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Dyspnea is defined as a subjective experience of breathing discomfort that consists of qualitatively distinct sensations that vary in intensity. It is a common symptom among patients with respiratory diseases that reduces daily activities, induces deconditioning, and is self-perpetuating. Although clinical interventions are needed to reduce dyspnea, its underlying mechanism is poorly understood depending on the intertwined peripheral and central neural mechanisms as well as emotional factors. Nonetheless, experimental and clinical observations suggest that dyspnea results from dissociation or a mismatch between the intended respiratory motor output set caused by the respiratory neuronal network in the lower brainstem and the ventilatory output accomplished. The brain regions responsible for detecting the mismatch between the two are not established. The mechanism underlying the transmission of neural signals for dyspnea to higher sensory brain centers is not known. Further, information from central and peripheral chemoreceptors that control the milieu of body fluids is summated at higher brain centers, which modify dyspneic sensations. The mental status also affects the sensitivity to and the threshold of dyspnea perception. The currently used methods for relieving dyspnea are not necessarily fully effective. The search for more effective therapy requires further insights into the pathophysiology of dyspnea.

The hypothalamus is a higher center of the autonomic nervous system and maintains essential body homeostasis including respiration. The paraventricular nucleus, perifornical area, dorsomedial hypothalamus, and lateral and posterior hypothalamus are the primary nuclei of the hypothalamus critically involved in respiratory control. These hypothalamic nuclei are interconnected with respiratory nuclei located in the midbrain, pons, medulla and spinal cord. We provide an extensive review of the role of the above hypothalamic nuclei in the maintenance of basal ventilation, and modulation of respiration in hypoxic and hypercapnic conditions, during dynamic exercise, in awake and sleep states, and under stress. Dysfunction of the hypothalamus causes abnormal breathing and hypoventilation. However, the cellular and molecular mechanisms how the hypothalamus integrates and modulates autonomic and respiratory functions remain to be elucidated.

Astrocytes are thought to play a crucial role in providing structure to the spinal cord and maintaining efficient synaptic function and metabolism because their fine processes envelop the synapses of neurons and form many neuronal networks within the central nervous system (CNS). To investigate whether putative astrocytes and putative neurons distributed on the ventral horn play a role in the modulation of lumbar locomotor central pattern generator (CPG) networks, we used extracellular recording and optical imaging techniques and recorded the neural output from the left L5 ventral root and the calcium activity of putative astrocytes and neurons in the L5 ventral horn at the same time when activating an isolated L1-L5 spinal cord preparation from rats aged 0-2 days. Optical measurements detected cells that showed a fluorescence intensity change under all experimental conditions, namely, (1) 5-HT + NMDA, (2) TTX, and (3) TTX + Low K

ATP-sensitive potassium (KATP) channels consist of two structurally different subunits: a pore-forming subunit of the Kir6.0-family (Kir6.1 or Kir6.2) and a regulatory sulfonylurea receptor subunit (SUR1, SUR2A or SUR2B). Although Kir6.2 is widely distributed in the brain, the mechanisms that underlie the impact of Kir6.2 on emotional behavior are not yet fully understood. To clarify the role of Kir6.2 in emotional behavior, in the present study, we investigated the behavioral characteristics of Kir6.2-knockout (Kir6.2-/-) mice. Kir6.2-/- mice showed impaired general behavior in a locomotor activity test and open field test. In addition, anxiety-like behavior was observed in the open field test, elevated plus-maze test and light-dark test. In particular, excessive anxiety-like behavior was observed in female Kir6.2-/- mice. Moreover, we investigated whether Kir6.2 is expressed on monoamine neurons in the brain. Immunohistochemical studies showed that Kir6.2 was co-localized with tryptophan hydroxylase (TPH), a marker of serotonergic neurons, in dorsal raphe nuclei. Kir6.2 was also co-localized with tyrosine hydroxylase (TH), a marker of dopaminergic/noradrenergic neurons, in the ventral tegmental area and locus coeruleus. Next, we checked the protein levels of TH and TPH in the midbrain. Interestingly, TPH expression was significantly elevated in female Kir6.2-/- mice. These results suggest that Kir6.2 in monoamine neurons, especially serotonergic neurons, could play a key role in emotional behavior.

