Sensorimotor dysfunction due to developmental manganese exposure is less severe in adult female than male rats and partially improved by acute methylphenidate treatment.

Epidemiological studies have reported associations between elevated manganese (Mn) exposure and poorer psychomotor performance in children. Our studies in adult male rats have established that this relationship is causal and that prolonged methylphenidate (MPH) treatment is efficacious in treating this area of dysfunction. However, it is unclear if sensitivity to these Mn deficits differs between females and males, and whether existing pharmacological therapies are efficacious in improving sensorimotor dysfunction in females. To address these questions, we used our rat model of childhood environmental Mn exposure and the Montoya staircase test to determine whether 1) there are sex differences in the lasting sensorimotor dysfunction caused by developmental Mn exposure, and 2) MPH treatment is efficacious in ameliorating the sensorimotor deficits in females. Female and male neonates were treated orally with Mn (50 mg Mn/kg/d) from postnatal day 1 to 21 and evaluated for skilled forelimb sensorimotor performance as adults. Subsequently, the efficacy of acute oral MPH treatment (doses of 0, 0.5, and 3.0 mg MPH/kg/d) was assessed in females using a within-subject MPH treatment design. Developmental postnatal Mn exposure produced lasting sensorimotor reaching and grasping deficits that were milder in females than in males. Acute MPH treatment of Mn-exposed females with the 0.5 mg/kg/d dose attenuated the reaching dysfunction without alleviating grasping dysfunction. These findings show sex-based variations in sensitivity to the sensorimotor impairment caused by developmental Mn exposure, and they are consistent with prior studies showing less vulnerability of females to Mn-induced dysfunction in other functional domains, possibly due to the protective effects of estrogen. Given our previous work showing the efficacy of MPH treatment to alleviate Mn-induced inattention, impulsiveness, and sensorimotor dysfunctions in adult male rats, they also highlight the need for further research into sex-based differences in cognitive and behavioral areas of brain function, and the efficacy of therapeutics in treating behavioral dysfunction in females. Supported by NIEHS R01ES028369.

Getting ahead of Alzheimer's disease: early intervention with focused ultrasound.

The amyloid-ß (Aß) hypothesis implicates Aß protein accumulation in Alzheimer's disease (AD) onset and progression. However, therapies targeting Aß have proven insufficient in achieving disease reversal, prompting a shift to focus on early intervention and alternative therapeutic targets. Focused ultrasound (FUS) paired with systemically-introduced microbubbles (µB) is a non-invasive technique for targeted and transient blood-brain barrier opening (BBBO), which has demonstrated Aß and tau reduction, as well as memory improvement in models of late-stage AD. However, similar to drug treatments for AD, this approach is not sufficient for complete reversal of advanced, symptomatic AD. Here we aim to determine whether early intervention with FUS-BBBO in asymptomatic AD could delay disease onset. Thus, the objective of this study is to measure the protective effects of FUS-BBBO on anxiety, memory and AD-associated protein levels in female and male triple transgenic (3xTg) AD mice treated at an early age and disease state. Here we show that early, repeated intervention with FUS-BBBO decreased anxiety-associated behaviors in the open field test by 463.02 and 37.42% in male and female cohorts, respectively. FUS-BBBO preserved female aptitude for learning in the active place avoidance paradigm, reducing the shock quadrant time by 30.03 and 31.01% in the final long-term and reversal learning trials, respectively. Finally, FUS-BBBO reduced hippocampal accumulation of Aß40, Aß42, and total tau in females by 12.54, 13.05, and 3.57%, respectively, and reduced total tau in males by 18.98%. This demonstration of both cognitive and pathological protection could offer a solution for carriers of AD-associated mutations as a safe, non-invasive technique to delay the onset of the cognitive and pathological effects of AD.

Describing the natural history of clinical, biochemical and radiological outcomes of children with familial partial lipodystrophy type 2 (FPLD2) from the United Kingdom: A retrospective case series.

