Male Births Research Articles

Placental expression of RNU44, RNU48 and miR-16-5p: stability and relations with fetoplacental growth.

The current study aimed to identify suitable reference miRNA for placental miRNA expression analysis in a set of well-characterized and fetal-sex balanced small- (SGA) and appropriate- (AGA) for gestational age full-term singleton pregnancies. In this retrospective study, placental samples (n = 106) from 35 SGA (19 male and 16 female) and 71 AGA (30 male and 41 female) full-term singleton pregnancies were utilized. Placental transcript abundance of three widely used reference miRNAs [miR-16-5p and Small nucleolar RNAs (snoRNAs) RNU44 and RNU48] were assessed by real-time quantitative PCR. Raw cycle threshold (Ct) analysis and RefFinder tool analysis were conducted for evaluating stability of expression of these miRNAs. Raw Ct values of miR-16-5p were similar between SGA and AGA births (P = 0.140) and between male and female births within SGA (P = 0.159) and AGA (P = 0.060) births while that of RNU44 and RNU48 were higher in SGA births (P = 0.008 and 0.006 respectively) and in male births within the SGA group (P = 0.005) for RNU44 and in female births within the AGA group (P = 0.048) for RNU48. Across all 106 samples tested using the RefFinder tool, miR-16-5p and RNU44 were equally stable reference miRNAs. We recommend miR-16-5p and RNU44 as suitable reference miRNAs for placental samples from settings similar to our study.

The impact of Hurricane Katrina, a major natural disaster, on assisted reproductive outcomes through an analysis of 451,848 ART cycles

To evaluate whether pregnancies conceived via assisted reproductive technology and exposed to Hurricane Katrina (HK), one of the most destructive natural disasters in United States history, were more prone to adverse perinatal outcomes, miscarriages, or sex disparities compared with pregnancies established but not directly exposed to the natural disaster. Retrospective cohort study. Women 18 years and older undergoing fresh ART cycles that resulted in singleton pregnancies and entered in the SART CORS database from 2004 to 2008. Incidence of full-term and preterm delivery, miscarriage rate, infant weight at birth, and infant sex ratio. Total follicle stimulating hormone (FSH) stimulation dosage and number of oocytes retrieved. Between January 2004 and December 2008, a total of 451,848 fresh autologous IVF cycles were recorded in SART CORS, leading to 190,624 pregnancies and 129,499 live births. After controlling for potential confounders, our results demonstrate no association between HK exposure and overall preterm deliveries (< 37 weeks) in women with singleton pregnancies conceived after ART. Other perinatal outcomes such as rate of spontaneous abortion or infant weight at birth in the exposed and unexposed groups were also not associated with HK. A comparison of pre and post disaster sex ratios revealed fewer males were born after HK (51.0% vs. 49.4%), showing a trend of decreased male infant births that was least in part associated with HK (CI 0.81–1.01; p = 0.07). Exposure to HK did not appear to affect perinatal outcomes such as the rate of preterm delivery or the rate of spontaneous abortion. Extreme stress may be a factor that contributes to a reduced male to female secondary sex ratio.

Bivariate binary analysis on composite index of anthropometric failure of under-five children and household wealth-index

