Inflammatory complications of CGRP monoclonal antibodies: a case series

BackgroundCalcitonin gene-related peptide (CGRP) is expressed throughout the body and is a known mediator of migraine, exerting this biological effect through activation of trigeminovascular, meningeal and associated neuronal pathways located in close proximity to the central nervous system. Monoclonal antibodies (mAb) targeting the CGRP pathway are an effective new preventive treatment for migraine, with a generally favourable adverse event profile. Pre-clinical evidence supports an anti-inflammatory/immunoregulatory role for CGRP in other organ systems, and therefore inhibition of the normal action of this peptide may promote a pro-inflammatory response.CasesWe present a case series of eight patients with new or significantly worsened inflammatory pathology in close temporal association with the commencement of CGRP mAb therapy.ConclusionThis case series provides novel insights on the potential molecular mechanisms and side-effects of CGRP antagonism in migraine and supports clinical vigilance in patient care going forward.     

Accuracy of Kvaal’s radiographic and translucent dentinal root techniques of extracted teeth in Malay adults for dental age estimation

The use of teeth to estimate the age of unknown bodies provides much help especially in skeletal remains with no soft tissues left for identification. However, dental age estimation utilizing degenerative changes in teeth like dentinal translucency is often hampered with large margin of error. This study aims to compare the accuracy of Kvaal’s radiographic method (intraoral periapical radiograph) with modified Bang-Ramm dentinal root translucency method in estimating dental age in Malay adults. One-hundred teeth of maxillary and mandibular incisors and canine were collected following dental extraction. Date of birth, date of extraction, gender and ethnicity were documented prior to extraction. All teeth were assessed using two methods of dental age estimation: 1) The equation from Kvaal’s radiographic method and 2) Formula from modified Bang-Ramm dentinal root translucency method. The results from the age estimation were compared to the chronological age of the persons from whom the teeth were extracted. The average dental age estimated using both methods significantly correlated with the chronological age for both men and women. Overestimation and underestimation with mean absolute error up to 13 years and 15 years was observed in modified Bang-Ramm and Kvaal, respectively. The estimated age calculated from both methods also showed increasing standard deviation as the patient gets older. From the obtained results it is reasonable to conclude that modified Bang-Ramm method gives better accuracy for dental age estimation in Malay adults.     

Non-tuberculous mycobacterium bacteraemia in a pregnant systemic lupus erythematosus (SLE) patient: a case review and pooled case analysis

Clinical Rheumatology - Non-tuberculous mycobacteria (NTM) are recognized as an important cause of human diseases and infections. It is commonly known to cause infections of the skin, soft tissue...     

Exposure to environmental microbiota explains persistent abdominal pain and irritable bowel syndrome after a major flood

Background

After an environmental disaster, the affected community is at increased risk for persistent abdominal pain but mechanisms are unclear. Therefore, our study aimed to determine association between abdominal pain and poor water, sanitation and hygiene (WaSH) practices, and if small intestinal bacterial overgrowth (SIBO) and/or gut dysbiosis explain IBS, impaired quality of life (QOL), anxiety and/or depression after a major flood.

Results

New onset abdominal pain, IBS based on the Rome III criteria, WaSH practices, QOL, anxiety and/or depression, SIBO (hydrogen breath testing) and stools for metagenomic sequencing were assessed in flood victims. Of 211 participants, 37.9% (n = 80) had abdominal pain and 17% (n = 36) with IBS subtyped diarrhea and/or mixed type (n = 27 or 12.8%) being the most common. Poor WaSH practices and impaired quality of life during flood were significantly associated with IBS. Using linear discriminant analysis effect size method, gut dysbiosis was observed in those with anxiety (Bacteroidetes and Proteobacteria, effect size 4.8), abdominal pain (Fusobacteria, Staphylococcus, Megamonas and Plesiomonas, effect size 4.0) and IBS (Plesiomonas and Trabulsiella, effect size 3.0).

