BIOE 402. Medical Technology Assessment. 2 or 3 hours. Bioentrepreneur course. Assessment of medical technology in the context of commercialization. Objectives, competition, market share, funding, pricing, manufacturing, growth, and intellectual property; many issues unique to biomedical products. Course Information: 2 undergraduate hours. 3 graduate hours. Prerequisite(s): Junior standing or above and consent of the instructor.

“Bioinformatics” 특집을 내면서

中枢神経系疾患の治療は正常細胞（ニューロン）の機能維持を目的とするが，脳血管障害のように機能障害の原因が細胞の死滅に基づくことは多い．一方，脳腫瘍の治療においては薬物療法や放射線療法といった腫瘍細胞の死滅を目標とするものが大きな位置を占める．いずれの場合にも，細胞死の機序を理解することは各種病態や治療法の理解のうえで重要である．現在のところ最も研究の進んでいる細胞死の型はアポトーシスである．そのなかで重要な位置を占めるミトコンドリアにおける反応および抗アポトーシス因子について概要を紹介する．

Neuroscience 細胞死：最近の知見

Breathing hyperbaric oxygen (HBO) is common practice in hyperbaric and diving medicine. The benefits of breathing HBO, however, are limited by the risk of central nervous system O2 toxicity, which presents as seizures. We tested the hypothesis that excitability increases in CA1 neurons of the rat hippocampal slice (400 microm) over a continuum of hyperoxia that spans normobaric and hyperbaric pressures. Amplitude changes of the orthodromic population spike were used to assess neuronal O2 sensitivity before, during, and following exposure to 0, 0.6, 0.95 (control), 2.84, and 4.54 atmospheres absolute (ATA) O2. Polarographic O2 electrodes were used to measure tissue slice PO2 (PtO2). In 0.95 ATA O2, core PtO2 at 200 microm deep was 115±16 Torr (mean±SE). Increasing O2 to 2.84 and 4.54 ATA increased core PtO2 to 1,222±77 and 2,037±157 Torr, respectively. HBO increased the orthodromic population spike amplitude and usually induced hyperexcitability (i.e., secondary population spikes) and, in addition, a long-lasting potentiation of the orthodromic population spike that we have termed "oxygen-induced potentiation" (OxIP). Exposure to 0.60 ATA O2 and hypoxia (0.00 ATA) decreased core PtO2 to 84±6 and 20±4 Torr, respectively, and abolished the orthodromic response. Reoxygenation from 0.0 or 0.6 ATA O2, however, usually produced a response similar to that of HBO: hyperexcitability and activation of OxIP. We conclude that CA1 neurons exhibit increased excitability and neural plasticity over a broad range of PtO2, which can be activated by a single, hyperoxic stimulus. We postulate that transient acute hyperoxia stimulus, whether caused by breathing HBO or reoxygenation following hypoxia (e.g., disordered breathing), is a powerful stimulant for orthodromic activity and neural plasticity in the CA1 hippocampus.

Hyperbaric hyperoxia and normobaric reoxygenation increase excitability and activate oxygen-induced potentiation in CA1 hippocampal neurons

Pressure above 1.1 MPa induces in mammals and humans the high pressure neurological syndrome (HPNS). HPNS is characterized by cognitive and motor decrements associated with sleep disorders, EEG changes, tremor, and convulsions that ultimately may lead to death. Previous theories proposed that augmented response of the glutamatergic N-methyl-D-aspartate receptor (NMDAR) or reduced GABAergic inhibition may be involved. Recently, we have reported that isolated NMDAR response was augmented at high pressure. We now test whether this augmentation induces neuronal hyperexcitability. We studied high pressure effects on pharmacologically isolated NMDAR field excitatory postsynaptic potentials (fEPSPs) and on their efficacy in generating population spikes (PSs). Sprague-Dawley male rats were used. Hippocampal coronal brain slices were prepared, constantly superfused with physiological solutions, gas-saturated at normobaric pressure, and compressed up to 10.1 MPa with helium. fEPSPs and PSs were recorded from the dendritic and the somatic layers of CA1 pyramidal neurons in response to Schaefer collaterals stimulation with trains of five stimuli at 25 Hz. Pressure caused PSs to appear earlier in the train. However, PS delay, rise time and decay time were increased and PS amplitude, frequency, and number were decreased in the last responses in the train. The decrease in late fEPSPs was associated with a reduction of the total number of PSs in the train, apparently without a change in the synaptic efficacy. These results may partially explain the neuronal hyperexcitability observed at pressure. Therefore, it is postulated that significant hyperexcitability is attained at pressure only when the normal fast fEPSP is intact.