BackgroundMalnutrition is the most common cause of mortality and morbidity of children in low and middle income countries including Ethiopia and household wealth index shares the highest contribution. Thus, in this study it is aimed to conduct bivariate binary logistic regression analysis by accounting the possible dependency of child composite index anthropometric failure and household wealth index.MethodsIn this study the data from Ethiopian Demographic and Health Survey (EDHS) 2016 involved 9411 under five children was considered. Child Composite Index Anthropometric Failure (CIAF) measures the aggregate child undernourished derived from the conventional anthropometric indices (stunting, underweight and wasting). The correlation between CIAF and wealth index was checked and significant correlation found. To address the dependency between the two outcome variables bivariate binary logistic regression was used to analyze the determinants of child CAIF and household wealth index jointly.ResultsStudy results show that region, place of residence, religion, education level of women and husband/partner, sex of child, source of drinking water, household size and number of under five children in the household, mothers body mass index, multiple birth and anemia level of child had significant association with child CIAF. Female children were 0.82 times less likely to be CIAF compared to male and multiple birth children were more likely to be CIAF compared to single birth. Children from Oromia, Somalie, Gambela, SNNPR, Harari and Addis Ababa region were 0.6, 0.56, 0.67, 0.52, 0.6 and 0.44 times less likely to be CIAF compared to Tigray. A household from rural area were 15.49 times more likely poor compared to a household. The estimated odds of children whose mothers attended primary, and secondary and higher education was 0.82, and 0.52 times respectively the estimated odds of children from mothers who had never attended formal education.ConclusionThe prevalence of children with composite index anthropometric failure was high and closely tied with the household wealth index. Among the determinants, region, religion, family education level, and anemia level of child were statistically significant determinants of both CIAF and household wealth index. Thus, the authors recommend to concerned bodies and policymakers work on household wealth index to reduce the prevalence of child composite anthropometric failure.

Maternal stress and sex ratio at birth in Sweden over two and a half centuries: a retest of the Trivers-Willard hypothesis.

STUDY QUESTIONIs there a negative relationship, as predicted in the Trivers–Willard hypothesis (TWH), between the intensity of maternal stress and sex ratio at birth (SRB)?SUMMARY ANSWERUsing a comprehensive data set with multiple indicators of maternal stress, most measures of stress show no statistically significant association with SRB over a period spanning 243 years, indicating no support for the TWH.WHAT IS KNOWN ALREADYEvolutionary biologists have proposed a widely discussed hypothesis that women in poor and stressful conditions during pregnancy are more likely to give birth to girls, and exposure to stressful events may therefore lead to a reduction in sex (male-to-female) ratio at birth. The empirical evidence so far is mixed.STUDY DESIGN, SIZE, DURATIONAnnual time series data, spanning 243 years between 1749 and 1991 for Sweden at the national level, were drawn from multiple sources. The outcome is defined as the percentage of male births relative to all births in Sweden in a given year. The covariates include a set of economic and climatic variables as proxies for maternal stress.PARTICIPANTS/MATERIALS, SETTING, METHODSWe conduct a series of ARIMA (autoregressive integrated moving average) models to examine the relationship between maternal stress and SRB during three periods: 1749–1991, 1749–1861 and 1862–1991.MAIN RESULTS AND THE ROLE OF CHANCEIn 1749–1991, economic proxies for maternal stress showed no statistically significant association with SRB. In 1749–1861, two indicators were significantly associated with SRB, but the coefficients were opposite in direction to the TWH. In 1862–1991, five out of six covariates showed no significant association with SRB. An additional analysis found no significant correlation between sex ratio of stillbirths and all covariates in 1862–1991. Our results are incompatible with the TWH and suggest that previous findings in support of the TWH are not robust.LIMITATIONS, REASONS FOR CAUTIONThis study provides population-level evidence that may not necessarily reflect the nature of all individuals due to the ecological fallacy. The time series analysed in this study are annual data, and we cannot examine the potential seasonality due to the lack of disaggregated monthly data. Our findings may not be generalised to the contexts of extreme maternal stress conditions such as famine and war.WIDER IMPLICATIONS OF THE FINDINGSThe results from existing studies in this topic may be speculative, and additional research with more comprehensive design, data and covariates is needed to reconsider the robustness of previous findings.STUDY FUNDING/COMPETING INTEREST(S)The author receives no external funding and has no conflict of interest to declare.TRIAL REGISTRATION NUMBERN/A.

X Chromosome Inactivation in Carriers of Fabry Disease: Review and Meta-Analysis.

