Understanding the pathophysiological mechanisms in the pediatric non-alcoholic fatty liver disease: The role of genetics

Classically, the non-alcoholic fatty liver disease(NAFLD) physiopathology and progression has been summarized in the two hits hypothesis. The first hit is represented by the action of hyperinsulinemia and insulin resistance, accompanying obesity, that leads to liver steatosis increasing the absolute non esterified fatty acids uptake in the liver and the esterification to form triacylglycerol. The oxidative stress is involved in the second hit leading to the progression to nonalcoholic steatohepatitis(NASH) because of its harmful action on steatosic hepatocytes. However, at the present time, the two hits hypothesis needs to be updated because of the discover of genetic polymorphisms involved both in the liver fat accumulation and progression to NASH that make more intriguing understanding the NAFLD pathophysiological mechanisms. In this editorial, we want to underline the role of PNPLA3 I148 M, GPR120 R270 H and TM6SF2 E167 K in the pediatric NAFLD development because they add new pieces to the comprehension of the NAFLD pathophysiological puzzle. The PNPLA3 I148 M polymorphism encodes for an abnormal protein which predisposes to intrahepatic triglycerides accumulation both for a loss-of-function of its triglyceride hydrolase activity and for a gain-of-function of its lipogenic activity.Therefore, it is involved in the first hit, such as TM6SF2 E167 K polymorphisms that lead to intrahepatic fat accumulation through a reduced very low density lipoprotein secretion. On the other hand, the GPR120 R270 H variant, reducing the anti-inflammatory action of the GPR120 receptor expressed by Kuppfer cells, is involved in the second hit leading to the liver injury.

Pediatric fatty liver disease:Role of ethnicity and genetics

Non-alcoholic fatty liver disease (NAFLD) comprehends a wide range of conditions, encompassing from fatty liver or steatohepatitis with or without fibrosis, to cirrhosis and its complications. NAFLD has become the most common form of liver disease in childhood as its prevalence has more than doubled over the past 20 years, paralleling the increased prevalence of childhood obesity. It currently affects between 3% and 11% of the pediatric population reaching the rate of 46% among overweight and obese children and adolescents. The prevalence of hepatic steatosis varies among different ethnic groups. The ethnic group with the highest prevalence is the Hispanic one followed by the Caucasian and the African-American. This evidence suggests that there is a strong genetic background in the predisposition to fatty liver. In fact, since 2008 several common gene variants have been implicated in the pathogenesis of fatty liver disease. The most important is probably the patatin like phospholipase containing domain 3 gene (PNPLA3) discovered by the Hobbs’ group in 2008. This article reviews the current knowledge regarding the role of ethnicity and genetics in pathogenesis of pediatric fatty liver.

Influencing Factors for Social Acceptance of Noma (Cancrum Oris) Patients in Niger: A Hospital-Based Cross-Sectional Study

Background: Noma, mostly identified in malnourished young children in the world’s low-income countries, causes severe orofacial disfigurement and significant mortality and morbidity. The majority of noma patients surviving with aesthetical effects are exposed to stigmatization and social rejection. Studies focusing on the socio-psychological impact of noma survivors have rarely been done. Our study aimed to identify the differences in social acceptance/rejection and the influencing factors associated with social acceptance in noma patients. Methods: A cross-sectional study was conducted at the NGO-Sentinelles (Niger) reception center on patients with noma from Zinder, Maradi, and Tahoua regions between 9th May 2017 and 2nd June 2017. The survey was conducted through a face-to-face interview on patients admitted to the center and those discharged from the centre after the treatment. The interview questionnaire comprised 45 questions (Cronbach’s alpha coefficient = 0.812) with pathological information, sociodemographic characteristics, and socio-psychological qualitative information. Findings: We recorded 50 noma patients (43 from Zinder and 7 from Maradi and Tahoua). The younger patients (1 - 5 years old), noma patients who stayed in school during follow-up treatment, patients who were referred by a health structure, patients enrolled into the centre in a short time (<30 days), and patients in the acute phase of noma had a significantly high social acceptance rate with 60.0%, 82.9%, 60.0%, 57.1% and 94.3% respectively;whereas single adults and cheek lesion site had the highest social rejection rate when compared to their corresponding factors with 60.0% and 86.7% respectively. There were significant differences in victims’ perception of noma [χ2 = 45.536, (P < 0.001)] and acceptance of their new faces [P = 0.023], between the social acceptance and social rejection rate, therefore all patients who accepted their new faces felt social acceptance. Social acceptance was significantly highly correlated with pathological history (admission method, phase of noma, care, and treatment received at center) with rs ranging from 0.609 to 0.810, moderately correlated with patient’s sociodemographic characteristics (age, marital status, and region) with rs ranging from 0.381 to 0.474. Lowly correlated with clinical evolution after treatment (rs = 0.293). Logistic regression results showed that the likelihood of social acceptance increased when the patient’s age was young (≤15 years), their marital status was minor, they were enrolled at the school before noma appearance, they were referred to the centre after diagnosis, the admission time to the centre was short (≤30 days), acute phase of noma, and care received at the centre was non-surgery. The location of the lesion on the cheek was a risk factor for social acceptance, indicating cheek lesions from noma increased the likelihood of social rejection in our study. Conclusion: The sociodemographic characteristics, pathological history, and psychological aspects of noma patients were correlated and were found to be important factors influencing their social acceptance/rejection rate.

