Amine N. Issa

Neuregulin-1 at synapses on phrenic motoneurons.

The neuregulin (NRG) family of trophic factors is present in the central and peripheral nervous systems and participates in the survival, proliferation, and differentiation of many different cell types, including motoneurons. NRG1 was first characterized by its role in the formation of the neuromuscular junction, and recently it was shown to play a crucial role in modulating glutamatergic and cholinergic transmission in the central nervous system of adult rats. However, little is known about NRG1s role in adult motor systems. Motoneurons receive dense glutamatergic and cholinergic input. We hypothesized that NRG1 is present at synapses on phrenic motoneurons. Confocal microscopy and 3D reconstruction techniques were used to determine the distribution of NRG1 and its colocalization with these different neurotransmitter systems. We found that NRG1 puncta are present around retrogradely labeled motoneurons and are distributed predominantly at motoneuron somata and primary dendrites. NRG1 is present exclusively at synaptic sites (identified using the presynaptic marker synaptophysin), making up ∼30% of all synapses at phrenic motoneurons. Overall, NRG1 immunoreactivity is found predominantly at cholinergic synapses (75% ± 14% colocalize with the vesicular acetylcholine transporter; VAChT). Nearly all (99% ± 1%) VAChT‐immunoreactive synapses expressed NRG1. NRG1 also is present at a subset of glutamatergic synapses expressing the vesicular glutamate transporter (VGLUT) type 2 (∼6%) but not those expressing VGLUT type 1. Overall, 26% ± 6% of NRG1 synapses are VGLUT2 immunoreactive. These findings provide the first evidence suggesting that NRG1 may modulate synaptic activity in adult motor systems. J. Comp. Neurol. 518:4213–4225, 2010.

Ambulatory arterial stiffness index is not correlated with the pressor response to laboratory stressors in normotensive humans

Background Ambulatory arterial stiffness index (AASI) is a novel estimate of arterial stiffness, which independently predicts cardiovascular mortality, even in normotensive individuals. Additionally, other markers derived from ambulatory blood pressure (BP) monitoring, including variability, pulse pressure, nocturnal dipping, and morning BP surge, have all been shown to be predictive of end-organ damage and cardiovascular disease. Exaggerated cardiovascular reactivity to sympathoexcitatory stimuli may also predict future incidence of hypertension. The purpose of this investigation was to test the hypothesis that AASI and other derivations of ambulatory BP, including pulse pressure, 24-h blood pressure variability, dipping, and morning surge, would be correlated with the pressor response to common physiological stress maneuvers. Method We measured continuous heart rate and arterial BP during head-up tilt, mental stress, cold pressor test, and isometric handgrip to fatigue in 67 healthy, normotensive, nonobese individuals (43 women, 24 men, mean age ± SD: 28 ± 6 years). Then, 24-h ambulatory BP was obtained, and AASI was defined as 1 minus the slope of diastolic on systolic BP in individual 24-h ambulatory BP recordings. Results Although all measures were widely variable among patients, there was no relationship between AASI, pulse pressure, blood pressure variability, dipping, and morning surge with the pressor responses. Conclusion We conclude that in the absence of aging, cardiovascular, or autonomic disease, the novel stiffness index (AASI) or other ambulatory BP indices are either poorly correlated with or mechanistically unrelated to the complex pressor response to common provocations of sympathoexcitation.

Association of Cognitive Performance with Time at Altitude, Sleep Quality, and Acute Mountain Sickness Symptoms

OBJECTIVE It is well documented that cognitive performance may be altered with ascent to altitude, but the association of various cognitive performance tests with symptoms of acute mountain sickness (AMS) is not well understood. Our objective was to assess and compare cognitive performance during a high-altitude expedition using several tests and to report the association of each test with AMS, headache, and quality of sleep. METHODS During an expedition to Mount Everest, 3 cognitive tests (Stroop, Trail Making, and the real-time cognitive assessment tool, an in-house developed motor accuracy test) were used along with a questionnaire to assess health and AMS. Eight team members were assessed pre-expedition, postexpedition, and at several time points during the expedition. RESULTS There were no significant differences (P >.05) found among scores taken at 3 time points at base camp and the postexpedition scores for all 3 tests. Changes in the Stroop test scores were significantly associated with the odds of AMS (P <.05). The logistic regression results show that the percent change from baseline for Stroop score (β = -5.637; P = .032) and Stroop attempts (β = -5.269; P = .049) are significantly associated with the odds of meeting the criteria for AMS. CONCLUSIONS No significant changes were found in overall cognitive performance at altitude, but a significant relationship was found between symptoms of AMS and performance in certain cognitive tests. This research shows the need for more investigation of objective physiologic assessments to associate with self-perceived metrics of AMS to gauge effect on cognitive performance.