Anderson-Fabry disease is an X-linked inborn error of glycosphingolipid catabolism caused by a deficiency of α-galactosidase A. The incidence ranges between 1: 40,000 and 1:117,000 of live male births. In Italy, an estimate of incidence is available only for the north-western Italy, where it is of approximately 1:4000. Clinical symptoms include angiokeratomas, corneal dystrophy, and neurological, cardiac and kidney involvement. The prevalence of symptomatic female carriers is about 70%, and in some cases, they can exhibit a severe phenotype. Previous studies suggest a correlation between skewed X chromosome inactivation and symptoms in carriers of X-linked disease, including Fabry disease. In this review, we briefly summarize the disease, focusing on the clinical symptoms of carriers and analysis of the studies so far published in regards to X chromosome inactivation pattern, and manifesting Fabry carriers. Out of 151 records identified, only five reported the correlation between the analysis of XCI in leukocytes and the related phenotype in Fabry carriers, in particular evaluating the Mainz Severity Score Index or cardiac involvement. The meta-analysis did not show any correlation between MSSI or cardiac involvement and skewed XCI, likely because the analysis of XCI in leukocytes is not useful for predicting the phenotype in Fabry carriers.

Cohort Selection In Utero against Male Twins and Childhood Cancers: A Population-Based Register Study.

Cancer ranks as the second leading cause of death among children ages 1 to 14 years in the United States. Previous research finds that strong cohort selection in utero against males precedes a reduction in live-born males considered frail. We examine whether such cohort selection in utero may similarly affect the frequency of childhood cancers among male live births. We examined 1,368 childhood cancers among males born in Sweden over 144 months, from January 1990 to December 2001, and followed to age 15 in the Swedish Cancer Registry. We retrieved the count of male twins by birth month from the Swedish Birth Registry. We applied autoregressive, integrated, moving average time-series methods to identify and control for temporal patterns in monthly childhood cancers and to evaluate robustness of results. Fewer childhood cancers occur among monthly male birth cohorts with elevated selection in utero (i.e., a low count of live-born male twins). This association appears in the concurrent month (coef = 0.04; 95% CI, 0.001-0.079) as well as in the following month in which most births from the twin's conception cohort are "scheduled" to be born (coef = 0.055; 95% CI, 0.017-0.094). Elevated cohort selection in utero may reduce the number of frail male gestations that would otherwise have survived to birth and received a cancer diagnosis during childhood. This novel result warrants further investigation of prenatal exposures, including those at the population level, that may induce cohort selection in utero for some cancer types but not others.

Whole genome sequencing identifies novel structural variant in a large Indian family affected with X-linked agammaglobulinemia.

X-linked agammaglobulinemia (XLA, OMIM #300755) is a primary immunodeficiency disorder caused by pathogenic variations in the BTK gene, characterized by failure of development and maturation of B lymphocytes. The estimated prevalence worldwide is 1 in 190,000 male births. Recently, genome sequencing has been widely used in difficult to diagnose and familial cases. We report a large Indian family suffering from XLA with five affected individuals. We performed complete blood count, immunoglobulin assay, and lymphocyte subset analysis for all patients and analyzed Btk expression for one patient and his mother. Whole exome sequencing (WES) for four patients, and whole genome sequencing (WGS) for two patients have been performed. Carrier screening was done for 17 family members using Multiplex Ligation-dependent Probe Amplification (MLPA) and haplotype ancestry mapping using fineSTRUCTURE was performed. All patients had hypogammaglobulinemia and low CD19+ B cells. One patient who underwent Btk estimation had low expression and his mother showed a mosaic pattern. We could not identify any single nucleotide variants or small insertion/ deletions from the WES dataset that correlates with the clinical feature of the patient. Structural variant analysis through WGS data identifies a novel large deletion of 5,296 bp at loci chrX:100,624,323-100,629,619 encompassing exons 3-5 of the BTK gene. Family screening revealed seven carriers for the deletion. Two patients had a successful HSCT. Haplotype mapping revealed a South Asian ancestry. WGS led to identification of the accurate genetic mutation which could help in early diagnosis leading to improved outcomes, prevention of permanent organ damage and improved quality of life, as well as enabling genetic counselling and prenatal diagnosis in the family.