Pediatric non-alcoholic fatty liver disease:New insights and future directions

One of the most common complications of childhood obesity is the non-alcoholic fatty liver disease(NAFLD),which is the most common form of liver disease in children.NAFLD is defined by hepatic fat infiltration > 5% hepatocytes,as assessed by liver biopsy,in the absence of excessive alcohol intake,viral,autoimmune and drug-induced liver disease.It encompasses a wide spectrum of liver diseases ranging from simple steatosis to non-alcoholic steatohepatitis,which,in turn,can evolve into cirrhosis and end stage liver disease.Obesity and insulin resistance are the main risk factors for pediatric NAFLD.In fact,NAFLD is strongly associated with the clinical features of insulin resistance especially the metabolic syndrome,prediabetes and type 2 diabetes mellitus(T2D).In particular,it has been clearly shown in obese youth that the prevalence of metabolic syndrome,pre-diabetes and type 2 diabetes increaseswith NAFLD severity progression.Evidence that not all of the obese patients develop NAFLD suggests that the disease progression is likely to depend on complex interplay between environmental factors and genetic predisposition.Recently,a non-synonymous SNP(rs738409),characterized by a C to G substitution encoding an isoleucine to methionine substitution at the amino acid position 148 in the patatin like phospholipase containing domain 3 gene(PNPLA3),has been associated with hepatic steatosis in a multiethnic cohort of adults as well as in children.Another important polymorphisms that acts with PNPLA3 to convey susceptibility to fatty liver in obese youths is the rs1260326 polymorphism in the glucokinase regulatory protein.The pharmacological approach in NAFLD children poorly adherent to or being unresponsive/partially responsive to lifestyle changes,is aimed at acting upon specific targets involved in the pathogenesis.There are some therapeutic approaches that are being studied in children.This article reviews the current knowledge regarding the pediatric fatty liver disease,the new insights and the future directions.

Appendicitis in children less than five years old:A challenge for the general practitioner

Acute appendicitis is one of the most common indications for abdominal surgery in pediatrics with peak incidence in the second decade of life. Acute appendicitis in the first years of life is an uncommon event. The clinical presentation is often varied and the diagnosis may be overshadowed by other medical conditions.Gastroenteritis is the most common misdiagnosis, with a history of diarrhea present in 33% to 41% of patients. Pain is the most common presenting symptom in children less than 5 years old, followed by vomiting, fever, anorexia and diarrhea. The most common physical sign is focal tenderness(61% of the patients) followed by guarding(55%), diffuse tenderness(39%), rebound(32%), and mass(6%). Neonatal appendicitis is a very rare disease with high mortality; presenting symptoms are nonspecific with abdominal distension representing the main clinical presentation. The younger the patient, the earlier perforation occurs: 70% of patients less than 3 years develop a perforation within 48 h of onset of symptoms. A timely diagnosis reduces the risk of complications. We highlight the epidemiology, pathophysiology, clinical signs and laboratory clues of appendicitis in young children and suggest an algorithm for early diagnosis.

The Impact of Body Mass Index on Assisted Reproductive Treatments

Multiparity amongst women with a body mass index (BMI) ≥ 30 Kg/m2 is a common occurrence despite there being a known clear association with a decline in fecundity in women who are overweight or obese. These women, also pose further concerns, as they are at increased risk of antenatal complications such as preeclampsia and gestational diabetes. Over the years, a number of different modalities of fertility treatments have been tried and tested in this cohort of women to find the optimal treatment to improve their reproductive capacity. There has been an exponential increase in knowledge and understanding towards managing patients with a raised BMI, particularly through assisted reproductive treatments. Although the efficacies of various forms of fertility treatments have been shown to be affected by a rise in BMI, there is yet to be a definitive understanding as to the optimal management of these patients. The literature supports weight loss alone as an effective intervention in improving the reproductive capacity of women with a raised BMI with unexplained infertility. Furthermore, if live birth rate is taken as the desired outcome measure, then ovarian drilling and in vitro fertilisation (IVF) treatment have been shown to yield the best results in overweight and obese patients when comparisons are drawn to other interventions such as natural conception and treatment with clomiphene citrate.

