Ahila Ayyavoo

Elimination of pain and improvement of exercise capacity in Camurati-Engelmann disease with losartan.

BACKGROUND Camurati-Engelmann disease (CED) is a rare disorder, with approximately 250 described cases in the literature. Treatment options are limited and have been suboptimal so far. PATIENT AND METHODS A prepubertal girl aged 9 years was diagnosed with CED. Treatment with losartan was initiated at a daily dose of 0.75 mg/kg. Over a period of 12 weeks, the dose was gradually increased to 1.0 mg/kg/d. The patient was reviewed in clinic regularly and underwent thorough clinical assessments 9, 17, and 38 months after treatment initiation. RESULTS The patient experienced marked clinical improvements with losartan. In particular, losartan treatment led to the complete elimination of the previously severe and incapacitating pain, with an increased ability to walk and perform physical activities. There was also a considerable improvement in body composition with increased lean and adipose tissue. Notably, the improvement in fat deposition had not been previously observed with other treatments in CED. Hematology, liver, and renal function tests were within normal ranges at presentation and remained so over the course of treatment. CONCLUSIONS In light of our findings, losartan may be a useful option in CED management.

Severe Hyperemesis Gravidarum Is Associated With Reduced Insulin Sensitivity in the Offspring in Childhood

BACKGROUND Hyperemesis gravidarum alters maternal (and possibly fetal) nutrition throughout pregnancy, but there are no data on long-term effects on offspring metabolism. Thus, we aimed to assess whether severe hyperemesis gravidarum (SHG) affects glucose homeostasis and body composition in the offspring in childhood. METHODS Healthy prepubertal children (aged 4-11 years) born at term were studied: offspring of mothers who were admitted to hospital with SHG (n = 36) and offspring of mothers from control pregnancies (n = 42). Primary outcome was insulin sensitivity measured using iv glucose tolerance tests and Bergmans minimal model. Other assessments included lipid and hormonal profiles and body composition using whole-body dual-energy x-ray absorptiometry. RESULTS Insulin sensitivity in SHG children was 20% lower than in controls (8.49 vs 10.60 × 10(-4)·min(-1)·(mU/L); P = .014). SHG children also had higher fasting insulin (6.88 vs 5.04 mIU/L; P = .024) and lower IGF binding protein 1 (11.8 vs 19.0 ng/mL; P = .004) concentrations than controls. Baseline cortisol concentrations were 22% higher in SHG offspring (256 vs 210 nmol/L; P = .021). Children in both groups were anthropometrically similar. CONCLUSION Children born to mothers who experienced SHG have lower insulin sensitivity, which may increase their long-term risk of developing diabetes mellitus. Follow-up of SHG offspring is essential to determine later risk of metabolic disease.

Pre-Pubertal Children Born Post-Term Have Reduced Insulin Sensitivity and Other Markers of the Metabolic Syndrome

Background There are no data on the metabolic consequences of post-term birth (≥42 weeks gestation). We hypothesized that post-term birth would adversely affect insulin sensitivity, as well as other metabolic parameters and body composition in childhood. Methods 77 healthy pre-pubertal children, born appropriate-for-gestational-age were studied in Auckland, New Zealand: 36 born post-term (18 boys) and 41 (27 boys) born at term (38–40 weeks gestation). Primary outcome was insulin sensitivity measured using intravenous glucose tolerance tests and Bergman’s minimal model. Other assessments included fasting hormone concentrations and lipid profiles, body composition from whole-body dual-energy X-ray absorptiometry, 24-hour ambulatory blood pressure monitoring, and inflammatory markers. Results Insulin sensitivity was 34% lower in post-term than in term children (7.7 vs. 11.6 x10-4·min-1·(mU/l); p<0.0001). There was a compensatory increase in acute insulin response among post-term children (418 vs 304 mU/l; p=0.037), who also displayed lower glucose effectiveness than those born at term (2.25 vs 3.11 x10-2·min-1; p=0.047). Post-term children not only had more body fat (p=0.014) and less fat-free mass (p=0.014), but also had increased central adiposity with more truncal fat (p=0.017) and greater android to gynoid fat ratio (p=0.007) compared to term controls. Further, post-term children displayed other markers of the metabolic syndrome: lower normal nocturnal systolic blood pressure dipping (p=0.027), lower adiponectin concentrations (p=0.005), as well as higher leptin (p=0.008) and uric acid (p=0.033) concentrations. Post-term boys (but not girls) also displayed a less favourable lipid profile, with higher total cholesterol (p=0.018) and LDL-C (p=0.006) concentrations, and total cholesterol to HDL-C ratio (p=0.048). Conclusions Post-term children have reduced insulin sensitivity and display a number of early markers of the metabolic syndrome. These findings could have important implications for the management of prolonged pregnancies. Future studies need to examine potential impacts later in life, as well as possible underlying mechanisms.

Hyperemesis gravidarum and long-term health of the offspring.