Bayesian Spatiotemporal Model for Life Expectancy Mapping; Changes in Barcelona From 2007 to 2018

When mapping life expectancy, and investigating its local variation in time, there is a conflict between using large areas and/or mortality data from long periods of time to have low variance life expectancy estimates, and using small areas and single‐year mortality data to explore the space–time variation of life expectancy in detail, without bias. Here a Bayesian model is proposed to smooth annual small‐area life expectancy estimates and help deal with that trade‐off. The specific area effect on life expectancy, together with its spatial and temporal dependencies are modeled through random effects, while the effect of covariates is modeled through a fixed effect component. By smoothing life expectancy estimates directly, instead of smoothing age‐specific mortality rates first the way done in the literature, the model used is easier to implement and interpret. The approach is illustrated, by using it to explore how life expectancy at birth of males and of females, and their gap, varied in space and in time in the city of Barcelona between 2007 and 2018, and their relationship with covariates. It is found that, on average, life expectancy has been growing by 0.23 years per year for males and 0.15 years per year for females. The female life expectancy is becoming more spatially homogeneous than the male one, while the rate of life expectancy growth for males turns out to be more homogeneous than for females.

Factors That Influence Maternal High-risk Births in Njombe District, Tanzania

Tanzania has recorded a decline in maternal deaths from 854 in 2000 to 524 in 2017. In spite of this achievement, much remains to be done to curb high maternal mortality rates and maternal high-risk births. This paper assesses factors that influence high-risk births of women in Njombe district. Specifically, it examines women’s participation in maternal health care services; evaluates intervention measures of high-risk births in four villages within the district, and prescribes the way high-risk births may be reduced. The paper draws data from a cross-sectional designed study that involved 298 mothers; selected randomly in four villages within the district. It employs the triangulation of methods that include questionnaire-based semi-structured interviews, focused group discussions, observations, and key informant interviews to yield qualitative and quantitative data. The study population was found to be at high-risk of maternal births due to maternal age, parity, the lack of antenatal and postnatal services, lifestyles, and bias towards male maternal births attendants. Other intermediate factors were education, occupation, place of residence, and culture. Intervention measures recommended and adopted by the government, nongovernmental and civil societies for reducing high-risk maternal births in the area included the construction of additional health facilities in villages, wards, districts, regions and at the national level to meet the needs of maternal health care services to minimize high-risk maternal births, as well as reduce high maternal mortality ratio.

Trends in the diabetes incidence and mortality in India from 1990 to 2019: a joinpoint and age-period-cohort analysis.

