Correction to: Pathology-supported genetic testing as a method for disability prevention in multiple sclerosis (MS). Part II. Insights from two MS cases

Metabolic Brain Disease - A Correction to this paper has been published: https://doi.org/10.1007/s11011-021-00722-7     

P21 Design and operation of a human breath freshness panel

Objective  Practical treatment of halitosis requires tongue cleaning since volatile sulphur compounds (VSC) seems mainly to be from the tongue coating. From this point of view, mechanical tools such as tongue brushes or scrapers have been developed. However, approaches by chemical tongue cleaning have not been reported. Thus we developed tablets containing protease from kiwifruits, which could resolve tongue coating, and assessed the effects of the protease tablet to control tongue coating.
Methods  Crossover studies and double blind experiments were designed using volunteers with informed consent. The trial was done twice per volunteer, that is, they had a tablet with or without the addition of protease from kiwifruits (test and placebo) with intervening washout periods of at least 2 weeks. The degree of change in tongue coating was evaluated visually using a tongue coating score which consisted of an area component (0–3) and a thickness component (0–3). An image analyzer was also used to measure the changing in actual area of coating.
Results  The average value of the tongue coating scores after taking a test tablet (11.4 ± 5.2) was significantly smaller ( P  < 0.01) than before taking the tablet (18.8 ± 7.0). Image analyzer measurements also showed significant reduction ( P  < 0.01) of tongue coating by taking test tablet. On the other hand, a placebo tablet showed no significant effects in both analyses.
Conclusions  This study indicated that taking protease tablets could reduce tongue coating. We are planning further clinical trials that can show reduced VSC concentrations in mouth air with decreasing tongue coating.     

Longitudinal dynamics of infection and serum antibody in A. actinomycetemcomitans periodontitis

OBJECTS: This report describes one of the first prospective studies delineating the relationship between infection, host antibody responses and disease exacerbations and remissions in a distinct subset of periodontitis patients infected with A. actinomycetemcomitans. DESIGN: The design of this longitudinal study included visits for each patient approximately every 2 months for up to 3 years. SUBJECTS AND METHODS: Subjects (n = 51) included 16 adult periodontitis (AP) and 11 early-onset periodontitis (EOP) patients with elevated serum IgG antibody to A. actinomycetemcomitans and infection with this microorganism, 12 AP patients with normal levels of anti-Aa antibody, and 12 normal subjects. MEASUREMENT OUTCOMES: Clinical parameters included a gingival index, plaque index, bleeding on probing, pocket depth, and attachment level. Disease activity was defined as loss of attachment during the monitoring intervals. Serum IgG, IgM and IgA antibody to A. actinomycetemcomitans Y4 (serotype b) was quantit-ated using an ELISA. Subgingival plaque samples were examined for A. actinomycetemcomitans using colony immunobiotting. Human serum IgG antibody specificities to outer membrane antigens (OMA) of A. actinomycetemcomitans Y4 were determined using Western immunoblotting. RESULTS: A. actinomycetemcomitans-infected AP patients had a higher frequency of teeth infected when compared to the EOP patients. However, the EOP patients exhibited a trend for higher levels of A. actinomycetemcomitans in those teeth that were infected. Active disease patients demonstrated a significantly greater frequency of infected sites, as well as significant elevations in the proportions of A. octinomycetemcomitans. Both EOP and AP groups showed significantly elevated IgG, IgM and IgA antibody to A. actinomycetemcornitans when compared to a periodontally normal group. The level of IgG antibody was significantly elevated in A. actinomycetemcomitans-positive patients with active disease, while IgA antibody was decreased in a number of the active group patients. Plaque samples derived from active sites showed a clear and significant increase in A. actinomycetemcomitans that occurred from 2–6 months prior to the identification of disease activity. Approximately 70% of the active disease patients showed an increase in IgG antibody level by 2–4 months prior to disease activity. Studies of the antigen reactivity patterns of serum IgG indicated that antibody to antigens of 65, 58, 48, 29 and 24 kDa were more frequent in patients who showed active disease, while those patients with the greatest frequency of active disease appeared to show a general decrease in the recognition of the A. actinomycetemcomitans OMA. CONCLUSIONS: It appears that A. actinomycetemcomitans infection relates to a particular type of disease with accompanying antibody responses that reflect periods of active disease. The dynamics of A. actinomycetemcomitans infection and the level and specificity of systemic antibody responses to this pathogen support an important contribution of the immune response to managing this infection.     

