Sex differences in circadian timing systems: Implications for disease

Virtually every eukaryotic cell has an endogenous circadian clock and a biological sex. These cell-based clocks have been conceptualized as oscillators whose phase can be reset by internal signals such as hormones, and external cues such as light. The present review highlights the inter-relationship between circadian clocks and sex differences. In mammals, the suprachiasmatic nucleus (SCN) serves as a master clock synchronizing the phase of clocks throughout the body. Gonadal steroid receptors are expressed in almost every site that receives direct SCN input. Here we review sex differences in the circadian timing system in the hypothalamic–pituitary–gonadal axis (HPG), the hypothalamic–adrenal–pituitary (HPA) axis, and sleep–arousal systems. We also point to ways in which disruption of circadian rhythms within these systems differs in the sexes and is associated with dysfunction and disease. Understanding sex differentiated circadian timing systems can lead to improved treatment strategies for these conditions.     

Resolution of epileptic encephalopathy following treatment with transdermal nicotine

We report resolution of an epileptic encephalopathy by administration of transdermal nicotine patches in an adolescent with severe nonlesional refractory frontal lobe epilepsy. The 18.5‐year‐old female patient had refractory epilepsy from the age of 11. Recurrent electroencephalography (EEG) recordings showed mostly generalized activity, albeit with right frontal predominance. Almost all antiepileptic medications failed to provide benefit. She developed an encephalopathic state with cognitive decline. The nonlesional frontal lobe epilepsy and a family history of a cousin with nocturnal epilepsy with frontal origin suggested genetic etiology. Transdermal nicotine patches brought complete resolution of the seizures, normalization of the EEG, and a significant improvement in her thinking process and speech organization. Sequencing of the CHRNB2 and CHRNA4 genes did not detect a mutation. Transdermal nicotine patches should be considered in severe pharmacoresistant frontal lobe epilepsy.     

Effects of a Serotonin S2-Receptor Blocker on Healing of Acute and Chronic Tendon Injuries

The beneficial effects of serotonin S₂-receptor blockers on healing skin and muscle ulcers and refractory lesions such as leprosy and diabetic and ischemic ulcers have been reported previously, but their mechanisms of actions are not clear. The present study sought to elucidate the action of an S₂-receptor blocker, metrenperone, on the healing of collagenase-induced injuries in superficial digital flexor tendons of two groups of rabbits. In one group, oral and topical therapy for 28 days with metrenperone, was started within 48 hr of a single acute injury. The animals were then left untreated for another 60 days, when it was found that most of the morphological, biochemical, and biomechanical characteristics of the healed tendons matched those of their normal uninjured controls. Injured, untreated controls showed poor healing. In the second group of animals, tendon injury was induced by four separate injections of collagenase at weekly intervals. The rabbits were left for another 60 days, before being treated with metrenperone for 26 days. This delayed treatment had no apparent effect on the biomechanical, biochemical, or morphological characteristics of the healing tendons. It appeared that metrenperone had a significant effect on collagen turnover and organization of scar tissue, but only while the inflammatory and fibroplastic processes were active in the early stages of healing. S₂-receptor blockers may, therefore, be of potential value for modulating repair in acutely injured collagenous tissue.     

Treatment Outcomes of West Syndrome in Infants With Down Syndrome

West syndrome constitutes the most frequent of all seizure types in infants with Down syndrome. We retrospectively reviewed records of 12 infants with Down syndrome and West syndrome, accounting for 5% of 239 infants with West syndrome from a comprehensive epilepsy database during a 17-year period. All demonstrated classic hypsarrhythmia on video electroencephalograms. One had clinically responded to clonazepam, and one was not treated because the parents refused any treatment. Seven of 10 infants demonstrated a complete response to high-dose natural adrenocorticotrophic hormone. Four (57%) of these seven infants relapsed. Relapses occurred as long as 2 years after cessation of the initial presentation of infantile spasms. At most recent follow-up (median age, 5 years), 8/12 (67%) were seizure-free, and seven were off any medications. Two of three nonresponders manifested intractable epilepsy and profound mental retardation. Developmentally, 6/8 who could be assessed met criteria for autistic spectrum disorder. Close follow-up is necessary even after successful initial treatment, because relapses are frequent and can occur as long as 2 years later.     

The Prevalence of Left Ventricular Hypertrophy in Obese Children Varies Depending on the Method Utilized to Determine Left Ventricular Mass

Obesity and left ventricular hypertrophy (LVH) have been identified as independent risk factors for cardiovascular events. The definition of LVH depends on the geometric algorithm used to calculate LV mass (LVM) by echocardiography and the method used to normalize LVM for body size. This study evaluates the effect of these methods on the prevalence of LVH in obese children. LVM for 109 obese and 109 age-matched non-obese children was calculated using M-mode or two-dimensional echocardiography (2DE). LVM was then normalized to height 2.7 as indexed LVM (LVMI), to body surface area (BSA), height, and lean body mass (LBM) as LVM Z-scores. LVH was defined as LVMI >95th ‰ using age-specific normal reference values or LVM Z-scores ≥2. The prevalence of LVH by LVMI and LVM Z-scores was compared. There was a correlation between LVM determined by M-mode and by 2DE (R ² = 0.91), although M-mode LVM was greater than 2DE LVM. However, the difference between these values was greater in obese children than in non-obese children. Based on the method of normalization, the prevalence of LVH among obese children was 64 % using LVMI, 15 % using LVM Z-scores for height, 8 % using LVM Z-scores for BSA and 1 % using LVM Z-scores for LBM. Height-based normalization correlates with obesity and hypertension. The methods used to measure and normalize LVM have a profound influence on the diagnosis of LVH in obese children. Further study is needed to determine which method identifies children at risk for cardiovascular morbidity and mortality.