Summary Hypoxia sensors are essential for regulating local oxygen (O2) homeostasis within the body. This is especially pertinent within the CNS, which is particularly vulnerable to O2 deprivation due to high energetic demand. Here, we reveal hypoxia-monitoring function exerted by astrocytes through an O2-regulated protein trafficking mechanism within the CNS. Strikingly, cultured mouse astrocytes isolated from the parafacial respiratory group (pFRG) and retrotrapezoid nucleus (RTN) region are capable of rapidly responding to moderate hypoxia via the sensor cation channel transient receptor potential (TRP) A1 but, unlike multimodal sensory neurons, are inert to hyperoxia and other TRPA1 activators (carbon dioxide, electrophiles, and oxidants) in normoxia. Mechanistically, O2 suppresses TRPA1 channel activity by protein internalization via O2-dependent proline hydroxylation and subsequent ubiquitination by an E3 ubiquitin ligase, NEDD4-1 (neural precursor cell-expressed developmentally down-regulated protein 4). Hypoxia inhibits this process and instantly accumulates TRPA1 proteins at the plasma membrane, inducing TRPA1-mediated Ca2+ influx that triggers ATP release from pFRG/RTN astrocytes, potentiating respiratory center activity. Furthermore, astrocyte-specific Trpa1 disruption in a mouse brainstem-spinal cord preparation impedes the amplitude augmentation of the central autonomic respiratory output during hypoxia. Thus, reversible coupling of the TRPA1 channels with O2-dependent protein translocation allows astrocytes to act as acute hypoxia sensors in the medullary respiratory center.

Background and objective Body weight of patients with obstructive sleep apnea after initiation of nasal continuous positive airway pressure appears to increase. We hypothesized that intermittent hypoxia (IH) will decrease energy expenditure (EE), and that normoxic recovery will lead to body weight gains. Methods C57BL/6 J male mice were exposed to either 12 h/day of mild IH (alternating FIO2-10-11% and 21%; 640 s cycle), or severe IH (FIO2-6-7%-21%; 180 s cycle) or sham IH daily for 4 or 8 weeks. After exposures, EE was evaluated while mice were kept under normoxia for 5 weeks and organ histology was evaluated. Results EE was not decreased by IH. However, visceral white adipocyte size after normoxic recovery was significantly increased in severe IH in an intensity-dependent manner. Conclusion Our hypothesis that IH would decrease EE was not corroborated. However, IH and normoxic recovery seem to promote severity-dependent enlargement of visceral adipocytes, likely reflecting altered energy preservation mechanisms induced by IH.

The pre-Bötzinger complex (preBötC) of the ventrolateral medulla is the kernel for inspiratory rhythm generation. However, it is not fully understood how inspiratory neural activity is generated in the preBötC and propagates to other medullary regions. We analyzed the detailed anatomical connectivity to and from the preBötC and functional aspects of the inspiratory information propagation from the preBötC on the transverse plane of the medulla oblongata. Tract-tracing with immunohistochemistry in young adult rats demonstrated that neurokinin-1 receptor- and somatostatin-immunoreactive neurons in the preBötC, which could be involved in respiratory rhythmogenesis, are embedded in the plexus of axons originating in the contralateral preBötC. By voltage-imaging in rhythmically active slices of neonatal rats, we analyzed origination and propagation of inspiratory neural activity as depolarizing wave dynamics on the entire transverse plane as well as within the preBötC. Novel combination of pharmacological blockade of glutamatergic transmission and mathematical subtraction of the video images under blockade from the control images enabled to extract glutamatergic signal propagations. By ultra-high-speed voltage-imaging we first demonstrated the inter-preBötC conduction process of inspiratory action potentials. Intra-preBötC imaging with high spatiotemporal resolution during a single spontaneous inspiratory cycle unveiled deterministic nonlinearities, i.e., chaos, in the population recruitment. Collectively, we comprehensively elucidated the anatomical pathways to and from the preBötC and dynamics of inspiratory neural information propagation: (1) From the preBötC in one side to the contralateral preBötC, which would synchronize the bilateral rhythmogenic kernels, (2) from the preBötC directly to the bilateral hypoglossal premotor and motor areas as well as to the nuclei tractus solitarius, and (3) from the hypoglossal premotor areas toward the hypoglossal motor nuclei. The coincidence of identified anatomical and functional connectivity between the preBötC and other regions in adult and neonatal rats, respectively, indicates that this fundamental connectivity is already well developed at the time of birth.

