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Biomedical subjects

N S Cherniack

Publications and source records attributed to N S Cherniack.

At least 19 recordsLinked to original sources
PubMed2005

Causes of Cheyne-Stokes respiration.

Cheyne-Stokes respiration (CSR) is one of several types of unusual breathing with recurrent apneas (dysrhythmias). Reported initially in patients with heart failure or stroke, it was then recognized both in other diseases and as a component of the sleep apnea syndrome. CSR is potentiated and perpetuated by changing states of arousal that occur during sleep. The recurrent hypoxia and surges of sympathetic activity that often occur during the apneas may have serious health consequences. Heart failure and stroke are risk factors for sleep apnea. The recurrent apneas and intermittent hypoxia occurring with sleep apnea further damage the heart and brain. Although all breathing dysrhythmias do not have the same cause, instability in the feedback control involved in the chemical regulation of breathing is the leading cause of CSR. Mathematical models have helped greatly in the understanding of the causes of recurrent apneas.

Cheyne-Stokes Respiration↗
PubMed2001

The perception of dyspnea in patients with mild asthma.

BACKGROUND: Airway function, as assessed by standard spirometry, and the intensity of dyspnea reported by asthmatic patients correlate poorly. OBJECTIVE: This study tests the following two hypotheses: (1) that measures of the tendency of a patient to somatize will reduce the variation in the report of dyspnea not explained by airway function; and (2) that plethysmography is a better tool with which to estimate the degree of dyspnea associated with asthma. DESIGN: A prospective laboratory study carried out over one study session. PARTICIPANTS: Forty asthmatic subjects who had withheld bronchodilator (BD) therapy overnight. INTERVENTIONS: We performed spirometry, plethysmography, and an assessment of dyspnea (ie, modified Borg scale) on all subjects before and after they received BD therapy. Standard questionnaires pertaining to psychological state and trait were administered as well. RESULTS: The change in specific airway conductance with BD therapy correlated with a decline in the Borg score (r = 0.47; p = 0.007). By contrast, neither spirographic measures nor measures of static lung volumes correlated. Correlation with the Borg scale score was not improved by adding indexes of either somatization or psychological state or trait. CONCLUSION: The relief of dyspnea reported by patients with mild asthma after BD therapy is related to dilatation of the central airways.

Adult↗
PubMed2000

Intracellular pathways linking hypoxia to activation of c-fos and AP-1.

Organisms respond to hypoxia through detection of blood oxygen levels by sensors at peripheral chemoreceptors and by receptors in certain key cells of the body. The pathways over which peripheral chemoreceptor signals are transmitted to respiratory muscles are well established. However, the intracellular pathways that transmit hypoxic stimulus to gene activation are just being identified. Using anti-sense c-fos strategy, we have shown that c-fos is essential for the activation of activator protein-1 transcription factor complex (AP-1) and subsequent stimulation of downstream genes such as tyrosine hydroxylase (TH; Mishra et al. 1998). The purpose of the present study was to identify intracellular pathways that link hypoxia to activation of c-fos. The results of the present study show that hypoxia causes Ca2+ influx through L-type voltage gated Ca2+ channels and that hypoxia-induced c-fos gene expression is Ca2+/calmodulin dependent. We also demonstrate that hypoxia activates the extracellular-regulated kinase (ERK) and p38, but not JNK. Further, phosphorylation of ERK is essential for c-fos activation via SRE cis-element. Further characterization of nuclear signalling pathways provides evidence for the involvement of Src, a non receptor protein tyrosine kinase, and Ras, a small G protein, in the hypoxia-induced c-fos gene expression. These results suggest a possible role for non-receptor protein tyrosine kinases in propagating signals from G-protein coupled receptors to the activation of immediate early genes such as c-fos during hypoxia.

Animals↗
PubMed2000

Altered structure and function of the carotid body at high altitude and associated chemoreflexes.

The ventilatory response to hypoxia is complex. First contact with hypoxia causes an increase in ventilation within seconds that reaches full intensity within minutes because of an increase in carotid sinus nerve (CSN) input to the brain stem. With continued exposure, ventilation increases further over days (ventilatory acclimatization). Initially, it was hypothesized that ventilatory acclimatization arose from a central nervous system (CNS) mechanism. Compensation for alkalosis in the brain and restoration of pH in the vicinity of central chemoreceptors was believed to cause the secondary increase in ventilation. However, when this hypothesis could not be substantiated, attention was turned to the peripheral chemoreceptors. With the lowering of arterial PO2 at high altitude, there is an immediate increase in firing of afferents from chemoreceptors in the carotid body. After peaking over the next few minutes, the firing rate of afferents begins to rise again within hours until a steady state is reached. This secondary increase occurs along with increase in neurotransmitter synthesis and release and altered gene expression followed by hypertrophy of carotid body glomus cells. Further exposure to hypoxia eventually leads to blunting of the CSN output and ventilatory response in some species. This mini review is about the altered structure and function of the carotid body at high altitude and the associated blunting of the chemoreceptor and ventilatory responses observed in some species.