Globally, a metabolic disorder like Diabetes is considered as one of the largest global health issues, as it accounts for the majority of the disease burden and happens to be one of the leading causes of mortality as well as reduced life expectancy across the world. As in 2019, India is home to the second-largest number (77million) of Diabetic adults and the number of people affected has been increasing rapidly over the years. Termed as "the diabetes capital of the world," with every fifth diabetic in the world being an Indian, there is an urgent need to address many critically significant challenges posed by Diabetes in India, like, increasing prevalence among young people in urban areas, less awareness among people, high cost of disease management, limited healthcare facilities, suboptimal diabetes control etc. In Indian context, not enough attempts have been made to observe and understand the long-term pattern of diabetes incidence and mortality. This study aims to provide deep insights into the recent trends of diabetes incidence and mortality in India from 1990 to 2019. This is an observational study based on the most recent data from the Global Burden of Disease (GBD) Study 2019. We extracted numbers, age-specific and age-standardized incidence and mortality rates of diabetes (from 1990 to 2019) from the Global Health Data Exchange. The average annual percentage changes in incidence and mortality were analysed by joinpoint regression analysis; the net age, period, and cohort effects on the incidence and mortality were estimated by age-period-cohort analysis. During the study period, age-standardized incidence and mortality rates of diabetes in India experienced an upsurge in numbers, the incidence rate increasedfrom 199.14 to 317.02, and consequently, mortality increased from 22.30 to 27.35 per 100,000 population. The joinpoint regression analysis showed that the age-standardized incidence significantly rose by 1.63 % (95 % CI: 1.57 %, 1.69 %) in Indian males and 1.56 % in Indian females (95 % CI: 1.49 %, 1.63 %) from 1990 to 2019. On the other hand, the age-standardized mortality rates rose by 0.77 % (95 % CI: 0.24 %, 1.31 %) in Indian males and 0.57 % (95 % CI: -0.54 %, 1.70 %) in Indian females. For age-specific rates, incidence increased in most age groups, with exception of age groups 5-9, 70-74, 75-79 and 80-84 in male, and age groups 5-9, 75-79 and 80-84 in female. Mortality in male saw a decreasing trend till age group 20-24, whereas in female, the rate decreased till age group 35-39. The age effect on incidence showed no obvious changes with advancing age, but the mortality significantly increased with advancing age; period effect showed that both incidence and mortality increased with advancing time period; cohort effect on diabetes incidence and mortality decreased from earlier birth cohorts to more recent birth cohorts, while incidence showed no material changes from 1975 to 1979 to 2000-2004 birth cohort. Mortality of diabetes decreased in younger age groups but increased in older age groups; however, Incidence increased in most age groups for both male and female. The net age or period effect showed an unfavourable trend while the net cohort effect presented a favourable trend. Aging was likely to drive a continued increase in the mortality of diabetes. Timely population-level interventions aiming for health education, lifestyle modification with special emphasis on the promotion of physical activity and healthy diet should be conducted, especially for male and earlier birth cohorts at high risk of diabetes.

IMPROVING SHEEP PRODUCTIVITY BY USING FRESH AND FROZEN SEMEN IN PALESTINE

Livestock sector in Palestine is an important one, contributing up to 46% of total agricultural income. The backbone of this sector is sheep and goats (small ruminants), dairy cattle and poultry. This study aimed to improve sheep productivity and develop long term breeding program for sheep breeds and crosses under field conditions in Palestine under different production systems. This experimental study included 169 ram sheep. The single semen collected from each ram was divided into four parts and extended using four extenders: milk, TRIS, TEST, and CJ-2 (diluted to 600 million sperm/ ml) and loaded into 0.25 ml straws for storage at 4 and 15° C. Most of the computer assisted sperm analyze the motility parameters were higher after extension and storage at 4 compared with 15°C (P < 0.05). Ram semen stored using milk or TRIS based extenders at 4° C. They are also retained similar sperm motility parameters but both were higher compared with TEST or CJ-2 extenders after storage for up to 3 days (P <0.05). Results showed that ram race AF recorded (151) with ratio 89.3 % while the race IA recorded (18) with ratio 10.7%. The entire169 ram from Ministry of Agriculture had pregnancy check after 41 days of semen insemination and the result was 100% pregnancy happened. Date of birth was after 5 months of semen insemination. On the other hand, average number of births was1.5. The greatest numbers of births (89) were belonged to females which represent 52.7% of the total births while the male births were 80 with ratio 47.3%. The net average weight of a newborn was about 5.6±1.4 kg. The weights of births were gradually increased and the average weight of a newborn at weaning was about 19.5±2.3 kg. The average amount of milk in the first stage of milking was about 1.7±0.29 L while in the second stage of milking was about 1.6±0.29 L and finally in the third stage of milking was about 1.46±0.28 L. In conclusion, the ram race AF recorded with higher ratio than the race IA. The average weight of a newborn at weaning was about 19.5±2.3 kg. Finally the third stage was reported to be with the least value of all the stages of milking.