Real-time effects of normobaric, transient near-anoxia on performance.

INTRODUCTION Recent physiological incidents involving pilots of high performance fighter aircraft have raised the question of whether inadvertent, short bursts of significantly reduced oxygen could negatively impact real-time performance. This study evaluated normobaric, real-time performance in the setting of transient near-anoxia to inform future countermeasure development. METHODS The study was performed on 12 healthy subjects without significant medical history. Following collection of baseline data, real-time performance changes were evaluated during sequentially increasing periods of near-anoxic gas exposure (F(I)0(2) = 1%) using a computer-based performance assessment tool. Both room air and 100% oxygen were used as the prebreathe/recovery gases. Statistical analysis was performed on the results. RESULTS Under normobaric conditions, subjects inspiring up to five near-anoxic breaths showed no significant performance decrement in either accuracy or effective actions per minute. Mean accuracy up to five near-anoxic breaths was 0.67 (SD = 0.01) as compared to a baseline mean of 0.68 (SD = 0.02). Hyperoxia had a protective effect on subject physiological response to near anoxia. DISCUSSION These normobaric findings offer an assessment of real-time performance changes in the setting of transient, near-anoxic gas exposure. Overall, the results help inform the design of increasingly complex aircraft oxygen delivery systems in terms of how tightly such systems must match the sea-level gas equivalent with increasing altitude. This is particularly relevant as such systems are being called upon to ensure safe aircrew operations across an expanding operational flight envelope.

Exhaled Nitric Oxide Changes During Acclimatization to High Altitude: A Descriptive Study

Summerfield, Douglas T., Kirsten E. Coffman, Bryan J. Taylor, Amine N. Issa, and Bruce D. Johnson. Exhaled nitric oxide changes during acclimatization to high altitude: a descriptive study. High Alt Med Biol. 19:215-220, 2018. AIMS This study describes differences in the partial pressures of exhaled nitric oxide (PeNO) between subjects fully acclimatized (ACC) to 5300 m and those who have just arrived to high altitude. METHODS PeNO was determined in eight subjects newly exposed and nonacclimatized (non-ACC) to high altitude and compared with that in nine subjects who had ACC to high altitude for 1 month. In addition, systolic pulmonary artery pressure (sPAP) and arterial oxygen saturation (SaO2) were measured in all participants. These measurements were repeated in the non-ACC group 5 and 9 days later. RESULTS PeNO levels on day 1 were significantly higher in the non-ACC versus ACC cohort (8.7 ± 3.5 vs. 3.9 ± 2.2 nmHg, p = 0.004). As the non-ACC group remained at altitude, PeNO levels fell and were not different when compared with those of the ACC group by day 9 (5.9 ± 2.4 vs. 3.9 ± 2.2 nmHg, p = 0.095). Higher sPAP was correlated with lower PeNO levels in all participants (R = -0.50, p = 0.043). PeNO levels were not correlated with SaO2. CONCLUSIONS As individuals acclimatized to high altitude, PeNO levels decreased. Even after acclimatization, PeNO levels continued to play a role in pulmonary vascular tone.

Interstitial lung fluid balance in healthy lowlanders exposed to high-altitude

We aimed to assess lung fluid balance before and after gradual ascent to 5150m. Lung diffusion capacity for carbon monoxide (DLCO), alveolar-capillary membrane conductance (DmCO) and ultrasound lung comets (ULCs) were assessed in 12 healthy lowlanders at sea-level, and on Day 1, Day 5 and Day 9 after arrival at Mount Everest Base Camp (EBC). EBC was reached following an 8-day hike at progressively increasing altitudes starting at 2860m. DLCO was unchanged from sea-level to Day 1 at EBC, but increased on Day 5 (11±10%) and Day 9 (10±9%) vs. sea-level (P≤0.047). DmCO increased from sea-level to Day 1 (9±6%), Day 5 (12±8%), and Day 9 (17±11%) (all P≤0.001) at EBC. There was no change in ULCs from sea-level to Day 1, Day 5 and Day 9 at EBC. These data provide evidence that interstitial lung fluid remains stable or may even decrease relative to at sea-level following 8days of gradual exposure to high-altitude in healthy humans.