Ventilatory responses to opioids are complex and not yet fully understood. We evaluated concentration-dependent effects of a selective μ-opioid receptor agonist [ d -Ala(2),N-Me-Phe(4),Gly(5)-ol]-enkephalin (DAMGO) on respiratory output in the arterially perfused in situ rat preparation, which preserves the integrity of the ponto-medullary respiratory network. DAMGO (300–3400 nM) was added accumulatively to the perfusate. DAMGO increased inspiratory time and diminished central vagal post-inspiratory activity. At 300–500 nM DAMGO caused rapid breathing with shortening of expiratory time. The change of breathing pattern occurred within a single breath. Bilateral vagotomy did not affect the change in respiratory pattern, suggesting that it was of central origin. Additional DAMGO up to 1800 nM did not affect the rapid breathing pattern, and further elevated concentrations (up to 3400 nM) caused inconsistent results. Since the rapid breathing pattern was associated with the obliteration of vagal post-inspiratory activity, we conclude that DAMGO reconfigures the respiratory output to an inspiratory phase-dominant, rapidly alternating inspiration–expiration pattern.

Introduction Since the invention of the pulse oximeter, physicians often or even routinely perform venous blood gas analysis (VBGA). However, it has not been generally agreed that the application of VBGA is practically meaningful in routine clinical situations such as in an ED. Methods We measured venous-arterial P co 2 difference ((v-a)P co 2) and arterial-venous pH difference ((a-v)pH), and analyzed the physiological factors that affect these differences in healthy volunteers and hyperventilation patients. Results In healthy volunteers, both (v-a)P co 2 and (a-v)pH increased during finger exercise or hyperventilation in an intensity-dependent manner. Doppler echography indicated that increases in (v-a)P co 2 and (a-v)pH during hyperventilation are induced by reduction of peripheral blood flow. Approximately 40% of patients with untreated respiratory alkalosis were found to be incorrectly diagnosed if based only on VBGA. Conclusions It must be noted that VBGA may lead to overestimation of acidosis and to underestimation of respiratory alkalosis when extremities muscles are active or patients are hyperventilating. Physicians should keep these limitations in mind when conducting VBGA.

In order to examine whether ATP-sensitive potassium channel Kir6.2 is involved in hypoxic ventilatory responses, especially in hypoxic ventilatory depression (HVD), and whether the involvement shows age-dependence, we measured the hypoxic ventilatory response in the Kir6.2-knockout mouse (Kir6.2−/−) in an unanesthetized unrestrained state by means of pressure plethysmography in the 2nd and 4th postnatal weeks, and compared the response with that of its wild type counterpart, the C57BL6/J mouse. In the 4th postnatal week, but not in the 2nd week, the Kir6.2−/− exhibited a larger and longer initial augmentation and a weaker subsequent depression of respiratory frequency and ventilation in response to hypoxia (FIO 2 = 0.12 in N 2 ). These findings suggest that Kir6.2 is involved in HVD of the mouse at a certain point during the postnatal development.

Although neuromuscular blocking agents (NMBAs) function as muscular nicotinic acetylcholine receptor (nAChR) antagonists, several studies have shown that they block neuronal nAChRs as well, which led us to hypothesize that these agents can affect neuronal nAChRs expressed in respiratory centers. To test this hypothesis, we studied the effects of two NMBAs on respiratory activity and respiratory neurons in brainstem-spinal cord preparations from neonatal rats. The application of either D-tubocurarine or vecuronium resulted in dose-dependent reductions in C4 respiratory rate. These reductions were concomitant with reductions in the depolarizing cycle rate of inspiratory (Insp) neurons; the depolarizing cycle rate of preinspiratory (Pre-I) neurons, however, was not affected. We also detected C4 burst activity during the depolarizing phase in Pre-I neurons, even during NMBA-induced respiratory depression. Both NMBAs inhibited drive potential amplitude and intraburst firing frequency in Insp and Pre-I neurons. These agents also induced a hyperpolarization and an increase in membrane resistance in Pre-I neurons, however they had no effect on these membrane properties in Insp neurons. Our findings indicate that these agents suppress central respiratory activity mainly through their inhibitory effects on Pre-I neurons and the Pre-I to Insp neuron synaptic drive, and that nAChRs are involved in central respiratory control.

To examine the role of GABA in the respiratory rhythm and pattern generation in neonatal mice, we analyzed the function of the respiratory control system of 67-kDa isoform of glutamic acid decarboxylase (GAD67)-deficient neonatal mice. In these mutant (GAD67-/-) mice, GABA levels in the brainstem were reduced to about 30% of those in wild-type (GAD67+/+) mice. In in vivo preparations, ventilatory parameters were analyzed by whole body plethysmography and electromyography of intercostal muscles. GAD67-/- mice exhibited abnormal respiratory patterns, i.e. irregular respiratory rhythm, and periodic gasp-like respiration followed by shallow breathing with short inspiratory duration and apnea. In in vitro GAD67-/- brainstem-spinal cord preparations, inspiratory C4 burst duration was shorter than that in GAD67+/+ preparations. Whole cell recordings revealed that activities of inspiratory neurons in the ventral medulla of GAD67-/- mice were characterized by a short depolarization period and a paucity of firing during the inspiratory phase. Superfusion of the in vitro GAD67-/- preparation with 10 microM GABA prolonged C4 burst duration and partly restored a normal pattern of inspiration, although the restoration was limited. These results indicate that reduced GABA levels during the perinatal period induce malfunction in the respiratory control system. We suggest that GABAergic transmission is not essential for basic respiratory rhythm generation but plays an important role in the maintenance of regular respiratory rhythm and normal inspiratory pattern in neonatal mice.

