Although Smith-Lemli-Opitz Syndrome (SLOS), a genetic condition of impaired cholesterol biosynthesis, is associated with autism [Tierney et al., 2001], the incidence of SLOS and other sterol disorders among individuals with autism spectrum disorders (ASD) is unknown. This study investigated 1) the incidence of biochemically diagnosed SLOS in blood samples from a cohort of subjects with ASD from families in which more than one individual had ASD and 2) the type and incidence of other sterol disorders in the same group. Using gas chromatography/mass spectrometry, cholesterol and its precursor sterols were quantified in one hundred samples from subjects with ASD obtained from the Autism Genetic Resource Exchange (AGRE) specimen repository. Although no sample had sterol levels consistent with SLOS, 19 samples had total cholesterol levels lower than 100 mg/dL, which is below the 5 th centile for children over age 2 years. These findings suggest that, in addition to SLOS, there may be other disorders of sterol metabolism or homeostasis associated with ASD. KeywordsSmith-Lemli-Opitz syndrome; hypocholesterolemia; Autism Genetic Resource Exchange; Asperger disorder; pervasive developmental disorder Smith-Lemli-Opitz syndrome (SLOS, MIM 270400) is an autosomal recessive malformation syndrome caused by a deficiency of the last step of cholesterol biosynthesis, 7-dehydrocholesterol reductase (DHCR7) [Tint et al, 1994]. Principal abnormalities include a typical facial appearance, microcephaly, hypotonia, cleft palate, hypogenitalism, 2-3 toe syndactyly, and a characteristic behavioral profile including autism, usually accompanied by mental retardation. The enzymatic deficiency manifests biochemically in blood and all tissues as a reduced level of cholesterol and increased levels of 7-dehydrocholesterol (7DHC) and its isomer, 8-dehydrocholesterol (8DHC), although a few very mildly affected patients have normal plasma cholesterol levels despite increases in 7DHC and 8DHC. This NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript sterol abnormality in turn affects the synthesis and metabolism of various sterol-derived compounds, including bile acids, adrenal steroids, neurosteroids, and the structure of sterolrich membranes, such as myelin, the plasma membrane, and various subcellular organelles.SLOS is a relatively common genetic disorder with an estimated incidence among those of European ancestry of approximately 1 in 50,000 births. SLOS has a wide spectrum of clinical and biochemical severity, from functionally normal individuals to malformed fetuses that die in utero [Lowry and Yong, 1980;Kelley and Hennekam, 2000]. Although the combined carrier frequency for several common DHCR7 null alleles of about 1.25% predicts an incidence of 1 in 25,000 births in European-derived populations, about 50% of conceptuses appear to be lost early in pregnancy [Kelley and Herman, 2001]. Most SLOS individuals who survive the newborn period are compound heterozygotes for a common DHCR7 null mutation and a mild...