AUTHOR REPLY

Many thanks indeed for the opportunity to reply to this editorial comment. Neonatal testicular torsion (NTT) is thankfully a rare event (6.1/100,000 live male births), with bilateral events arising at an estimated incidence of 0.9/100,000 live male births. Of these >98% are extravaginal in nature.

The Effect of Communication, Resources, Disposition And Structure of Bureaucracy on Medical Participation of Men's Operations in City of Bandar Lampung (Study of George Edward III Policy Implementation Model)

The Population and Family Planning Control Office of Bandar Lampung City has implemented a Family Planning Program to reduce birth rates so that population growth in Bandar Lampung is controlled. Since 2009, men and women have had the same rights and position in achieving the success of the Family Planning Program in Bandar Lampung City. But the fact the Family Planning Program in Bandar Lampung City still seems biased to gender, this is evidenced by the achievement of family planning acceptors who are still being majority among women compared to men. KB Male Medical Surgery (MOP) is the male birth control that attains the lowest acceptor and has decreased in five years in the city of Bandar Lampung. Based on the problems obtained in the field, the study wanted to see the influence of communication variables, resources, disposition, and bureaucratic structure on KB MOP participation in Bandar Lampung City. The independent variable used in this study is the implementation model variable proposed by George Edward III. The method used in this study a descriptive and associative method with a quantitative approach. The results showed that the communication variables obtained the magnitude of influence of 4.4% and the disposition variable obtained the magnitude of influence of 4.3%, these two variables did not have a significant effect on KB MOP participation in Bandar Lampung City. While the resource variable obtained the magnitude of influence of 21.1% and the bureaucratic structure variable obtained the magnitude of influence of 25.6%, these two variables had a significant influence on KB MOP participation in Bandar Lampung City. But simultaneously the communication, resource, disposition and bureaucratic structure variables have a significant influence on KB MOP participation in Bandar Lampung City and the magnitude of the effect obtained is 25.1%.

Impact of CRISPR-Cas9-Based Genome Engineering in Farm Animals.

Humans are sorely over-dependent on livestock for their daily basic need of food in the form of meat, milk, and eggs. Therefore, genetic engineering and transgenesis provide the opportunity for more significant gains and production in a short span of time. One of the best strategies is the genetic alteration of livestock to enhance the efficiency of food production (e.g., meat and milk), animal health, and welfare (animal population and disease). Moreover, genome engineering in the bovine is majorly focused on subjects such as disease resistance (e.g., tuberculosis), eradicate allergens (e.g., beta-lactoglobulin knock-out), products generation (e.g., meat from male and milk from female), male or female birth specifically (animal sexing), the introduction of valuable traits (e.g., stress tolerance and disease resistance) and their wellbeing (e.g., hornlessness). This review addressed the impressive genome engineering method CRISPR, its fundamental principle for generating highly efficient target-specific guide RNA, and the accompanying web-based tools. However, we have covered the remarkable roadmap of the CRISPR method from its conception to its use in cattle. Additionally, we have updated the comprehensive information on CRISPR-based gene editing in cattle.