Hereditary Vesicoureteral Reflux: A Study of 66 Families

Purpose: We studied the inheritance pattern, clinical features and outcome in children with vesicoureteral reflux (VUR). Characteristics of known familial VUR cases were also compared with those of sporadic VUR. Material and Methods: 726 patients were treated for VUR between 1990-2004. The families were contacted by letter inquiring if other members of the family were affected. The phenotype of all cases (familial and non-familial) was characterized in terms of presenting symptoms, reflux grade, recurrent urinary tract infections, kidney damage, and the natural course of reflux. Results: The response rate was 79%. A total of 99 individuals (22%) reported relatives with VUR. Since some of the 99 index cases belonged to the same family, the total number of families was ultimately 66. The distribution of relatives with VUR was: 38 siblings, 20 parents (15 mothers), 19 cousins, 15 aunts/uncles and 12 grandparents. The phenotype of VUR did not differ between familial and non-familial cases. However, VUR among relatives was of milder grade than index and sporadic cases. Conclusions: The proportion of hereditary reflux in our material was lower than in other studies (22%). We found a strong overrepresentation of maternal transmission of reflux. Severity of the disease did not differ between familial and non-familial VUR.

Therapeutic Potential of Thunbergia laurifolia L.Extract in Gestational Diabetes Mellitus:Insights from a Rat Model

Objective:To assess the effects of Thunbergia laurifolia L.extract(TLE)on gestational diabetes mellitus(GDM)in a rat model.Methods:Thunbergia laurifolin L.leaves were subjected to ethanolic extraction.In vivo study,50 pregnant rats were randomly divided into 5 groups(10 for each):non-GDM group,GDM induced by streptozotocin(STZ,60 mg/kg i.p.),metformin(MET)100 mg/kg,TLE 50,and 500 mg/kg groups.Administration was performed on gestation day 7 until term(day 21).The effects of TLE on blood glucose,insulin levels,lipid profiles,liver enzymes,and maternal performances were assessed.In in vitro study,the effect of TLE was examined using the organ bath for uterine force measurement.Results:In in vivo study,TLE significantly reduced blood glucose as compared to GDM(P<0.05)with gradually increased insulin level.This effect was consistent with islets of Langerhans restoration.Histologically,the uterine muscular layer displayed a marked increase in fiber area in response to both doses as compared to GDM(P<0.05).Additionally,TLE significantly reduced total cholesterol,triglyceride,and alanine transaminase levels(P<0.05).Intriguingly,TLE also led to a notable augmentation in gravid uterus size,live fetuses count,and implantation numbers,while significantly reducing the post-implantation loss rate associated with fetal classification(P<0.05).Thus,GDM improvements were close to those produced by MET.In in vitro study,TLE exerted a concentration-dependent inhibition of spontaneous uterine contractility(half-maximal inhibition concentration=1.2 mg/L).This inhibitory effect extended to potassium chloride depolarization and oxytocin-mediated contractions.When combined with its major constituent,rosmarinic acid,TLE produced an enhanced inhibitory effect(P<0.05).Conclusions:TLE ameliorated blood glucose levels,enhanced uterine muscular structure,and improved maternal and fetal performance in GDM.TLE also displayed tocolytic properties.These findings underscore the need for further exploration of TLE as a potential tocolytic agent to mitigate GDM-associated complications.

Management of Preeclampsia in Low-and Middle-Income Countries:Lessons to Date,and Questions Arising,from the PRE-EMPT and Related Initiatives