Unintended consequences of policy change to watchful waiting for asymptomatic inguinal hernias

Introduction

In 2009 the Department of Health instructed McKinsey & Company to provide advice on how commissioners might achieve world class National Health Service productivity. Asymptomatic inguinal hernia repair was identified as a potentially cosmetic procedure, with limited clinical benefit. The Birmingham and Solihull primary care trust cluster introduced a policy of watchful waiting for asymptomatic inguinal hernia, which was implemented across the health economy in December 2010. This retrospective cohort study aimed to examine the effect of a change in clinical commissioning policy concerning elective surgical repair of asymptomatic inguinal hernias.

Methods

A total of 1,032 patients undergoing inguinal hernia repair in the 16 months after the policy change were compared with 978 patients in the 16 months before. The main outcome measure was relative proportion of emergency repair in groups before and after the policy change. Multivariate binary logistic regression was used to adjust the main outcome for age, sex and hernia type.

Results

The period after the policy change was associated with 59% higher odds of emergency repair (3.6% vs 5.5%, adjusted odds ratio [OR]: 1.59, 95% confidence interval [CI]: 1.03–2.47). In turn, emergency repair was associated with higher odds of adverse events (4.7% vs 18.5%, adjusted OR: 3.68, 95% CI: 2.04–6.63) and mortality (0.1% vs 5.4%, p<0.001, Fisher’s exact test).

Conclusions

Introduction of a watchful waiting policy for asymptomatic inguinal hernias was associated with a significant increase in need for emergency repair, which was in turn associated with an increased risk of adverse events. Current policies may be placing patients at risk.     

Patterns of arteriosclerotic lesions of the lower extremity in a West Indian population based on angiographic findings and ethnicity

Introduction

This study aimed to determine whether ethnic differences show different patterns of arterial disease in the lower limb.

Methods

A prospective analysis of 100 consecutive patients with 160 lower limb arteriograms was performed looking at the pattern of disease with relation to ethnicity in Trinidad and Tobago.

Results

There were 53 male and 47 female patients with an age range of 43–90 years (mean: 66 years). Of the 100 patients, 45 were of East Indian descent, 36 of Afro-Caribbean descent, 14 of mixed descent and 5 had other backgrounds. There were 32 smokers and 69 diabetics.The most commonly affected artery in East Indians was the anterior tibial artery (ATA, 70%) followed by the peroneal artery (60%), superficial femoral artery (SFA, 60%), posterior tibial artery (PTA, 57%) and tibioperoneal trunk (TPT, 39%). In Afro-Caribbeans, the most commonly affected artery was the ATA (79%) followed by the PTA (74%), peroneal artery (66%) and TPT (55%). The mixed group showed the PTA (85%) to be most diseased followed by the peroneal artery (75%), ATA (70%), SFA (70%), dorsalis pedis artery (DPA, 60%) and TPT (50%). Overall, the most diseased vessel in all groups was the ATA (73%) followed by the PTA (66%), peroneal artery (64%), SFA (59%), TPT (46%), DPA (38%), popliteal artery (31%) and medial plantar artery (MPA, 29%), with the proximal vessels not being affected severely.

Conclusions

Ethnic divisions were only statistically significant (p<0.05) with East Indians showing worse disease in the profunda femoris artery and Afro-Caribbeans showing worse disease in the PTA, DPA and MPA. This suggests that environmental factors may play a significant role in the disease process including smoking and dietary factors rather than purely genetics.     

Genomic insights into abdominal aortic aneurysms

Introduction

An individual’s genetic background plays a significant role in his or her chances of developing an abdominal aortic aneurysm (AAA). This risk is likely to be due to a combination of multiple small effect genetic factors acting together, resulting in considerable difficulty in the identification of these factors.

Methods

Methods for the identification of genetic factors associated with disease are usually based on the analysis of genetic variants in case-control studies. Over the last decade, owing to advances in bioinformatics and laboratory technology, these studies have progressed from focusing on the examination of a single genetic variant in each study to the examination of many millions of variants in a single experiment. We have conducted a series of such experiments using these methods.

