Why considering sexual differences is necessary when studying encephalopathy of prematurity through rodent models

Preterm birth is a high‐risk factor for the development of gray and white matter abnormalities, referred to as “encephalopathy of prematurity,” that may lead to life‐long motor, cognitive, and behavioral impairments. The prevalence and clinical outcomes of encephalopathy of prematurity differ between sexes, and elucidating the underlying biological basis has become a high‐priority challenge. Human studies are often limited to assessment of brain region volumes by MRI, which does not provide much information about the underlying mechanisms of lesions related to very preterm birth. However, models using KO mice or pharmacological manipulations in rodents allow relevant observations to help clarify the mechanisms of injury sustaining sex‐differential vulnerability. This review focuses on data obtained from mice aged P1–P5 or rats aged P3 when submitted to cerebral damage such as hypoxia‐ischemia, as their brain lesions share similarities with lesion patterns occurring in very preterm human brain, before 32 gestational weeks. We first report data on the mechanisms underlying the development of sexual brain dimorphism in rodent, focusing on the hippocampus. In the second part, we describe sex specificities of rodent models of encephalopathy of prematurity (RMEP), focusing on mechanisms underlying differences in hippocampal vulnerability. Finally, we discuss the relevance of these RMEP. Together, this review highlights the need to systematically search for potential effects of sex when studying the mechanisms underlying deficits in RMEP in order to design effective sex‐specific medical interventions in human preterms.     

The efficiency of glutamate uptake differs between neonatal and adult cortical microvascular endothelial cells

Glutamate transporters (excitatory amino-acid transporters (EAATs)) are essential for brain homeostasis. While previous studies indicate that the vascular endothelium contributes to glutamate efflux in the adult brain, little information is available regarding glutamate uptake in the immature brain. The present study shows a differential expression pattern of EAATs between cortical microvessels in adults and newborns. In addition, adult cortical endothelial cells take up glutamate more efficiently than neonatal cells. Our findings indicate age-specific changes in extracellular glutamate regulation by brain endothelial cells, suggesting differences in the efficiency of glutamate efflux during an excitotoxic process that, in turn, may contribute to age-specific brain vulnerability.     

Celecoxib is as efficacious as naproxen in the management of acute shoulder pain

This study compared the analgesic efficacy and safety of the cyclo-oxygenase-2 specific inhibitor celecoxib with the non-specific non-steroidal anti-inflammatory drug, naproxen, in patients with acute shoulder pain. Adult patients with shoulder pain, onset within the previous 14 days and shoulder pain of > or = 40 mm on a 100 mm visual analogue scale (VAS), were treated with oral doses of celecoxib or naproxen for 14 days and followed by a visit at day 42 in a double-blind, randomized study. The primary efficacy assessment was change in maximum pain at rest on a 100 mm VAS at day 14 compared with baseline. In addition, secondary efficacy pain and functional assessments were analysed at baseline, day 14 and day 42. A total of 202 patients were included in the trial (99 celecoxib 400 mg/day; 103 naproxen 1 g/day). The difference in change from baseline at day 14 in maximum pain at rest was not statistically significant between the two treatment groups, but was numerically higher for celecoxib than for naproxen (-47.9 +/- 2.5 versus -42.3 +/- 2.5, respectively). According to the limits of the 95% confidence interval of the difference between groups (-12.52; 1.38), celecoxib appeared to be at least as effective as naproxen. All secondary efficacy measures followed the same pattern, showing similarity between the two treatments with a trend in favour of celecoxib. The incidences of adverse events were similar for both groups. Fewer patients experienced epigastric pain with celecoxib (seven patients versus 14 with naproxen). This adverse event led to discontinuation in two patients receiving celecoxib and five receiving naproxen. Celecoxib 400 mg/day was at least as effective as naproxen 1 g/day in managing pain in this condition.     

Use of bone biochemical markers with dual-energy x-ray absorptiometry for early determination of bone loss in persons with spinal cord injury

Our cross-sectional study aimed at the early determination of changes in bone metabolism in terms of bone mineral density (BMD) and bone turnover in persons with complete spinal cord injury (SCI) during the acute phase of paraplegia. Combined dual-energy x-ray absorptiometry (DXA) and specific biochemical markers of bone turnover were used to determine bone metabolism. Seven persons with SCI (age, 31.3 +/- 9.5 years) who had sustained injury an average of 3 months earlier (103 +/- 10.8 days) were compared with 10 able-bodied controls (27.5 +/- 4.3 years). Four paraplegics and 3 quadriplegics composed the SCI group. BMD was measured by DXA, while bone turnover was evaluated by serum osteocalcin (OC), bone alkaline phosphatase (B-ALP), and serum and urinary type I collagen C-telopeptide (CTXs and CTXu). Regional BMD (proximal femur, lumbar spine, radius, lower limb) was similar in the 2 groups except in the upper limb (P <.05). CTXs and CTXu were significantly higher in SCI (P <.01 and P <.001, respectively), whereas among the bone formation markers used, only serum OC was affected by immobilization (P <.05). The SCI group developed hypercalciuria (0.76 +/- 0.37 v 0.35 +/- 0.14), whereas calcemia was normal (2.42 +/- 0.09 v 2.31 +/- 0.10). Intact parathyroid hormone (iPTH) and 1.25 (OH)(2) vitamin D levels were suppressed in persons with SCI (P <.001) by 80.6% and 66%, respectively. In conclusion, it was not possible to detect any variation in BMD from the DXA technique at this early stage of demineralization, but the sensitivity and early response of the biochemical markers strongly suggested their usefulness for the early identification of persons with SCI at risk of severe osteoporosis.