Mboat7 down-regulation by hyper-insulinemia induces fat accumulation in hepatocytes

BACKGROUND: Naturally occurring variation in Membrane-bound O-acyltransferase domain-containing 7 (MBOAT7), encoding for an enzyme involved in phosphatidylinositol acyl-chain remodelling, has been associated with fatty liver and hepatic disorders. Here, we examined the relationship between hepatic Mboat7 down-regulation and fat accumulation. METHODS: Hepatic MBOAT7 expression was surveyed in 119 obese individuals and in experimental models. MBOAT7 was acutely silenced by antisense oligonucleotides in C57Bl/6 mice, and by CRISPR/Cas9 in HepG2 hepatocytes. FINDINGS: In obese individuals, hepatic MBOAT7 mRNA decreased from normal liver to steatohepatitis, independently of diabetes, inflammation and MBOAT7 genotype. Hepatic MBOAT7 levels were reduced in murine models of fatty liver, and by hyper-insulinemia. In wild-type mice, Mboat7 was down-regulated by refeeding and insulin, concomitantly with insulin signalling activation. Acute hepatic Mboat7 silencing promoted hepatic steatosis in vivo and enhanced expression of fatty acid transporter Fatp1. MBOAT7 deletion in hepatocytes reduced the incorporation of arachidonic acid into phosphatidylinositol, consistently with decreased enzymatic activity, determining the accumulation of saturated triglycerides, enhanced lipogenesis and FATP1 expression, while FATP1 deletion rescued the phenotype. INTERPRETATION: MBOAT7 down-regulation by hyper-insulinemia contributes to hepatic fat accumulation, impairing phosphatidylinositol remodelling and up-regulating FATP1. FUNDING: LV was supported by MyFirst Grant AIRC n.16888, Ricerca Finalizzata Ministero della Salute RF-2016-02,364,358, Ricerca corrente Fondazione IRCCS Ca\u27 Granda Ospedale Maggiore Policlinico; LV and AG received funding from the European Union Programme Horizon 2020 (No. 777,377) for the project LITMUS- Liver Investigation: Testing Marker Utility in Steatohepatitis . MM was supported by Fondazione Italiana per lo Studio del Fegato (AISF) \u27Mario Coppo\u27 fellowship

The Impact of CISO Appointment Announcements on the Market Value of Firms

Previous studies concerning the economic impact of security events on publicly listed companies have focussed on the negative effect of data breaches and cyberattacks with a view to encouraging firms to improve their cyber security posture to avoid such incidents. This paper is an initial study on the impact of investment in human capital related to security, specifically appointments of chief information security officers (CISO), chief security officers (CSO) or similar overall head of security roles. Using event study techniques, a dataset of 37 CISO type appointment announcements spanning multiple world markets between 2012 and 2019 was analysed and statistically significant (at the 5% level) positive cumulative abnormal returns (CAR) of around 0.8% on average were observed over the three-day period before, during and after the announcement. Furthermore, this positive CAR was found to be highest, at nearly 1.8% on average, within the financial services sector and showing statistical significance at the 1% level. In addition to the industry sector, other characteristics were investigated such as job title, reporting structure, comparison of internal versus external appointments, gender and variations between markets. Although these findings were not as conclusive they are, nevertheless, good pointers for future research in this area. This overall positive market reaction to CISO related announcements is a strong case for publicly listed firms to be transparent in such appointments and to, perhaps, review where that function sits within their organisation to ensure it delivers the greatest benefits. As 24% of the firms analysed were listed outside the US, this study also begins to counter the strong US bias seen in similar and related studies. This research is expected to be of interest to business management, cyber security practitioners, investors and shareholders as well as researchers in cyber security or related fields

The Impact of Data Breach Announcements on Company Value in European Markets

Recent research on the economic impact of data breach announcements on publicly listed companies was found to be sparse, with the majority of existing studies having a strong US bias. Here, a dataset of 45 data breach disclosures between 2017 and 2019 relevant to European publicly listed companies was hand-gathered (from various sources) and detailed analyses of share price impact carried out using event study techniques with the aim of supporting business cases for firms to invest in cyber security. Differences from existing studies (in particular, the US market) are highlighted and discussed along with pointers to future research in this area. Although some evidence of negative cumulative abnormal returns (CAR) in the days surrounding the announcement were observed, along with one extreme case leading to insolvency, the results were not statistically significant overall with the notable exception of the Spanish market, which appeared to be more sensitive to data breaches, reacting rapidly. Therefore, justification for cyber security investment purely based on the market value effect of a data breach disclosure would be challenging. Other factors would need to be taken into consideration such as risk appetite, industry sector and nature of the information compromised as well as relevant legislation. Certain other observations were noted such as the lack of a comprehensive breach database for Europe (unlike US) and the effect of the introduction of the General Data Protection Regulation (GDPR). This research would be of benefit to business management, practitioners of cyber security, investors and shareholders as well as researchers in cyber security or related fields