Rehabilitation in Duchenne Muscular Dystrophy: A Case Report

Background: Duchenne muscular dystrophy (DMD) seems to be the most common X-linked muscular dystrophy condition in children marked by proximal muscle weakness and calf hypertrophy and affected mostly in boys. In more than 20 muscular dystrophies the most prevalent form is Duchenne muscular dystrophy. Each 1/3500 male births, the presence of DMD worldwide, indicating that in the UK alone there are approximately 2400 people living with DMD. Assessing improvements in severity, range of motion and functional mobility, implementation of therapies and guidance on positioning are important key factors.&#x0D; Clinical Finding: Mostly in proximal muscles around the hips and shoulders, which are those around the trunk of the body, muscle weakness occurs mainly. In the lower extremities, weakness usually begins proximally, and then passes distally. Symptoms typically begin about the age of 1-3 years. To see the child run and get up off the floor while searching for signs of DMD is necessary.&#x0D; Diagnosis: A very common physical finding in boys with Duchenne's is Gower's Sign. In order to get up, it requires using their hands to 'climb' their legs. It is because of a weakness in the boy's hip muscles, which was seen in this patient in progressive in nature. The proper examination and evaluation the symptoms the child presented to the physiotherapy clinic played an important in reaching to the diagnosis of the condition.&#x0D; Conclusion: Prevent the child from developing contracture, correct posture of the child and maintain quality of life these are important criteria in for the child suffered from Duchenne muscular dystrophy.

Impact of Pan-Ethnic Expanded Carrier Screening in Improving Population Health Outcomes: Proceedings from a Multi-Stakeholder Virtual Roundtable Summit, June 25, 2020.

Impact of Pan-Ethnic Expanded Carrier Screening in Improving Population Health Outcomes: Proceedings from a Multi-Stakeholder Virtual Roundtable Summit, June 25, 2020.

Male to female birth ratios over a 35-year period.

Aim Along with changes to the human physique recorded over the past decades in certain countries, there are also changes concerning the male-female birth ratio. The aim of this study was to establish the movement of male-female birth ratios and factors affecting the ratio. Methods This retrospective study was conducted in Zagreb, Croatia, in the period from 1985 to 2019 on a sample of 3804 newborns. Results In the 35-year period the ratio of boys and girls at birth did not change significantly. Girls had lower birth weight, and boys had higher birth length. In the war period (1992-1994), a mild increase in the ratio of boys was noted, but not statistically significant. Father's age in the last period examined (2007-2009) showed to be a statistically significant predictor of the child's gender. Namely, the descendants of younger fathers were statistically significantly more frequently girls, while the descendants of older fathers were more frequently boys. Married mothers had higher percentage of male births (51.5%), and a lower percentage (47.1%) by unmarried mothers. Conclusion The changes in birth ratios are particularly pronounced in different age and socioeconomic groups of parents nowadays when the growth of living standards is accompanied by significant changes of the human physique.

Cholesterol metabolism is a potential therapeutic target in Duchenne muscular dystrophy.

BackgroundDuchenne muscular dystrophy (DMD) is a lethal muscle disease detected in approximately 1:5000 male births. DMD is caused by mutations in the DMD gene, encoding a critical protein that links the cytoskeleton and the extracellular matrix in skeletal and cardiac muscles. The primary consequence of the disrupted link between the extracellular matrix and the myofibre actin cytoskeleton is thought to involve sarcolemma destabilization, perturbation of Ca2+ homeostasis, activation of proteases, mitochondrial damage, and tissue degeneration. A recently emphasized secondary aspect of the dystrophic process is a progressive metabolic change of the dystrophic tissue; however, the mechanism and nature of the metabolic dysregulation are yet poorly understood. In this study, we characterized a molecular mechanism of metabolic perturbation in DMD.MethodsWe sequenced plasma miRNA in a DMD cohort, comprising 54 DMD patients treated or not by glucocorticoid, compared with 27 healthy controls, in three groups of the ages of 4–8, 8–12, and 12–20 years. We developed an original approach for the biological interpretation of miRNA dysregulation and produced a novel hypothesis concerning metabolic perturbation in DMD. We used the mdx mouse model for DMD for the investigation of this hypothesis.ResultsWe identified 96 dysregulated miRNAs (adjusted P‐value <0.1), of which 74 were up‐regulated and 22 were down‐regulated in DMD. We confirmed the dysregulation in DMD of Dystro‐miRs, Cardio‐miRs, and a large number of the DLK1‐DIO3 miRNAs. We also identified numerous dysregulated miRNAs yet unreported in DMD. Bioinformatics analysis of both target and host genes for dysregulated miRNAs predicted that lipid metabolism might be a critical metabolic perturbation in DMD. Investigation of skeletal muscles of the mdx mouse uncovered dysregulation of transcription factors of cholesterol and fatty acid metabolism (SREBP‐1 and SREBP‐2), perturbation of the mevalonate pathway, and the accumulation of cholesterol in the dystrophic muscles. Elevated cholesterol level was also found in muscle biopsies of DMD patients. Treatment of mdx mice with Simvastatin, a cholesterol‐reducing agent, normalized these perturbations and partially restored the dystrophic parameters.ConclusionsThis investigation supports that cholesterol metabolism and the mevalonate pathway are potential therapeutic targets in DMD.