Results

Our original methods using candidate gene approaches led to the initial identification of a genetic variant in the interleukin-10 gene associated with AAA. However, further studies failed to confirm this association and highlighted the necessity for adequately powered studies to be conducted, as well as the need for confirmatory studies to be performed, prior to the acceptance of a variant as a risk for disease. The subsequent application of genomic techniques to our sample set, in a global collaboration, has led to the identification of three robustly verified risk loci for AAA in the LRP1, LDLR and SORT1 genes.

Conclusions

Genomic studies of AAA have led to the identification of new pathways involved in the pathogenesis of AAA. The exploration of these pathways has the potential to unlock new avenues for therapeutic intervention to prevent the development and progression of AAA.     

Neuropeptide Y Attenuates Stress‐Induced Bone Loss Through Suppression of Noradrenaline Circuits

Chronic stress and depression have adverse consequences on many organ systems, including the skeleton, but the mechanisms underlying stress‐induced bone loss remain unclear. Here we demonstrate that neuropeptide Y (NPY), centrally and peripherally, plays a critical role in protecting against stress‐induced bone loss. Mice lacking the anxiolytic factor NPY exhibit more anxious behavior and elevated corticosterone levels. Additionally, following a 6‐week restraint, or cold‐stress protocol, Npy‐null mice exhibit three‐fold greater bone loss compared to wild‐type mice, owing to suppression of osteoblast activity. This stress‐protective NPY pathway acts specifically through Y2 receptors. Centrally, Y2 receptors suppress corticotropin‐releasing factor expression and inhibit activation of noradrenergic neurons in the paraventricular nucleus. In the periphery, they act to control noradrenaline release from sympathetic neurons. Specific deletion of arcuate Y2 receptors recapitulates the Npy‐null stress response, coincident with elevated serum noradrenaline. Importantly, specific reintroduction of NPY solely in noradrenergic neurons of otherwise Npy‐null mice blocks the increase in circulating noradrenaline and the stress‐induced bone loss. Thus, NPY protects against excessive stress‐induced bone loss, through Y2 receptor‐mediated modulation of central and peripheral noradrenergic neurons. © 2014 American Society for Bone and Mineral Research.     

CRIPTO promotes an aggressive tumour phenotype and resistance to treatment in hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is the third leading cause of cancer‐related death worldwide. Despite increasing treatment options for this disease, prognosis remains poor. CRIPTO (TDGF1) protein is expressed at high levels in several human tumours and promotes oncogenic phenotype. Its expression has been correlated to poor prognosis in HCC. In this study, we aimed to elucidate the basis for the effects of CRIPTO in HCC. We investigated CRIPTO expression levels in three cohorts of clinical cirrhotic and HCC specimens. We addressed the role of CRIPTO in hepatic tumourigenesis using Cre‐loxP‐controlled lentiviral vectors expressing CRIPTO in cell line‐derived xenografts. Responses to standard treatments (sorafenib, doxorubicin) were assessed directly on xenograft‐derived ex vivo tumour slices. CRIPTO‐overexpressing patient‐derived xenografts were established and used for ex vivo drug response assays. The effects of sorafenib and doxorubicin treatment in combination with a CRIPTO pathway inhibitor were tested in ex vivo cultures of xenograft models and 3D cultures. CRIPTO protein was found highly expressed in human cirrhosis and hepatocellular carcinoma specimens but not in those of healthy participants. Stable overexpression of CRIPTO in human HepG2 cells caused epithelial‐to‐mesenchymal transition, increased expression of cancer stem cell markers, and enhanced cell proliferation and migration. HepG2‐CRIPTO cells formed tumours when injected into immune‐compromised mice, whereas HepG2 cells lacking stable CRIPTO overexpression did not. High‐level CRIPTO expression in xenograft models was associated with resistance to sorafenib, which could be modulated using a CRIPTO pathway inhibitor in ex vivo tumour slices. Our data suggest that a subgroup of CRIPTO‐expressing HCC patients may benefit from a combinatorial treatment scheme and that sorafenib resistance may be circumvented by inhibition of the CRIPTO pathway. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.