Obesity exacerbates imiquimod‐induced psoriasis‐like epidermal hyperplasia and interleukin‐17 and interleukin‐22 production in mice

Psoriasis is a chronic inflammatory skin disorder that is accompanied by an imbalance between the proliferation and differentiation of keratinocytes. A number of studies have suggested an association between obesity and severe psoriasis; however, it remains to be clarified whether obesity exacerbates psoriasis. To address this unsolved question, we induced psoriasiform dermatitis in mouse models for obesity. We found that obesity exaggerated the severity of psoriasiform dermatitis induced by topical application of the Toll‐like receptor (TLR) 7 agonist, imiquimod. Ear swelling and epidermal hyperplasia were more prominent in the obese mice than in the control mice. When compared to imiquimod‐treated control mice, imiquimod‐treated obese mice expressed higher levels of psoriasis mediators, interleukin‐17A (IL‐17A) and IL‐22 in the skin. Food intake restriction partially abrogated enhanced ear swelling and cytokine overproduction in obese mice. Furthermore, the obesity environment and imiquimod treatment synergistically induced an IL‐17A downstream molecule, regenerating islet‐derived 3γ (Reg3γ), which is a critical molecule for psoriatic epidermal hyperplasia. Palmitic acid, one of the fatty acids released by subcutaneous adipocytes, increased the expression of REG3A (a human homologue of mouse Reg3γ) in both the HaCaT keratinocyte cell line and normal human keratinocytes. Taken together, these results strongly suggest that obesity exacerbates psoriasiform dermatitis in mice by upregulating IL‐17A, IL‐22 and Reg3γ.     

Case of autoimmune neutropenia with severe marginal periodontitis

Early onset periodontitis is rarely seen in infants, though often leads to an acute and serious clinical course when encountered in such patients. Autoimmune neutropenia presents systemic and dental symptoms, as depressed resistance to bacterial infection is caused by a disorder that reduces the number of neutrophils. This disease can result in not only gingival inflammation but also destruction of periodontal tissues, such as attachment loss, alveolar bone absorption, and early tooth loss in primary as well as mixed dentition. Here, we report treatment of a child with marginal periodontitis from the age of 3 years–7 years 9 months. No systemic manifestations were noted until 3 years of age, thus the patient had never received a detailed examination or medication related to the disease. Following examinations at our department, we referred the patient to a pediatrician at our university hospital for possible systemic disease, who made a diagnosis of autoimmune neutropenia. Although administration of antibiotics and professional dental care were continued, neutrophil count was not increased and progressive periodontal destruction was observed. Extraction of teeth with poor prognosis was performed and a prosthetic strategy for the missing teeth developed. It is important to recognize that periodontitis along with autoimmune neutropenia can appear in infants, even though the incidence is quite low. Early detection and early treatment of this disease is necessary for delaying progression of periodontitis and optimal occlusal induction of permanent teeth.     

Pharmaceuticals and Medical Device Agency approval summary: Amenamevir for the treatment of herpes zoster

In July 2017, Japan’s Ministry of Health, Labor and Welfare issued a marketing authorization valid throughout Japan for N-(2,6-dimethylphenyl)-N-(2-{[4-(1,2,4-oxadiazol-3-yl)phenyl]amino}-2-oxoethyl)-1,1-dioxothiane-4-carboxamide (amenamevir) for the first time worldwide. The decision was based on the favorable opinion of the Pharmaceuticals and Medical Device Agency (PMDA) recommending a marketing authorization of amenamevir for treatment of herpes zoster (HZ). Amenamevir has a different action mechanism from previously approved synthetic nucleoside compounds for the treatment of HZ including acyclovir, valacyclovir and famciclovir. The usual adult dose is 400 mg amenamevir p.o. once daily for 7 days. The benefit is its ability to cure HZ as well as preventing postherpetic neuralgia. The most common side-effects are increase of urine N-acetyl-β-D-glucosaminidase and α1-microglobulin levels. However, based on the detailed evaluation of the submitted clinical studies, there seems to be no serious safety concerns about amenamevir regarding the kidney of both renally normal and impaired patients. The objective of this article is to summarize the scientific review of the application. The detailed scientific assessment report and product information, including the summary of product characteristics, are available on the PMDA website ( www.pmda.go.jp/PmdaSearch/iyakuSearch/ ).     

Prenatal tobacco use and the risk of mood disorders in offspring: a systematic review and meta-analysis

Purpose

It is plausible that offspring born to mothers using tobacco during pregnancy may have increased risk of mood disorders (depression and bipolar disorders); however, mixed results have been reported. We conducted a systematic review and meta-analysis to investigate the magnitude and consistency of associations reported between prenatal tobacco use and mood disorders in offspring.

Methods

We systematically searched EMBASE, SCOPUS, PubMed and Psych-INFO for studies on mood disorders and prenatal tobacco use. Methodological quality of studies was assessed with the revised Newcastle–Ottawa Scale. We estimated pooled relative risk (RR) with inverse variance weighted random-effects meta-analysis. We performed leave-one-out analyses, and stratified analyses by a subgroup (depression and bipolar disorder). Potential publication bias was assessed by inspection of the funnel plot and Egger’s test for regression asymmetry. This study protocol was prospectively registered in PROSPERO (CRD42017060037).