Acclimatization↗
PubMed2000

L-type Ca(2+) channel activation regulates induction of c-fos transcription by hypoxia.

In the present study we examined the intracellular pathways that link hypoxia to activation of c-fos gene expression. Experiments were performed on rat pheocromocytoma-12 (PC-12) cells. c-fos mRNA and promoter activities were analyzed by RT-PCR and reporter gene assays, respectively. BAPTA, a Ca(2+) chelator, inhibited c-fos mRNA and promoter activation by hypoxia. Nitrendipine, an L-type Ca(2+)-channel blocker, abolished, whereas BAY K 8644, an L-type channel agonist, enhanced c-fos activation by hypoxia. Ca(2+) currents were augmented reversibly by hypoxia, suggesting that Ca(2+) influx mediated by L-type Ca(2+) channels is essential for c-fos activation by hypoxia. We next determined downstream pathways activated by intracellular Ca(2+) concentration. Immunoblot analysis revealed Ca(2+)/calmodulin-dependent kinase II (CaMKII) protein in PC-12 cells and revealed that hypoxia increased the enzyme activity. KN-93, a CaMK inhibitor, blocked CaMKII activation and c-fos promoter stimulation by hypoxia. Ectopic expression of an active mutant of CaMKII (pCaMKII290) stimulated c-fos promoter activity under normoxia. Hypoxia increased phosphorylation of CREB at the serine residue 133 (Ser-133), and KN-93 attenuated this effect. Point mutations at the Ca(2+)/cAMP-responsive cis-element (Ca/CRE) attenuated, whereas point mutations in the serum-responsive cis-element (SRE) abolished transcriptional activation of c-fos by hypoxia. These results demonstrate that c-fos activation by hypoxia involves CaMK activation and CREB phosphorylation at Ser-133 and requires Ca/CRE and SRE. These observations demonstrate that Ca(2+)-dependent signaling pathways play a crucial role in induction of c-fos gene expression, which may underlie long-term adaptive responses to hypoxia.

Animals↗
PubMed2000

Into thin air.

Explore the source record for details and available documents.

Adaptation, Physiological↗
PubMed2000

Psychological profile and ventilatory response to inspiratory resistive loading.

The purpose of this study was to explore the contribution of psychological state to both the ventilatory response and the intensity of dyspnea experienced after the addition of small inspiratory loads to breathing. We hypothesized that patients with either a specific psychiatric diagnosis or a specific psychological trait will associate a greater degree of dyspnea with a loaded breathing task than will control subjects. To insure the inclusion of persons with relevant psychological profiles, we recruited both subjects enrolled in the Chronic Fatigue Center and normal control subjects. In all, 52 subjects inspired first through a small (1.34 cm H(2)O/L/s) and second through a moderate (3.54 cm H(2)O/L/s) inspiratory resistive load (IRL). Ventilation was monitored throughout the 5-min sessions. Dyspnea was quantified with the Borg scale at specified times during the protocol. Standard psychological tests were administered. We found that subjects could be divided into two groups. One, the "responders," reported Borg scores higher than those of the second, or "nonresponder" group, at all times during the protocol. By contrast, there was no difference between groups with respect to ventilation. Responders had higher scores on tests of depression (the Center for Epidemiological Study depression scale) than did nonresponders. We conclude that the variability observed in subjective responses to IRL is explained, in part, by differences in psychological state.

Adult↗
PubMed1998

Role of c-fos in hypoxia-induced AP-1 cis-element activity and tyrosine hydroxylase gene expression.

Previous studies have demonstrated that hypoxia stimulates expression of the c-fos gene in intact animals and isolated cells. The purpose of the present study was to assess the functional significance of c-fos activation during hypoxia. Using antisense c-fos strategy, we tested the hypothesis that c-fos is essential for activation of activator protein-1 transcription factor complex (AP-1) and subsequent stimulation of down stream genes such as tyrosine hydroxylase (TH) gene during hypoxia. Experiments were performed on rat pheochromocytoma 12 (PC12) cells. AP-1 activity was determined by a reporter gene assay using a luciferase expression vector driven by two copies of an AP-1 cis-element (AP-1-Luc). Cells transfected with AP-1-Luc construct were exposed to normoxia (21% O2) or to varying intensities and/or durations of hypoxia. AP-1 activity increased in response to hypoxia. The magnitude of the response depended on the intensity and duration of the hypoxic stimulus. Increases in AP-1 activity could not be elicited in neuroblastoma cells, indicating that hypoxia-induced increase in AP-1 activity is a cell selective phenomenon. Antisense c-fos abolished hypoxia-induced AP-1 activation in PC12 cells. Hypoxia increased tyrosine hydroxylase-chloramphenicol acetyl transferase activity (TH-CAT), and antisense c-fos and mutations at AP-1 binding sites in TH promoter abolished this effect. These results provide direct evidence that c-fos is essential for functional activation of AP-1 and subsequent activation of delayed response genes such as TH in PC12 cells.

Animals↗