The Impact of GDPR Infringement Fines on the Market Value of Firms

Previous studies have shown (varying degrees of) evidence of a negative impact of data breach announcements on the share price of publicly listed companies. Following on from this research, further studies have been carried out in assessing the economic impact of the introduction of legislation in this area to encourage firms to invest in cyber security and protect the privacy of data subjects. Existing research has been predominantly US-centric. This paper looks at the impact of the General Data Protection Regulation (GDPR) infringement fine announcements on the market value of mostly European publicly listed companies with a view to reinforcing the importance of data privacy compliance, thereby informing cyber security investment strategies for organisations. Using event study techniques, a dataset of 25 GDPR fine announcement events was analysed, and statistically significant cumulative abnormal returns (CAR) of around-1% on average up to three days after the event were identified. In almost all cases, this negative economic impact on market value far outweighed the monetary value of the fine itself, and relatively minor fines could result in major market valuation losses for companies, even those having large market capitalisations. A further dataset of four announcements where sizeable GDPR fines were subsequently appealed was also analysed and although positive returns for successful appeals were observed (and the reverse), they could not be shown to be statistically significant-perhaps due, at least in part, to COVID-19 related market volatility at that time. This research would be of benefit to business management, practitioners of cyber security, investors and shareholders as well as researchers in cyber security or related fields (pointers to future research are given). Data protection authorities may also find this work of interest

Guidance for the diagnosis and treatment of hypolipidemia disorders

The Abetalipoproteinemia and Related Disorders Foundation was established in 2019 to provide guidance and support for the life-long management of inherited hypocholesterolemia disorders. Our mission is to improve the lives of individuals and families affected by abetalipoproteinemia and related disorders . This review explains the molecular mechanisms behind the monogenic hypobetalipoproteinemia disorders and details their specific pathophysiology, clinical presentation and management throughout the lifespan. In this review, we focus on abetalipoproteinemia, homozygous hypobetalipoproteinemia and chylomicron retention disease; rare genetic conditions that manifest early in life and cause severe complications without appropriate treatment. Absent to low plasma lipid levels, in particular cholesterol and triglyceride, along with malabsorption of fat and fat-soluble vitamins are characteristic features of these diseases. We summarize the genetic basis of these disorders, provide guidance in their diagnosis and suggest treatment regimens including high dose fat-soluble vitamins as therapeutics. A section on preconception counseling and other special considerations pertaining to pregnancy is included. This information may be useful for patients, caregivers, physicians and insurance agencies involved in the management and support of affected individuals

Knowledge and Health Beliefs Regarding Sickle Cell Disease Among Omanis in a Primary Healthcare Setting : Cross-sectional study

Objectives: Sickle cell disease (SCD) is a global health concern associated with high childhood morbidity and mortality; in Oman, the prevalence of SCD is 0.2%. Public awareness of SCD and the need for premarital screening (PMS) are essential to reduce the incidence of this disease. This study aimed to assess awareness of and beliefs regarding SCD and PMS among Omanis in a primary healthcare setting. Methods: This cross-sectional study took place in five health centres located in Al-Seeb Province, Muscat, Oman, between June and August 2015. A total of 500 Omanis aged ≥18 years old attending the clinics were invited to participate in the study. A previously described questionnaire by Gustafson et al. was used to measure awareness of and beliefs regarding SCD and PMS. Results: A total of 450 Omani adults completed the questionnaire (response rate: 90.0%). The majority (67.8%) were aware that SCD is genetically inherited and 85.1% believed in the value of PMS; however, only 24.4% reported having undergone PMS previously. Few participants were aware that SCD can be very painful (20.2%) and can cause strokes, infections and organ damage (20.0%). More than half (56.7%) reported that the availability of educational material on SCD or PMS in Oman was inadequate. Participants’ education levels were positively associated with accurate SCD knowledge (P <0.05). Conclusion: Despite the free availability of PMS services in local health centres, few Omanis reported having undergone PMS previously. Health promotion and education programmes are therefore needed in Oman in order to increase public awareness of SCD and the value of PMS

The Effect of Antepartum Depression on the Outcomes of Pregnancy and Development of Postpartum Depression: A prospective cohort study of Omani women

Objectives: This study aimed to identify the relationship between antenatal depression and pregnancy outcomes, including the risk of developing postpartum depression in Oman. Methods: This follow-up prospective longitudinal cohort study included pregnant women attending primary healthcare institutions in Muscat, Oman from January to November 2014. The Edinburgh Postnatal Depression Scale (EPDS) was used to screen for antenatal and postnatal depression. Pregnant Omani women with a gestational age ≥32 weeks attending 12 local health centres for antenatal care in Muscat were invited to participate. Recruited women were followed-up at 6–8 weeks after delivery. The following pregnancy outcomes were assessed: mode of delivery (normal or Caesarean section [CS]), gestational age at delivery (preterm or fullterm), baby’s birth weight and development of postnatal depression. Results: A total of 959 women participated in this study (response rate: 97.3%). In total, 233 women (24.4%) had antenatal depression with a score of ≥13 on the EPDS. Of the 592 participants (61.7%) who attended postnatal clinics at 6–8 weeks post-delivery, 126 (21.3%) were positive for postnatal depression. Logistic multivariate regression analysis showed that antenatal depression was associated with increased risk of CS (odds ratio [OR] = 1.79; 95% confidence interval [CI]: 1.20–2.66) and postnatal depression (OR = 8.63; 95% CI: 5.56–13.39). Conclusion: Screening women for antenatal depression and providing appropriate management may reduce adverse pregnancy outcomes and the risk of developing postnatal depression.Keywords: Depression; Postnatal depression; Women Health Services; Maternal Health Services; Pregnancy; Primary Health Care; Oman