CONTEXT: Familial partial lipodystrophy type 2 (FPLD2) results from autosomal dominant mutations in the LMNA gene, causing lack of subcutaneous fat deposition and excess ectopic fat accumulation, leading to metabolic complications and reduced life expectancy. The rarity of the condition means that the natural history of FPLD2 throughout childhood is not well understood. We report outcomes in a cohort of 12 (5M) children with a genetic diagnosis of FPLD2, under the care of the UK National Severe Insulin Resistance Service (NSIRS) which offers multidisciplinary input including dietetic, in addition to screening for comorbidities. OBJECTIVE: To describe the natural history of clinical, biochemical and radiological outcomes of children with FPLD2. DESIGN: A retrospective case note review of children with a genetic diagnosis of FPLD2 who had been seen in the paediatric NSIRS was performed. PATIENTS: Twelve (5M) individuals diagnosed with FPLD2 via genetic testing before age 18 and who attended the NSIRS clinic were included. MEASUREMENTS: Relationships between metabolic variables (HbA1c, triglycerides, fasting insulin, fasting glucose and alanine transaminase [ALT]) across time, from first visit to most recent, were explored using a multivariate model, adjusted for age and gender. The age of development of comorbidities was recorded. RESULTS: Three patients (all female) developed diabetes between 12 and 19 years and were treated with Metformin. One female has hypertrophic cardiomyopathy and four (1M) patients developed mild hepatic steatosis at a median [range] age of 14(12-15) years. Three (1M) patients reported mental health problems related to lipodystrophy. There was no relationship between biochemical results and age. Patients with diabetes had higher concentrations of ALT than patients who did not have diabetes, adjusted for age, gender and body mass index standard deviation scores. CONCLUSIONS: Despite dietetic input, some patients, more commonly females, developed comorbidities after the age of 10. The absence of relationships between biochemical results and age likely reflects a small cohort size. We propose that, while clinical review and dietetic support are beneficial for children with FPLD2, formal screening for comorbidities before age 10 may not be of benefit. Clinical input from an multidisciplinary team including dietician, psychologist and clinician should be offered after diagnosis.

Gonadotrophin-independent Precocious Puberty Secondary to an Estrogen Secreting Adrenal Tumor.

BACKGROUND: Adrenal masses are rare in children and most commonly present with clinical features of virilization in the absence of activation of the pituitary axis-gonadotrophin-independent precocious puberty. OBSERVATIONS: We report an unusual case of a 7-year-old girl who presented with clinical signs suggestive of exposure to both androgens and estrogens. Imaging revealed a left-sided adrenal mass with no evidence of metastasis. She underwent successful laparoscopic unilateral adrenalectomy. Histology confirmed an adrenal adenoma. CONCLUSION: We conclude that adrenocortical tumors should be considered in children presenting with gonadotrophin-independent precocious puberty and raised estrogens.

Catch-Up Growth in Children Born Small for Gestational Age Related to Body Composition and Metabolic Risk at Six Years of Age in the UK.

OBJECTIVES: To determine differences in body composition and glucose metabolism according to childhood growth outcomes in a population-based sample of children born small for gestational age (SGA). METHODS: A single-centre study of 259 children born SGA identified through hospital records and contacted when aged 4-7 years. Questionnaire data on pre/perinatal history and growth parameters during childhood was collected from the parents, and in a subgroup of 150 children face-to-face assessments were performed, including anthropometric parameters, lean and fat mass, blood pressure, fasting glucose, and C-peptide. RESULTS: Based on the questionnaires, few children had formal clinic follow-up of growth, but 7% of the cohort showed a height and weight of <-2SDS during childhood, and only 2 children met the criteria for growth hormone therapy. Out of the 150 children assessed at a mean age of 6.1 ± 0.8 years, 122 (81%) showed a catch-up growth in weight. Compared to those without weight catch-up, these children had a higher fat mass index (3.13 ± 1.36 vs. 2.56 ± 0.91 kg/m2, p = 0.04), trunk-to-limb fat mass ratio (0.63 ± 0.14 vs. 0.56 ± 0.08, p = 0.002), systolic blood pressure SDS (0.09 ± 0.71 vs. -0.32 ± 0.63, p = 0.008), fasting glucose (4.5 ± 0.5 vs. 4.3 ± 0.5 mmol/L, p = 0.03), and C-peptide (306 ± 116 vs. 256 ± 112 pmol/L, p = 0.08). Among children with weight catch-up growth, those with less height gain had a lower limb lean mass index (4.25 ± 0.48 vs. 4.48 ± 0.56 kg/m2, p = 0.02) and fat mass index (1.57 ± 0.59 vs. 1.83 ± 0.77 kg/m2, p = 0.04). CONCLUSIONS: Within this population-based sample of SGA children, catch-up growth in weight was associated with higher abdominal fat mass, blood pressure and glycemia; furthermore, in these children, less height gain was associated with reduced limb lean and fat mass.