Conclusion

Disturbed gut microbiota because of environmentally-derived organisms may explain persistent abdominal pain and IBS after a major environmental disaster in the presence of poor WaSH practices.

     

Expanding the phenotype in argininosuccinic aciduria: need for new therapies

Objectives

This UK-wide study defines the natural history of argininosuccinic aciduria and compares long-term neurological outcomes in patients presenting clinically or treated prospectively from birth with ammonia-lowering drugs.

Methods

Retrospective analysis of medical records prior to March 2013, then prospective analysis until December 2015. Blinded review of brain MRIs. ASL genotyping.

Results

Fifty-six patients were defined as early-onset (n?=?23) if symptomatic?<?28 days of age, late-onset (n?=?23) if symptomatic later, or selectively screened perinatally due to a familial proband (n?=?10). The median follow-up was 12.4 years (range 0–53). Long-term outcomes in all groups showed a similar neurological phenotype including developmental delay (48/52), epilepsy (24/52), ataxia (9/52), myopathy-like symptoms (6/52) and abnormal neuroimaging (12/21). Neuroimaging findings included parenchymal infarcts (4/21), focal white matter hyperintensity (4/21), cortical or cerebral atrophy (4/21), nodular heterotopia (2/21) and reduced creatine levels in white matter (4/4). 4/21 adult patients went to mainstream school without the need of additional educational support and 1/21 lives independently. Early-onset patients had more severe involvement of visceral organs including liver, kidney and gut. All early-onset and half of late-onset patients presented with hyperammonaemia. Screened patients had normal ammonia at birth and received treatment preventing severe hyperammonaemia. ASL was sequenced (n?=?19) and 20 mutations were found. Plasma argininosuccinate was higher in early-onset compared to late-onset patients.

Conclusions

Our study further defines the natural history of argininosuccinic aciduria and genotype–phenotype correlations. The neurological phenotype does not correlate with the severity of hyperammonaemia and plasma argininosuccinic acid levels. The disturbance in nitric oxide synthesis may be a contributor to the neurological disease. Clinical trials providing nitric oxide to the brain merit consideration.

     

Biologic interaction of three-dimensional periodontal fibroblast spheroids with collagen-based and synthetic membranes

Background: Cell‐based therapy using autologous cells has been suggested as a potential approach for periodontal tissue regeneration. Spheroid systems are a form of three‐dimensional cell culture that promotes cell matrix interaction, which could recapitulate the aspect of cell homeostasis in vivo. The aim of this study is to assess the interaction of periodontal fibroblast spheroids with synthetic and collagen‐based membranes that have been used in guided tissue regeneration. Methods: Commercially available normal human periodontal ligament fibroblasts were grown in spheroid forms using a liquid overlay technique and then transplanted onto a collagen‐based and a polyglycolic acid–based membrane. The biologic interaction of the spheroids with the membranes was assessed using basic histology, Alamar blue tissue viability assay, scanning electron microscopy, and immunohistochemical analysis. Results: Periodontal fibroblast spheroids adhered to both membranes, and the cells were able to proliferate and migrate from the spheroids both horizontally and vertically into the membrane scaffolds. Immunohistochemical analysis showed expression of collagen type I, periostin, and Runx2 by the periodontal fibroblasts. Conclusion: Periodontal fibroblast spheroids were able to grow three‐dimensionally on the biologic membranes and may have the potential to be used together with guided tissue regeneration approaches as an adjunct for periodontal regeneration.     

Modulation of collagen synthesis and its gene expression in human skin fibroblasts by tocotrienol-rich fraction

Introduction

Skin aging may occur as a result of increased free radicals in the body. Vitamin E, the major chain-breaking antioxidant, prevents propagation of oxidative stress, especially in biological membranes. In this study, the molecular mechanism of tocotrienol-rich fraction (TRF) in preventing oxidative stress-induced skin aging was evaluated by determining the rate of total collagen synthesis and its gene expression in human skin fibroblasts.