Results

Eight cohort and two case–control studies were included in the final meta-analysis. We found an increased pooled relative risk of mood disorders in offspring exposed to maternal prenatal tobacco use RRs 1.43 (95% CI 1.27–1.60) compared to no prenatal tobacco use. Similarly, the pooled relative risks of bipolar and depressive disorders in offspring were 1.44, (95% CI 1.15–1.80) and 1.44, (95% CI 1.21–1.71), respectively. Moreover, the pooled estimated risk of mood disorders was not significantly attenuated in the studies that reported sibling comparison results [RR = 1.21 (95% CI 1.04–1.41)].

Conclusion

Taken together, there was strong evidence for a small (RR < 2) association between prenatal tobacco use and mood disorders in offspring.

     

A Systematic Review and Meta-Analysis of the Prevalence of Post-Traumatic Stress Disorder among Homeless People

Post-traumatic stress disorder (PTSD) is common among homeless people and is associated with an increased risk of mortality from suicide, medical causes, and drug-related problems. However, there are no previous systematic review and meta-analysis studies that reported the consolidated magnitude of PTSD among homeless people. A literature search was conducted on PubMed, Embase, and Scopus to discover pertinent studies that determined the prevalence of PTSD among the homeless. Articles were evaluated by titles, abstracts, and full-text. Comprehensive meta-analysis software was used to conduct the meta-analysis. Subgroup and sensitivity analysis were performed and Cochran’s Q- and the I² test were used to assess heterogeneity. The evidence of publication bias was evaluated by using Egger’s test and visual inspection of the symmetry in funnel plots. From the total, 19 studies with 20,364 participants across seven countries were included in the final analysis. Our meta-analysis revealed that the pooled prevalence of PTSD among homeless people was 27.38% (95% CI; 21.95–33.57). In our subgroup analysis, we found that the prevalence of PTSD was considerably high as measured by the screening instrument (35.93%) than the diagnostic instrument (23.57% %). The prevalence of PTSD among homeless showed a significant variation by the location of the studies, the instruments used to measure PTSD as well as the quality of the included studies. This review showed that the pooled prevalence estimate of PTSD among homeless peoples was remarkably high (27.38%). Early screening and treatment of PTSD among homeless peoples are warranted to alleviate suffering.

     

Cerebellar Contribution to Pattern Separation of Human Hippocampal Memory Circuits

The cerebellum is a crucial structure for cognitive function as well as motor control. Benign brain tumors such as schwannomas, meningiomas, and epidermoids tend to occur in the cerebellopontine angle cisterns and may cause compression of the posterior lateral cerebellum near the superior posterior fissure, where the eloquent area for cognitive function was recently identified. The present study examined cognitive impairment in patients with benign cerebellar tumors before and after surgical intervention in order to clarify the functional implications of this region in humans. Patients with cerebellar tumors showed deficits in psychomotor speed and working memory compared with healthy controls. Moreover, these impairments were more pronounced in patients with right cerebellar tumors. Functional magnetic resonance imaging during performance of a lure task also demonstrated that cerebellar tumors affected pattern separation or the ability to distinguish similar experiences of episodic memory or events with discrete, non-overlapping representations, which is one of the important cognitive functions related to the hippocampus. The present findings indicate that compression of the human posterior lateral cerebellum affects hippocampal memory function.     

The trans-chromosomic mouse-derived human monoclonal antibody promotes phagocytosis of Porphyromonas gingivalis by neutrophils

BACKGROUND: As a safe immunotherapeutic approach, human monoclonal antibody (hMAb) may be effective in clearing periodontopathic bacteria. The trans-chromosomic (TC) technology has recently been applied to construction of the TC mouse, which enables us to incorporate entire human chromosome fragments containing immunoglobulin (Ig) gene cluster. The aim of this study is to establish TC mouse-derived hMAb, and to test the in vitro opsonophagocytic activity. METHODS: Human Ig-producing TC mouse was immunized by recombinant 40-kDa outer membrane protein (r40-kDa OMP) of Porphyromonas gingivalis 381, and the spleen cells were fused with the mouse myeloma cell line. The specificity of antir40- kDa OMP hMAb was evaluated with the enzyme-linked immunosorbent assay (ELISA) and surface plasmon resonance assays. Flow cytometric analyses were performed to assess the opsonophagocytic activity. RESULTS: We successfully constructed 99 IgG isotype clones (IgG1: 84; IgG2: 11; IgG4: four clones), which were specifically reactive with r40-kDa OMP. The anti-r40-kDa OMP IgG1 hMAbs promoted phagocytosis of P. gingivalis by neutrophils. Futhermore, an increased opsonophagocytic activitity of anti-r40-kDa OMP IgG1 hMAbs was observed not only in P. gingivalis 381, but also in the W50, W83, and Su63 strains. CONCLUSION: Our results document the TC mouse-derived hMAb to promote neutrophil phagocytosis of P. gingivalis, suggesting an immunotherapeutic option for clearance of P. gingivalis.