We reviewed the previous reports on the fine anatomy of the mammalian ventral medulla with special attention to the cytoarchitecture of the superficial chemosensitive regions to summarize what is known, what is not yet known, and what should be studied in the future. We also reviewed studies on anatomical relationship between neurons and vessels, and morphological studies on dendrites of respiratory or chemosensitive neurons. When we compared the morphological reports on the ventral and dorsal putative chemosensitive regions, similarities were found as follows. Chemosensitive cells were often found not only near the ventral surface but near the dorsal surface of the brainstem. Dendritic projection towards the surface was a common characteristic in the ventral and dorsal chemosensitive neurons. Morphological abnormality in the brainstem of sudden infant death syndrome victims was also summarized. On the basis of the previous reports we discussed the perspective on the future study on central chemoreception. Among various unanswered questions in central chemosensitivity studies, physiological significance of surface cells and surface extending dendrites is the most important topic, and must be thoroughly investigated.

We have measured the precise lattice parameter of undoped and impurity-doped ZnSe single crystals by the Fewster method. The lattice parameter of undoped ZnSe single crystals was 0.566919±0.000002 nm and it remained unchanged after the Zn-treatment at 1000°C. On the other hand, dilation of lattice parameter observed in I-doped ZnSe depended on Zn-treatment temperature. Increase of lattice parameter also occurred in Al-doped ZnSe. These results suggest that I and Al impurities in ZnSe crystal play an important role with point defects formation during and after the Zn heat treatment.

Lattice parameters of annealed ZnSe crystals have been measured by the Bond method. The annealing was carried out at 1000°C under a definite Zn partial pressure maintained by heating a Zn reservoir after growth from the melt under Zn partial pressure. The lattice parameter, a , depends on the Zn reservoir temperature during annealing, T Zn (A); a =0.566898±0.000005 nm at T Zn (A) of 450–600°C, a =0.566910±0.000005 nm at T Zn (A) of 750°C and a =0.566913±0.000003 nm at T Zn (A) of 900°C. The dependence of lattice parameter on Zn partial pressure is discussed.

Dependence of the lattice parameter of melt-grown ZnSe on Zn partial pressure have been measured by the Bond method. The lattice parameters changed between 0.566902 and 0.566908 nm depending on the partial pressure of Zn during growth. The minimum lattice parameter was observed at the Zn reservoir temperature of 1000°C, where the melt composition was near stoichiometry.

The refractive indices and lattice constants of large KTP single crystals grown from a flux of K 6 P 4 O 13 have been investigated. Changes in their refractive index and lattice constant along the growth direction result from compositional deviation of the solution. Strong correlation is implied in the similar behavior of both the lattice constant and the refractive index. The lattice constant dependence on the compositional deviation seems to be due to variations in the solid solution range among the KTP components.

LiNbO3 films of higher crystalline quality than underlying LiNbO3 substrates have been successfully grown from a solid-liquid coexisting melt using a new liquid phase epitaxial technique. The dependence of crystallinity and lattice mismatch on film thickness and growth temperature has been investigated in detail through X-ray rocking curve analysis.

This article reports the notable effect of N doping in ZnSe on the band-gap energy. The free exciton energy in the epilayers with different N A − N D was measured by means of reflectance and photoreflectance spectroscopies. The temperature dependence of reflectance, photoreflectance and photoluminescence spectra of ZnSe:N epilayers was investigated in detail. It is found that the free exciton energy shifts to low energy side with increasing N concentration, indicating the shrinkage of the band-gap energy due to N doping. The peak positions of near-band-edge emissions shift to low energy side due to the shrinkage of energy gap. The lattice constant and the strain in N-doped ZnSe were measured by means of X-ray diffraction (XRD). The origins for the shrinkage of energy gap are discussed on the basis of the optical and XRD results.

