allele. Mechanistically, APOE4-mediated induction of ITGB8-transforming growth factor-ß (TGFß) signaling impairs the MGnD response via upregulation of microglial homeostatic checkpoints, including Inpp5d, in mice. Deletion of Inpp5d in microglia restores MGnD-astrocyte cross-talk and facilitates plaque clearance in APP/PS1 mice. We identify the microglial APOE4-ITGB8-TGFß pathway as a negative regulator of microglial response to AD pathology, and restoring the MGnD phenotype via blocking ITGB8-TGFß signaling provides a promising therapeutic intervention for AD.

What the Cardiologist Needs to Know About Cancer Immunotherapies and Complications.

OPINION STATEMENT: Immunotherapies have transformed the current landscape for cancer treatment and demonstrated unparalleled improvements in survival rates. Now, a third of cancer patients are eligible for treatment with the most widely used class of immunotherapy, immune checkpoint inhibitors (ICIs). As more patients are treated with these novel agents, it is critical for both oncologists and subspecialists to establish a better understanding of the adverse events which can occur. The incidence of myocarditis associated with ICI therapy has been reported to be between 0.27 and 1.14%, 5 times that of myocarditis from other cancer therapies, and, of those patients, 20-50% develop a fulminant form. However, because of unclear risk factors, a broad clinical spectrum, and lack of specific noninvasive studies for diagnosis, the care of patients with ICI-associated cardiotoxicity can be challenging. Here, we have provided a brief overview of the current immunotherapy agents with a focus on the emerging evidence regarding diagnosis and management of cardiac adverse events.

A puzzling case: SCC or not?

We present a 37-year-old woman who underwent extensive facial surgery for removal of multiple eruptive squamous cell carcinoma (SCC)-like lesions resembling invasive SCC histologically. The patient's mother had undergone numerous surgical procedures and radiotherapy for facial SCC. A review of the histology and immunohistochemistry for DNA mismatch repair proteins excluded Muir-Torre syndrome. A diagnosis of Ferguson-Smith disease (or multiple self-healing squamous epitheliomata) was suspected. Blood was sent for DNA analysis. Twelve months later, mutations of the TGFBR1 gene were demonstrated in 18 families (67 individuals) with Ferguson-Smith disease; among whom our patient and her mother were family 11.

Blastic plasmacytoid dendritic cell neoplasm.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare haematological malignancy that originates from the precursors of plasmacytoid dendritic cells. It commonly presents with findings isolated to the skin although it usually progresses to a leukaemic phase. It has a poor prognosis but is curable, particularly in younger patients treated with allogeneic bone marrow transplantation. We report a case of a 79-year old man who had 6 months of progressive, asymptomatic BPDCN manifestations limited to the skin, before developing a leukaemic phase.

Prevalence of Staphylococcus aureus and antibiotic resistance in children with atopic dermatitis: a New Zealand experience.

BACKGROUND/OBJECTIVES: Children with atopic dermatitis often have infective exacerbations which are treated with antibiotics and/or antiseptics. The most common infective cause is Staphylococcus aureus with a worldwide trend towards antibiotic resistance. This prospective observational audit aimed primarily to establish the prevalence of S. aureus colonisation in New Zealand children with atopic dermatitis attending a specialised paediatric dermatology clinic. Secondary aims were to assess whether S. aureus colonisation correlated to clinical severity, the sensitivity patterns to antibiotics (in particular methicillin-resistant S. aureus, and to identify any demographic or management risk factors. METHODS: Subjects were children aged 18 years or younger attending a tertiary public hospital dermatology clinic with a diagnosis of atopic dermatitis. Demographic and social data, as well as current and previous systemic and topical treatments, were recorded. Patients were examined and the extent of atopic dermatitis determined using a standardised scale (Scoring Atopic Dermatitis (SCORAD)). Two skin swabs were taken for culture and standard sensitivities; one from the left antecubital fossa and one from the worst area of atopic dermatitis. Microbiological cultures and density of S. aureus colonisation were recorded. SCORAD and density of S. aureus culture were correlated. Demographic and clinical data from children with S. aureus was analysed. RESULTS: One hundred children were recruited from March 2007 to May 2008. S. aureus was isolated from 68 patients. There was a positive correlation between the density of S. aureus culture and severity of SCORAD (Spearman r = 0.55, P < 0.0001). There was also a positive, though weaker, correlation between SCORAD and ethnicity with Maori /Polynesian children generally having more severe atopic dermatitis (r = 0.22, P = 0.028). Although a greater proportion of Maori or Pacific Island children were colonised by S. aureus than other ethnic groups this did not reach statistical significance (78% and 60%, respectively, P = 0.0842). There was no significant correlation between either S. aureus prevalence or its density and age (r = 0.09, P = 0.39 and r = 0.12, P = 0.23, respectively). There were no significant differences in sex or treatments (use of antibiotics, antiseptics, calcineurin inhibitors, emollients or corticosteroids) between S. aureus-positive and S. aureus-negative children. Only 12 S. aureus-positive children demonstrated antibiotic resistance, 10 to erythromycin and only two to flucloxacillin. CONCLUSIONS: Three quarters of children with atopic dermatitis have at least one positive culture, of which the vast majority is S. aureus. The density of S. aureus colonisation correlates to severity of atopic dermatitis. Children who are S. aureus culture-positive had no significant demographic or clinical features different to children who were culture-negative. Only two children grew S. aureus resistant to flucloxacillin (2% resistance rate), which remains the ideal first line of treatment in our local population.