Sex ratio trajectory in mouse

Skewing of the sex ratio towards males occurs in humans. The possible explanation for excess male births could be a preference for Y-bearing sperm at fertilization and/or selective elimination of female embryos during pregnancy. In this study, we have tested the sex ratio in the preimplantation embryo (2–3 cells stage/closest possible primary sex ratio), the post-implantation embryo (day E7.5), and at birth (secondary sex ratio) on a homogenous (genetic, environmental, and dietary) population of mice to ascertain the biological reason i.e., male preference at fertilization or female elimination during pregnancy or both. Primary sex ratio on early preimplantation embryos (2–3 cells stage) was studied on 598 embryos and secondary sex ratio (at birth) on 721 pups using PCR-based sexing (both X & Y chromosome-specific) besides sex ratio of 80 post-implantation embryos (day E7.5). We have also investigated whether the fat content (high & low) of the diet affects the sex ratio. We observed a skewed sex ratio (more female) in preimplantation embryos (0.436; 95 % CI 0.39, 0.48), and post-implantation embryos (0.462; 95 % CI 0.35, 0.57) but reverse skewing (more male) at birth (0.539; 95 % CI 0.5, 0.58). We also observed that high-fat diet promoted male sex ratio at birth (0.657; 95 % CI 0.57, 0.74) whereas a low-fat diet had the opposite effect (0.46; 95 % CI 0.36, 0.56) but no effect at fertilization (2–3 cells stage embryos). This indicates selective elimination of female embryo and fetus throughout pregnancy in mice, more so with a high-fat diet.

Quantifying lung and diaphragm morphology using radiographs in normative pediatric subjects, and predicting CT-derived lung volume.

To quantify the effect of age on two-dimensional (2D) radiographic lung and diaphragm morphology and determine if 2D radiographic lung measurements can be used to estimate computer tomography (CT)-derived lung volume in normative pediatric subjects. Digitally reconstructed radiographs (DRRs) were created using retrospective chest CT scans from 77 pediatric male and female subjects aged birth to 19 years. 2D lung and diaphragm measurements were made on the DRRs using custom MATLAB code, and Spearman correlations and exponential regression equations were used to relate 2D measurements with age. In addition, 3D lung volumes were segmented using CT scans, and power regression equations were fitted to predict each lung's CT-derived volume from 2D lung measurements. The coefficient of determination (R2 ) and standard error of the estimate (SEE) were used to assess the precision of the predictive equations with p < .05 indicating statistical significance. All 2D radiographic lung and diaphragm measurements showed statistically significant positive correlations with age (p < .01), including lung major axis (Spearman rho ≥ 0.90). Precise estimations of CT-derived lung volumes can be made using 2D lung measurements (R2 ≥ 0.95), including lung major axis (R2 ≥ 0.97). The reported pediatric age-specific reference data on 2D lung and diaphragm morphology and growth rates could be clinically used to identify lung and diaphragm pathologies during chest X-ray evaluations. The simple, precise, and clinically adaptable radiographic method for estimating CT-derived lung volumes may be used when pulmonary function tests are not readily available or difficult to perform.