Preeclampsia remains associated with an increased risk of maternal and perinatal morbidity and mortality,and the burden of that excess risk is largely borne by pregnant women and their families in low-and middle-income countries(LMICs).Therefore,the Bill&Melinda Gates Foundation funded the PREeclampsia–Eclampsia Monitoring,Prevention,and Treatment(PRE-EMPT)initiative to accelerate progress.From PRE-EMPT,and related activity,have come a number of impactful findings.First,there is increasing global support for broadening the definition of preeclampsia to include women with hypertension and either significant proteinuria or evidence of target organ damage or fetoplacental compromise(including evidence angiogenic imbalance).Second,using blood pressure(BP)data from the Community-Level Interventions for Preeclampsia trials in India,Mozambique,and Pakistan,acquired on validated-for-pregnancy,semi-automated,low-cost BP devices,there are now population-level,rather than facility-based,estimates for the burden of pregnancy hypertension(sub-categorized into preeclampsia(4%–6%),gestational hypertension(7%–12%),and chronic hypertension(0.3%–0.6%)).Third,there is an identified need to understand biological pathways that underlie the causation of preeclampsia in LMICs.Fourth,the Community-Level Interventions for Preeclampsia trials have shown that providing at least eight antenatal contacts,in this case using digital health-supported community health workers,cost-effectively reduces the burden of maternal(by 60%),fetal(60%),and neonatal(40%)mortality.Fifth,what is the utility and cost-effectiveness of routine proteinuria screening of normotensive pregnant women?Sixth,clinical risk factor-based prediction of preeclampsia remains most relevant for most women in LMICs;calcium replacement(≥1 g/day)and low-dose aspirin(100–175 mg/day)are the most useful directly preventative interventions.However,achieving sustainable development goals(SDGs)not directly related to health are more likely to reduce the global burden of preeclampsia and its consequences.Seventh,should a woman develop preeclampsia,personalized maternal time-of-disease risk estimates are available through the PIERS(Preeclampsia Integrated Estimate of RiSk)models,either with(fullPIERS)or without(miniPIERS)access to laboratory testing.Assessment of perinatal risks in LMICs is largely driven by gestational age;however,evidence of significant angiogenic imbalance may identify risk of intrauterine fetal death.Eighth,Control of Hypertension in Pregnancy Study trial data show that women with non-severe pregnancy hypertension(systolic BP 140–159 mmHg or diastolic BP(dBP)90–109 mmHg)should receive an antihypertensive medication for a target dBP of 85 mmHg.Ninth,for women with severe pregnancy hypertension(systolic BP≥160 mmHg or dBP≥110 mmHg),oral antihypertensive management with either nifedipine,labetalol,or,less so,methyldopa will lower BP into the non-severe hypertension range.Tenth,magnesium sulfate remains the sole agent of choice for preventing and treating eclamptic seizures.Eleventh,corticosteroids should be administered to women at risk of delivery<35+0 weeks’gestation.Twelfth,although delivery of the placenta initiates resolution of the maternal syndrome of preeclampsia,decisions to initiate delivery should be guided by gestational age and maternal and fetal status.Many women will experience significant postpartum deterioration;delivery should not be equated with“cure”.Thirteenth,whether the development of preeclampsia identifies women at increased risk for early-onset cardiovascular disease in LMICs must be determined.

Verification of SARS-CoV-2-encoded small RNAs and contribution to infection-associated lung inflammation

To the Editor:Severe_acute_respiratory,syndrome coronavirus 2(SARS-CoV-2)is the virus causing coronavirus disease2019(COVID-19).[1]As anewevolutionary branch within coronaviruses,SARS-CoV-2 contains around 29.8 kilobase and shows 79.2%identity with SARS-CoV-1.

Management of Hypertension in Pregnancy

Hypertension in pregnancy is currently defined as a systolic blood pressure(BP)of 140 mmHg or more,or a diastolic BP of 90 mmHg or more.This level of BP warrants antihypertensive therapy.Treating to a target BP of 135/85 mmHg halves the risk of severe hypertension that is itself associated with adverse maternal and perinatal outcomes,similar in magnitude to preeclampsia.While based on the results of the Control of Hypertension in Pregnancy Study(CHIPS)trial,this finding is consistent with all antihypertensive trials to date.Also,in the CHIPS trial,“tight”BP control also halved the risk of progression to thrombocytopenia and elevated liver enzymes for the mother,without adverse effects for the fetus or newborn.This was true regardless of the gestational age at which BP control was instituted.While methyldopa,labetalol,and nifedipine are the most commonly-recommended oral antihypertensives,it is not clear that one antihypertensive agent has advantages over the others for treatment of non-severe hypertension in pregnancy.No antihypertensives,including renin-angiotensin-aldosterone system(RAAS)inhibitors,have been shown to be teratogenic,although there may be an increase in malformations associated with the underlying condition of chronic hypertension.Atenolol and RAAS inhibitors should not be used once pregnancy is diagnosed,based on fetotoxicity.At present,BP treatment targets used in clinic are the same as those used at home as the differences are quite variable among hypertensive women.For treatment of acute severe hypertension,the most commonly-recommended antihypertensives are oral nifedipine,IV labetalol,and IV hydralazine,although oral agents have also been shown to be effective in the majority of women;while concerns raised about IV hydralazine-induced maternal hypotension and its consequences have not been confirmed,this medication may be an inferior antihypertensive to oral nifedipine.While treatment recommendations are based on evidence,women should be engaged in decision-making,as their values may alter target BP and antihypertensive choice.Future work will clarify the optimal target BP based on home BP measurements;whether BP targets should be lowered further if the definition of hypertension is based on a lower BP;which,if any,antihypertensive medication for non-severe hypertension is better with regards to maternal and perinatal outcomes;and whether factors beyond BP level(such as variability,race,and other physiological variables)should inform antihypertensive therapy in pregnancy.