Blood pressure (BP) management is a crucial part of critical care that directly affects morbidity and mortality. While BP has become a mainstay in patient care, the accuracy and precision of BP measures across commonly used sites (left upper arm, right upper arm, etc.) and methods have not been established. This study begins to fill this gap in literature by testing the null hypothesis that BP measurement does not vary according to site. this is a prospective, non-randomized, cross-sectional study of 80 neurocritical care unit patients. Near simultaneous non-invasive blood pressure (NIBP) readings from 4 different locations (bilateral upper arm, bilateral wrist) and, when available, intraarterial blood pressure readings (IABP) were included. Pearson correlation coefficients and one-way repeated measures ANOVA were used to observe the systolic, diastolic, and mean arterial pressure (MAp) correlations. the Bp measured at the four most common sites (left upper arm, left wrist, right upper arm, right wrist) had adequate correlation coefficients but were statistically significantly different and highly unpredictable. The median inter-site systolic variability was 10 mmHg (IQR 2 to 10 mmHg). The median inter-site MAP variability was 6mmHg with an interquartile range (IQR) of 3 to 9 mmHg. As expected, the values correlated to show that patients with high Bp in one site tended to have high Bp in another site. However, the unpredictable inter-site variability is concerning within the clinical setting where oftentimes BP measurement site is not standardized but resulting values are nevertheless used for treatment. There is prominent inter-site variability of BP measured across the 4 most common measurement sites. The variability persists across non-invasive (NIBP) and invasive (IABP) methods of assessment. Blood pressure (BP) monitoring is essential to neuroscience intensive care unit (NSICU) patient management. Adequate cerebral perfusion is dependent upon central BP control, maintained through the modulation of various factors such as cardiac output, vascular tone, systemic vascular resistance, and intravascular volume. Although BP can be measured at multiple sites (e.g., upper arm, wrist, thigh), there is no gold standard for site selection. Inconsistencies in BP readings may occur due to inter-observer variability, technical issues, or methods and locations for measurement. The true value of a patient's BP cannot be measured with total precision, owing to its natural variability over time, as well as the limitations of the methods used to measure BP 1. Moreover, BP measurement is influenced by other physiological factors, such as position changes (e.g., orthostatic stress due to gravitational blood volume shift) and external factors, such as the measurement site used for the non-invasive blood pressure (NIBP) machine 2. This variability lends ambiguity to BP measurements in the critical care setting, where accuracy is paramount as a basis for medical interventions. It is particularly crucial in the NSICU setting, where...

Background: Adrenal insufficiency (AI) is associated with increased cardiovascular morbidity and mortality and reduced quality of life (QoL).Optimum glucocorticoid (GC) dosing and timing are crucial in the treatment of AI, yet the natural circadian secretion of cortisol is difficult to mimic. The once-daily dual-release hydrocortisone (DR-HC) preparation, (Plenadren®), offers a more physiological cortisol profile and may address unmet needs. Methods:An investigator-initiated, prospective, cross-over study in patients with AI. Following baseline assessment of cardiometabolic risk factors and QoL, patients switched from their usual hydrocortisone regimen to a once-daily dose equivalent of DR-HC and were reassessed after 12 weeks of treatment. Results: Fifty-one patients (21 PAI/30 SAI) completed the study. Mean age was 41.6 years (SD 13), and 58% (n=30) were male. The median daily HC dose before study entry was 20mg (IQR 15-20mg). After 3 months on DR-HC, the mean SBP decreased by 5.7mmHg, p=0.0019 and DBP decreased by 4.5mmHg, p=0.0011. There was also a significant reduction in mean body weight (-1.23kg, p=0.006) and BMI (-0.3 kg/m2,p=0.003). In a sub-analysis, there was a greater reduction in SBP observed in patients with SAI when compared to PAI post DR-HC. Patients reported significant improvements in QoL using three validated QoL questionnaires, with a greater improvement in PAI. Conclusion: Dual-release hydrocortisone decreases BP, weight and BMI compared with conventional HC treatment, even at physiological GC replacement doses. Additionally, DR-HC confers significant improvements in QoL compared to immediate-release HC, particularly in patients with PAI, which is also reflected in the patient preference for DR-HC.

BACKGROUND: Assessing the pupillary light reflex is a core component of neurological assessments. Pupil size and reactivity can provide early warning about early neurological decline. Automated infrared pupillometry is noninvasive and easy to use and has greater reliability compared with manual assessments to obtain objective and consistent measurements of pupillary size and reactivity to light. METHODS: This is a case series of 3 patients who had poor baseline clinical neurological examinations. Because it would be more difficult to detect acute neurological deterioration, automated infrared pupillometry and the Neurological Pupil index (NPi) were used in addition to the clinical neurological examination. NPi values < 3.0 prompted further imaging. RESULTS: In each case, abnormal NPi values prompted emergent imaging that confirmed acute cerebral edema and resulted in a change in management and treatment plan. CONCLUSION: The automated infrared pupillometry is a noninvasive monitor that can provide additional objective data in patients with a poor baseline neurological examination in whom it may otherwise be difficult to detect neurological deterioration.