We have used the isolated brainstem-spinal cord preparation of the neonatal rat to study the effects of theophylline on the ventilatory response to hypoxia. The brainstem-spinal cord was isolated from neonatal rats (0-4 days) and superfused with mock cerebrospinal fluid (CSF), equilibrated with a gas mixture (FO2, 0.90; FCO2, 0.02; FN2, 0.08; control CSF) at 27 degrees C. We recorded phrenic nerve discharge from C4 roots, using suction electrodes, and measured respiratory frequency (fR) and the amplitude of the integrated phrenic neurogram (integral of phr). We examined how theophylline and the specific adenosine antagonist, 8-p-sulfophenyltheophylline (SPT), modify the ventilatory response to hypoxia. The response during superfusion with hypoxic CSF (FO2, 0.06) consisted of a marked decrease in fR (to 60% of control) and a slight decline in integral of phr (to 85% of control). By contrast, in the presence of theophylline (30 mg/L = 165 microM) and SPT (5 mg/L = 15 microM) in the superfusate hypoxia reduced fR only moderately (to 87% of control) and exerted virtually no effect on integral of phr (105% of control). Theophylline and SPT attenuated the rate of decrease in fR and completely blocked the decrease in integral of phr. There was no difference between the effects of theophylline and those of SPT. The results suggest that theophylline attenuates hypoxic respiratory depression, and that this effect is mediated by the blockade of adenosine.

AlAs/Al/AlAs heterostructures are fabricated on (001)GaAs by molecular beam epitaxy (MBE) and migration enhanced epitaxy (MEE). The Al and successive AlAs layers are grown at room temperature by MBE and MEE, respectively, while the underlying AlAs layer is grown at 600°C by MBE. Single crystal Al layers are grown successfully. The epitaxy relationship of Al with the underlying AlAs layer is (011)[100]Al‖(001)[110]AlAs. Detailed RHEED analysis elucidates the lattice relaxation processes of Al on AlAs as well as the growth process. It is suggested that the initially deposited 2(1) ML thick Al layers occupy sublattice sites in the AlAs lattice with the same lattice spacing as AlAs on As- (Al-) stabilized AlAs and that the lattice relaxation and the formation of the fcc Al lattice is initiated during deposition of the 3rd (2nd) layer on As- (Al-) stabilized AlAs. The top AlAs layer is single crystalline and grows in an island growth mode. The observed epitaxy relationship of AlAs on Al is (001)[110]AlAs‖(011)[100]Al.

Peripheral airways of 2 mm or less in diameter were observed in 142 patients by means of an ultrathin bronchofiberscope measuring 1.8 mm in outside diameter. On the basis of the observed and photographed endoscopic findings, an endoscopic classification of peripheral airway lesions was proposed. The endoscopic findings showed changes in the bronchial wall consisting of reddening, pallor, absence of mucosal luster, edema, engorgement of blood vessels, irregular mucosal surface, and elevated mucosa. In the lumen, stenosis, obstruction, ectasis, and deformation due to pressure were recognized, in addition to excessive secretion and pigmentation as morphologic abnormalities or abnormal findings at bifurcation.

The effect of lattice deformation on optical properties and lattice parameters of ZnSe thin films, whose thickness ranges from 0.05 to 22 μm, grown by either atomic layer epitaxy or molecular beam epitaxy on (100)GaAs substrates, has been investigated. It is observed from the X-ray analysis that ZnSe layers thinner than 1μm suffer two-dimensional compressive stress due to the lattice misfit, while those thicker than ca. 1 μm suffer two-dimensional tensile stress due to the difference in the thermal expansion coefficients. It is found that the valence band structure of the epitaxial ZnSe film is modified considerably due to the residual stress. The energy shifts of excitonic emissions in the photoluminescence spectra and of exciton resonance dips in the reflectance spectra are consistent with the stress as investigated by X-ray analysis.

Heating-up of bulk As-T-Ge glass by switching has been visualized for various stages during the delay time. The voltage and the current have been also recorded. A comparison of these results with the resistivity-temperature characteristic presents an evidence for thermal pinching.

Lock-on (memory) and unlocking (memory-off) phenomena observed in semiconducting glass of As-Te-Ge system have been investigated by electrical and calorimetrical methods. It has been clarified that these phenomena are attributed to thermally induced phase transformations and that the conductive filament formed on As-Te-Ge glasses with high As concentration consists of degenerate As 2 Te 3 crystal.

Temperature dependence of the threshold voltage for switching phenomenon was measured in amorphous materials both of AsxTeyGe10 and AsxTeySi10 systems. A simple experimental relationship Vth = K. exp[ C. (Tg − T)] was obtained, where Vth = d.c. threshold voltage for switching, Tg = glass transition temperature. Constant K different values for each system, while constant C has the same value in both systems.