Notch1 Modulation of Cellular Calcium Regulates Mitochondrial Metabolism and Anti-Apoptotic Activity in T-Regulatory Cells.

As the major hub of metabolic activity and an organelle sequestering pro-apoptogenic intermediates, mitochondria lie at the crossroads of cellular decisions of death and survival. Intracellular calcium is a key regulator of these outcomes with rapid, uncontrolled uptake into mitochondria, activating pro-apoptotic cascades that trigger cell death. Here, we show that calcium uptake and mitochondrial metabolism in murine T-regulatory cells (Tregs) is tuned by Notch1 activity. Based on analysis of Tregs and the HEK cell line, we present evidence that modulation of cellular calcium dynamics underpins Notch1 regulation of mitochondrial homeostasis and consequently anti-apoptotic activity. Targeted siRNA-mediated ablations reveal dependency on molecules controlling calcium release from the endoplasmic reticulum (ER) and the chaperone, glucose-regulated protein 75 (Grp75), the associated protein Voltage Dependent Anion Channel (VDAC)1 and the Mitochondrial Calcium Uniporter (MCU), which together facilitate ER calcium transfer and uptake into the mitochondria. Endogenous Notch1 is detected in immune-complexes with Grp75 and VDAC1. Deficits in mitochondrial oxidative and survival in Notch1 deficient Tregs, were corrected by the expression of recombinant Notch1 intracellular domain, and in part by recombinant Grp75. Thus, the modulation of calcium dynamics and consequently mitochondrial metabolism underlies Treg survival in conditions of nutrient stress. This work positions a key role for Notch1 activity in these outcomes.

The spinal cord in lightning injury: a report of two cases.

We present 2 patients in whom the predominant neurological complication following lightning strike was spinal cord injury. One patient, who was followed for 5 years, showed clinical, electrophysiologic and MRI evidence of cervical spinal cord injury. This patient had significant recovery, which in part, may be related to early and intense rehabilitation. The second patient presented with the symptoms and signs of spinal shock which then evolved into a myelopathy. Follow-up several months later showed almost complete resolution of symptoms. These patients demonstrate that the prognosis of spinal cord injury complicating a lightning strike may not be uniformly poor.

Clinically significant but unsuspected restless legs syndrome in patients with sleep apnea.

In this prospective study, the prevalence of clinically significant restless legs syndrome (RLS) with symptoms at least 2 to 3 days per week was 8.3% in 60 sequentially polysomnographically studied patients with clinically significant sleep apnea (Apnea Index score > 5 or Respiratory Disturbance Index score > 10). Age-matched spouses were used as a control group and showed a comparable prevalence of RLS at 2.5% (not significant). Although RLS appears to be only slightly more common in sleep apnea patients than in controls, the importance of this study lies in the fact that clinically significant RLS occurred in 1 of every 12 patients with sleep apnea and, in every case, the RLS was unsuspected before polysomnography. We recommend that all patients undergoing polysomnography to rule out sleep apnea be screened for the symptoms of RLS. We have found the MEMO-NIH consensus conference questionnaire administered at the time of polysomnography to be useful in this regard.