Lack of VMP1 impairs hepatic lipoprotein secretion and promotes non-alcoholic steatohepatitis

BACKGROUND & AIMS: Vacuole membrane protein 1 (VMP1) is an endoplasmic reticulum (ER) transmembrane protein that regulates the formation of autophagosomes and lipid droplets. Recent evidence suggests that VMP1 plays a critical role in lipoprotein secretion in zebra fish and cultured cells. However, the pathophysiological roles and mechanisms by which VMP1 regulates lipoprotein secretion and lipid accumulation in non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) are unknown. METHODS: Liver-specific and hepatocyte-specific Vmp1 knockout mice as well as Vmp1 knock-in mice were generated by crossing Vmp1 RESULTS: Hepatocyte-specific deletion of Vmp1 severely impaired VLDL secretion resulting in massive hepatic steatosis, hepatocyte death, inflammation and fibrosis, which are hallmarks of NASH. Mechanistically, loss of Vmp1 led to decreased hepatic levels of phosphatidylcholine and phosphatidylethanolamine as well as to changes in phospholipid composition. Deletion of Vmp1 in mouse liver also led to the accumulation of neutral lipids in the ER bilayer and impaired mitochondrial beta-oxidation. Overexpression of VMP1 ameliorated steatosis in diet-induced NASH by improving VLDL secretion. Importantly, we also showed that decreased liver VMP1 is associated with NAFLD/NASH in humans. CONCLUSIONS: Our results provide novel insights on the role of VMP1 in regulating hepatic phospholipid synthesis and lipoprotein secretion in the pathogenesis of NAFLD/NASH. LAY SUMMARY: Non-alcoholic fatty liver disease and its more severe form, non-alcoholic steatohepatitis, are associated with a build-up of fat in the liver (steatosis). However, the exact mechanisms that underly steatosis in patients are not completely understood. Herein, the authors identified that the lack of a protein called VMP1 impairs the secretion and metabolism of fats in the liver and could therefore contribute to the development and progression of non-alcoholic fatty liver disease

Localised Skin Hyperpigmentation as a Presenting Symptom of Vitamin B12 Deficiency Complicating Chronic Atrophic Gastritis

Vitamin B12 deficiency is common in developing countries and should be suspected in patients with unexplained anaemia or neurological symptoms. Dermatological manifestations associated with this deficiency include skin hyper- or hypopigmentation, angular stomatitis and hair changes. We report a case of a 28-year-old man who presented to the Sultan Qaboos University Hospital in Muscat, Oman, in November 2013 with localised hyperpigmentation of the palmar and dorsal aspects of both hands of two months’ duration. Other symptoms included numbness of the hands, anorexia, weight loss, dizziness, fatigability and a sore mouth and tongue. There was no evidence of hypocortisolaemia and a literature search revealed a possible B12 deficiency. The patient had low serum B12 levels and megaloblastic anaemia. An intrinsic factor antibody test was negative. A gastric biopsy revealed chronic gastritis. After B12 supplementation, the patient’s symptoms resolved. Family physicians should familiarise themselves with atypical presentations of B12 deficiency. Many symptoms of this deficiency are reversible if detected and treated early

Transdermal drug delivery by coated microneedles : geometry effects on effective skin thickness and drug permeability

Although transdermal drug delivery has been used for about three decades, the range of therapeutics that are administered this way is limited by the barrier function of the stratum corneum (the top layer of skin). Microneedle arrays have been shown to increase the drug permeability in skin by several orders of magnitude by bypassing the stratum corneum. This 15 can potentially allow the transdermal delivery of many medicaments including large macromolecules that typically cannot diffuse through the skin. This paper addresses the use of microneedles coated with a drug solution film. In particular, we identify how the geometries of various microneedles affect the drug permeability in skin. Effective skin permeability is calculated for a range of microneedle shapes and dimensions in order to identify the most 20 efficient geometry. To calculate effective permeability (Peff), the effective skin thickness (Heff) is calculated. These are then plotted for insulin as a model drug to see how various microneedle parameters affect the profiles of both Heff and Peff. It is found that the depth of penetration from the microneedle array is the most important factor in determining Peff, followed by the microneedle spacings. Other parameters such as microneedle diameter and 25 coating depth are less significant