High pressure modulation of NMDA receptor dependent excitability

Little is known about the ecological and physiological processes governing depth distribution limits in species. Temperature and hydrostatic pressure are considered to be two dominant factors. Research has shown that some marine ectotherms are shifting their bathymetric distributions in response to rapid anthropogenic ocean surface warming. Shallow-water species unable to undergo latitudinal range shifts may depend on bathymetric range shifts to seek refuge from warming surface waters. As a first step in constraining the molecular basis of pressure tolerance in shallow water crustaceans, we examined differential gene expression in response to acute pressure and temperature exposures in juveniles of the shallow-water shrimp Palaemonetes varians. Significant increases in the transcription of genes coding for an NMDA receptor-regulated protein, an ADP ribosylation factor, β-actin, two heat shock protein 70 kDa isoforms (HSP70), and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) were found in response to elevated pressure. NMDA receptors have been implicated in pathways of excitotoxic damage to neurons and the onset of high pressure neurological syndrome (HPNS) in mammals. These data indicate that the sub-lethal effects of acute barotrauma are associated with transcriptional disturbances within the nervous tissue of crustaceans, and cellular macromolecular damage. Such transcriptional changes lead to the onset of symptoms similar to that described as HPNS in mammals, and may act as a limit to shallow water organisms' prolonged survival at depth.

Acute combined pressure and temperature exposures on a shallow-water crustacean: novel insights into the stress response and high pressure neurological syndrome.

In humans, hyperbaric pressure induces the high-pressure neurological syndrome (HPNS). HPNS is characterized by tremor, sleep disorders, electroencephalographic changes, and impairment of cognitive and motor performances. In animals, higher pressures result in convulsions and death. An increased N-methyl-d-aspartate receptor (NMDAR) response has been implicated with HPNS. We studied high-pressure effects on pharmacologically isolated NMDAR field excitatory postsynaptic potentials (fEPSPs). Hippocampal coronal brain slices from male Sprague-Dawley rats were prepared, constantly superfused with physiological solutions, gas-saturated at normobaric pressure and compressed up to 10.1 MPa with helium. fEPSPs were recorded from the dendritic layer of CA1 pyramidal neurones. High pressure significantly increased the single fEPSP delay, maximal initial slope, amplitude, decay time and time integral (elevated Na(+) and Ca(2+) influx) despite the known general decrease in glutamatergic synaptic release. The estimated negative and positive activation volumes (DeltaV*) for various kinetic segments of the fEPSP suggest a complex response of the receptor to pressure. The NMDAR frequency response was tested by a train of five stimuli. At 50-100 Hz, high pressure did not increase the fEPSPs' frequency-dependent depression and the train's time integral remained unchanged. At 25 Hz, pressure induced a larger frequency-dependent depression and significantly increased the time integral. Our results provide, for the first time, direct information on the isolated brain NMDAR response under hyperbaric conditions. These observations may explain some increase in the excitability of single normal glutametergic fEPSPs and their frequency responses.

Modulation of isolated N-methyl-d-aspartate receptor response under hyperbaric conditions.

Professional deep-water divers exposed to high pressure (HP) above 1.1 MPa suffer from High Pressure Neurological Syndrome (HPNS), which is associated with CNS hyperexcitability. We have previously reported that HP augments N-methyl-D-aspartate receptor (NMDAR) synaptic responses, increases neuronal excitability, and potentially causes irreversible neuronal damage. We now report that HP (10.1 MPa) differentially affects eight specific NMDAR subtypes. GluN1(1a or 1b) was co-expressed with one of the four GluN2(A-D) subunits in Xenopus laevis oocytes. HP increased ionic currents (measured by two electrode voltage clamps) of one subtype, reduced the current in four others, and did not affect the current in the remaining three. 3D theoretical modeling was aimed at revealing specific receptor domains involved with HP selectivity. In light of the information on the CNS spatial distribution of the different NMDAR subtypes, we conclude that the NMDAR’s diverse responses to HP may lead to selective HP effects on different brain regions. These discoveries call for further and more specific investigation of deleterious HP effects and suggest the need for a re-evaluation of deep-diving safety guidelines.

/pdf/pressure-selective-modulation-of-nmda-receptor-subtypes-may-4nd94q884e.pdf

Pressure-selective modulation of NMDA receptor subtypes may reflect 3D structural differences

Pressure Effects on Mammalian Central Nervous System

High pressure, which induces central nervous system (CNS) dysfunction (high-pressure neurological syndrome) depresses synaptic transmission at all synapses examined to date. Several lines of eviden...

Amir Mor

Papers

High pressure modulation of NMDA receptor dependent excitability

Modulation of isolated N-methyl-d-aspartate receptor response under hyperbaric conditions.

Pressure-selective modulation of NMDA receptor subtypes may reflect 3D structural differences

Pressure Effects on Mammalian Central Nervous System

Differential modulation of cerebellar climbing fiber and parallel fiber synaptic responses at high pressure