Nausea and vomiting of pregnancy is a very common occurrence, but the reported incidence of hyperemesis gravidarum (a more severe form of vomiting in pregnancy) is much lower, estimated to vary from 0.3-3.6%. Studies have shown that nausea and vomiting of pregnancy is associated with improved fetal outcomes, such as lower rates of miscarriage. However, there are limited data on outcomes associated with hyperemesis gravidarum, which have focused on pregnancy and neonatal outcomes. Recently, studies showed adverse health outcomes, such as a reduction in insulin sensitivity in childhood and increased incidence of psychological disorders in adulthood. The effects of hyperemesis gravidarum in the offspring need to be further examined throughout childhood, adolescence, and into adulthood, so that long-term disease risks can be evaluated.

Metabolic, cardiovascular and anthropometric differences between prepubertal girls and boys

We aimed to assess possible differences in insulin sensitivity and other metabolic, anthropometric and cardiovascular parameters between boys and girls prior to puberty.

Postterm Births: Are Prolonged Pregnancies Too Long?

“P ostterm pregnancy” is defined by the World Health Organization as the end of gestation at

Increasing maternal prepregnancy body mass index is associated with reduced insulin sensitivity and increased blood pressure in their children

42 completed weeks’ gestation, measured from the first day of the lastmenstrual period (LMP) and based on a 28-day cycle. However, in reality, this definition is arbitrary, and there are no clear scientific data underpinning it. As pregnancies that last beyond 42 weeks have been associated with adverse events historically, they have been considered a separate at-risk group. It is clear that postterm births remain a common event worldwide, and management of postterm pregnancies is somewhat variable and therefore best-practice guidelines are lacking. There are limited data across countries on long-term trends in the incidence of postterm births. Pregnancies were previously dated based on the LMP, but now rely on both LMP and early ultrasound scans, improving gestational age accuracy. Data from 81 singleton pregnancies after in vitro fertilization (where conceptions can be accurately timed) showed that ultrasound scans in the first 20 weeks underestimated gestation length by just 2.8 days (SEM 0.2), so that fetal age was determined to within 7 days in >95% of cases. Thus, in Finland, for example, the incidence of postterm births dropped from 10.3% to 2.7% once ultrasound scans became the standard technique to date pregnancies. Nonetheless, postterm births are a common occurrence globally. The rate of postterm births varies considerably between and within countries, and in the developed world it ranges from 0.4% to 11%. In Sweden, the incidence of postterm births is 7.5% compared with 5.6% for preterm births. As a result, the Swedish birth registry recorded nearly 311 000 children born postterm in 1983-2006. It is important to note that in many nations (particularly in poorer countries), mothers may not have access to ultrasound scans and will be unsure of the LMP date. Therefore, it is likely that the incidence of postterm births inmany countries is higher than that officially recorded.

Losartan improves clinical outcome in Camurati Engelmann Disease

We aimed to assess the effects of maternal prepregnancy body mass index (BMI) on insulin sensitivity, metabolism and blood pressure in the offspring.

Is being first-born another risk factor for metabolic and cardiovascular diseases?

We hypothesized that losartan would help in achieving clinical remission in CED (Camurati Engelmann Disease) patients by blocking TGFB1(transforming growth factor beta 1) with fewer side-effects than steroids. CED characterised by progressive diaphyseal dysplasia is associated with debilitating bone pain in the limbs, muscle weakness, fatiguability and waddling gait.[1] Clinical manifestations are due to mutations in the TGFB1 gene leading to its over-expression and effect on bone. Losartan is an antagonist of TGFB1 and it slows the progress of aortic root dilatation inMarfan’s syndrome by blocking the over-expression of TGFB1.[2] Steroids which have long been used for treatment of CED and been linked to long term side effects including those on growth, blood pressure and spinal osteoporosis. A 10 year old child with mutation is in exon 4, position C652T causing an R218C amino acid substitution on chromosome 19q13 had severe limitation of activity since 4 years of age due to pain in the limbs. She underwent a physical examination, a dual energy xray absorptiometry scan(DEXA), pain score and 6 minute walk test prior to the start of losartan with a repeat of the tests 9 and 17 months later. She is being treated with losartan at a dose of 0.75mg/kg/day. Table ​Table11 Table 1 Losartan improves the quality of life in children with CED by reducing the bone pain along with improvement in their activity levels, fat & muscle mass, without major effects on growth, blood pressure and spinal osteoporosis.

Early markers of the metabolic syndrome in children born post-term

Future Cardiol. (2013) 9(4), 447–450 Birth rates have been steadily declining throughout the world, particularly in Europe and many Asian countries [1]. This reduction in birth rates is a result of a number of factors, including govern ment policies (e.g. one-child policy in mainland China), greater family planning, personal choice and economic constraints [2]. As a result, there has been a large increase in the number of one-child families and, consequently, a considerable increase in the proportion of first-born children within many populations [2]. Thus, any adverse health outcomes that are associated with being first-born (primogeniture) would likely affect an ever-increasing proportion of the world’s population. Notably, only recently has evidence emerged on the consequences of primogeniture on long-term metabolic and cardiovascular health risks.