Material and methods

Primary culture of human skin fibroblasts was derived from circumcision foreskin of 9 to 12 year-old boys. Fibroblast cells were divided into 5 different treatment groups: untreated control, hydrogen peroxide (H₂O₂)-induced oxidative stress (20 µM H₂O₂ exposure for 2 weeks), TRF treatment, and pre- and post-treatment of TRF to H₂O₂-induced oxidative stress.

Results

Our results showed that H₂O₂-induced oxidative stress decreased the rate of total collagen synthesis and down-regulated COL I and COL III in skin fibroblasts. Pre-treatment of TRF protected against H₂O₂-induced oxidative stress as shown by increase in total collagen synthesis and up-regulation of COL I and COL III (p<0.05) genes. However, similar protective effects against H₂O₂-induced oxidative stress were not observed in the post-treated fibroblasts.

Conclusions

Tocotrienol-rich fraction protects against H₂O₂-induced oxidative stress in human skin fibroblast culture by modulating the expression of COL I and COL III genes with concomitant increase in the rate of total collagen synthesis. These findings may indicate TRF protection against oxidative stress-induced skin aging.     

Hot water extract of Chlorella vulgaris induced DNA damage and apoptosis

OBJECTIVES:

The aim of this study was to determine the antiproliferative and apoptotic effects of hot water extracts of Chlorella vulgaris on hepatoma cell line HepG2.

INTRODUCTION:

The search for food and spices that can induce apoptosis in cancer cells has been a major study interest in the last decade. Chlorella vulgaris, a unicellular green algae, has been reported to have antioxidant and anti‐cancer properties. However, its chemopreventive effects in inhibiting the growth of cancer cells have not been studied in great detail.

METHODS:

HepG2 liver cancer cells and WRL68 normal liver cells were treated with various concentrations (0‐4 mg/ml) of hot water extract of C. vulgaris after 24 hours incubation. Apoptosis rate was evaluated by TUNEL assay while DNA damage was assessed by Comet assay. Apoptosis proteins were evaluated by Western blot analysis.

RESULTS:

Chlorella vulgaris decreased the number of viable HepG2 cells in a dose dependent manner (p < 0.05), with an IC₅₀ of 1.6 mg/ml. DNA damage as measured by Comet assay was increased in HepG2 cells at all concentrations of Chlorella vulgaris tested. Evaluation of apoptosis by TUNEL assay showed that Chlorella vulgaris induced a higher apoptotic rate (70%) in HepG2 cells compared to normal liver cells, WRL68 (15%). Western blot analysis showed increased expression of pro‐ apoptotic proteins P53, Bax and caspase‐3 in the HepG2 cells compared to normal liver cells WRL68, and decreased expression of the anti‐apoptotic protein Bcl‐2.

CONCLUSIONS:

Chlorella vulgaris may have anti‐cancer effects by inducing apoptosis signaling cascades via an increased expression of P53, Bax and caspase‐3 proteins and through a reduction of Bcl‐2 protein, which subsequently lead to increased DNA damage and apoptosis.     

成人Coats病1例

目的:报告成人Coats病1例,并探讨其引起的视网膜病变。方法:病例报告。结果:马来西亚63岁糖尿病患者1例,男,右眼无痛性视力下降1a,视力指数/2英尺,而左眼最佳矫正视力为6/12。右眼眼底表明颞侧后极部出现广泛的视网膜渗出物,可累及黄斑区和鼻侧视盘。异常分布的多区域血管位于黄斑颞侧且呈衰减趋势。眼底荧光血管造影显示,毛细血管扩张在视网膜渗出区域且有荧光素渗漏现象存在。左眼表现正常。根据临床和FFA结果,患者被诊断为成人Coats病,右眼行氩激光光凝治疗。激光后6mo,患者的视力保持在6/120并出现视网膜最小限度的回退。结论:临床和血管造影结果是视网膜毛细血管扩张症的重要诊断依据。渗漏区域激光光凝治疗有利于防止视力丧失。