Methotrexate for treatment of atopic dermatitis in children and adolescents.

BACKGROUND: Low-dose methotrexate is becoming established as a second-line treatment for atopic eczema in the adult population, but there has been a paucity of data to support its use for this indication in the pediatric population. METHODS: A retrospective review was undertaken of patients aged 18 years and under started on methotrexate between January 2005 and April 2010, at a hospital-based dermatology department in New Zealand. RESULTS: Thirty-one patients (17 females, mean age 10 years, range 3-18 years) were reviewed. Methotrexate was found to be effective or very effective in 75% and ineffective in 25%. The mean duration of treatment for those who responded to methotrexate was 14 months (range 2-38 months), 74% of patients were still on treatment at the time of last review. The most common adverse effect was minor nausea in four patients (14%) and non-significant elevation of liver enzymes (four patients). No serious adverse effects were noted. CONCLUSION: In our experience, methotrexate has a good safety/tolerability profile when used in low dose for the treatment of atopic dermatitis in children and adolescents and appears to be effective. Formal comparative studies are needed.

A can of red herrings.

Lymphomatoid granulomatosis is a rare disease. Anti-cyclic citrullinated peptide (anti-CCP) antibody is more commonly found in patients with rheumatoid arthritis and less frequently in some of the other rheumatic and non-rheumatic conditions. It is not recognized to be present in lymphoproliferative disease on its own. We report the first case of anti-CCP antibody positivity in lymphomatoid granulomatosis presenting with polyarthritis. This case illustrates the evolving nature of this disease and its characteristics at different stages leading to the challenge of an accurate diagnosis in the setting of a paraneoplastic polyarthritis.

Pseudochromhidrosis: blue discolouration of the head and neck.

A 57-year-old man is presented with blue pseudochromhidrosis affecting the face and neck following combination treatment with lansoprazole, a proton pump inhibitor, and ranitidine, a type two histamine receptor antagonist. The diagnosis was made on the basis of clinico-histological features and growth of Malassezia furfur, and Bacillus species, not Bacillus cereus, in the absence of lipofuscin. The pseudochromhidrosis resolved on stopping both medications and did not recur on restarting only the proton pump inhibitor.

Flushing due to solitary cutaneous mastocytoma can be prevented by hydrocolloid dressings.

Solitary mastocytomas occur commonly and can occasionally be associated with troublesome flushing related to rubbing. We report a child with a solitary mastocytoma who repeatedly and reproducibly caused flushing only with rubbing and scratching. Conventional treatment with antihistamines was not completely effective and caused sedation. A trial application of double-layer hydrocolloid dressing led to complete abolition of flushing episodes until the child reached an age where he could peel off the dressings. This treatment is particularly suited to very young children with solitary mastocytomas whose parents do not feel comfortable with antihistamine treatment, topical or intralesional corticosteroids, or surgical interventions. This treatment may be used alone or in conjunction with conventional therapy where there has been a failure to achieve complete control of flushing and/or blistering.

Two unusual cases of toxic epidermal necrolysis.

Two cases of toxic epidermal necrolysis (TEN) are presented. A 27-year-old woman presented with peripherally located targetoid plaques, papules, blisters and lip erosions which began 9 days after 'recreational' use of 'speed' (dexamphetamine and ephedrine) consistent with erythema multiforme major. Three days later she developed widespread lesions with large areas of blistering affecting 40% of body surface area. The diagnosis was revised to TEN. Intravenous cyclosporin led to rapid prevention of new blister formation. A 71-year-old woman, 3 months after commencing amiodarone, developed extensive erythema, blistering and erosions affecting 50% of body surface area, with a maculopapular rash affecting the limbs and extremities consistent with a diagnosis of TEN. She developed septicaemia following bilateral pneumonia with pleural effusions and died 7 days after admission.