Breathing patterns, pulmonary mechanics and gas exchange: role of vagal innervation in neonatal lamb.
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Animals↗
Biomedical subjects
S Lalani
Publications and source records attributed to S Lalani.
Effects of vagal denervation on cardiorespiratory and behavioral responses in the newborn lamb.
Recently, Wong et al. (Wong KA, Bano A, Rigaux A, Wang B, Bharadwaj B, Schurch S, Green F, Remmers JE, and Hasan SU, J Appl Physiol 85: 849-859, 1998) demonstrated that fetal lambs that have undergone vagal denervation prenatally do not establish adequate alveolar ventilation shortly after birth. In their study, however, vagal denervation was performed prenatally and the deleterious effects of vagal denervation on breathing patterns and gas exchange could have resulted from the prenatal actions of the neurotomy. To quantify the relative roles of pre- vs. postnatal vagal denervation on control of breathing, we studied 14 newborn lambs; 6 were sham operated, and 8 were vagally denervated below the origin of the recurrent laryngeal nerve. Postoperatively, all denervated animals became hypoxemic and seven of eight succumbed to respiratory failure. In vagally denervated lambs, expiratory time increased, whereas respiratory rate, minute ventilation, and lung compliance decreased compared with the sham-operated animals. In the early postoperative period, the frequency of augmented breaths was lower but gradually increased over time in the denervated vs. sham-operated group. The dynamic functional residual capacity was significantly higher than the passive functional residual capacity among the sham-operated group compared with the denervated group. No significant differences were observed in the prevalence of various sleep states and in the amount of total phospholipids or large- and small-aggregate surfactants between the two groups. We provide new evidence indicating that intrauterine actions of denervation are not required to explain the effects of vagal denervation on postnatal survival. Our data suggest that vagal input is critical in the maintenance of normal breathing patterns, end-expiratory lung volume, and gas exchange during the early neonatal period.
Animals↗
Significance of vagal innervation in perinatal breathing and gas exchange.
The mechanisms responsible for the establishment of continuous breathing at birth remain unknown. Several studies have shown that postnatal vagal denervation produces deleterious effects on ventilation as well as breathing patterns during the newborn period. However, the validity of these studies was compromised by anesthesia, tracheostomy or possible secondary laryngeal obstruction. We have recently developed an unanesthetized lamb model in which vagal denervation was performed antenatally and below the recurrent laryngeal nerves thereby avoiding anesthesia, tracheostomy and laryngeal paralysis. The denervated animals developed life-threatening respiratory failure shortly after birth, implying that vagal innervation of the lungs plays an essential role in establishing adequate gas exchange in the first hours after birth. We have subsequently investigated various mechanisms of respiratory failure in denervated animals. Our results show that the surfactant system dysfunction and loss of vagally mediated volume feedback likely contributed to the respiratory failure observed in the intrathoracically denervated animal model.
Animals↗
Human pharmacokinetics of intravenous, sublingual, and buccal buprenorphine.
Buprenorphine is a potent opioid analgesic used in the treatment of moderate to severe pain. At higher doses, it has demonstrated potential for treating heroin dependence. This study was undertaken to investigate buprenorphine pharmacokinetics by different routes of administration at dosages approximating those used in opioid-dependence studies. Six healthy men who were nondependent but who had a history of heroin use were administered buprenorphine in a crossover design study by intravenous (1.2 mg), sublingual (4.0 mg), and buccal (4.0 mg) routes of administration. Plasma samples were collected up to 96 h and assayed for buprenorphine and norbuprenorphine by negative chemical ionization tandem mass spectrometry. Plasma concentrations of buprenorphine and norbuprenorphine were analyzed by nonlinear regression analysis with standard noncompartmental methods. Buprenorphine biovailability by the sublingual and buccal routes was estimated as 51.4% and 27.8%, respectively, although there was considerable interindividual variability by both routes of administration. The terminal elimination half-lives were longer for the sublingual and buccal routes than for the intravenous route. The extended elimination half-lives may be due to a shallow depot effect involving sequestration of buprenorphine in the oral mucosa. Norbuprenorphine mean peak plasma concentrations were less than 1 ng/mL and were highly variable among different routes of administration and individuals. The terminal elimination half-life of norbuprenorphine was longer than buprenorphine.
Administration, Buccal↗
Immune deficiency following thermal trauma is associated with apoptotic cell death.
Thermal injury-associated specific immune deficiency occurs despite indicators of systemic activation of the lymphoid compartment. We investigated the possibility that postburn immune failure and T cell activation are casually related through activation-induced (apoptotic) cell death. The relationship between the cellular immune response and cell mortality was examined in cultures of peripheral blood mononuclear cells (PBMC) from 14 immunosuppressed patients with extensive burns (35-90% total body surface area). Impaired cellular immunity coincided with significantly reduced cell viability as ascertained by propidium iodide staining and dye reduction assays. Following stimulation with the mitogenic lectin, phytohemagglutinin (PHA), the majority of DNA in patient cultures was fragmented, suggesting the occurrence of apoptotic cell death. Even without stimulation a portion of patient cells was apoptotic as indicated by oligonucleosomal bands on agarose gel electrophoresis. Exogenous interleukin-2 or phorbol ester markedly reduced constitutive as well as PHA-induced DNA fragmentation. In situ demonstration of DNA strand breaks in freshly isolated patient PBMC, by a TdT-based labeling technique, confirmed that a larger fraction (up to 60%) of circulating lymphocytes was undergoing apoptosis on the periphery. These novel observations suggest that apoptosis may play a major role in thermal injury-related cellular immunodeficiency.
Adult↗
Tumor necrosis factor alpha regulation of immunoglobulin secretion in trauma patients.
Major trauma-related immune dysfunction is observed at the time of augmented release of immunopathologic mediators. In the present study, T cell-dependent immunoglobulin (Ig) synthesis in peripheral blood mononuclear cell (PBMC) cultures from blunt trauma patients (N = 12, injury severity score (ISS) 27-50), was reduced by 30- > 90%. This coincided with significantly (P < 0.001-0.01) elevated secretion of the biologically active tumor necrosis factor alpha (TNF alpha). Modulation of the TNF alpha activity by anti-TNF alpha antibody (anti-TNF alpha Ab) led to dose-dependent alterations in IgG synthesis. IgG production increased (up to 300%) in cultures treated with 0.5-2 micrograms/ml of the antibody, where low levels of TNF alpha activity often persisted. However, immunoglobulin synthesis was eradicated in preparations exposed to higher concentrations (10 micrograms/ml) of anti-TNF alpha Ab and devoid of TNF alpha biological activity. The treatment with anti-TNF alpha Ab had no effect on mitogen- or alloantigen-induced PBMC proliferation. Thus, in severely traumatized patients, biological activities of endogenous TNF alpha may include modulation of T cell-dependent B lymphocyte function. Immunoregulatory potential of TNF alpha should, therefore, be considered in therapeutic strategies to abrogate its activity.
Adult↗
IL-2 regulation of soluble IL-2 receptor levels following thermal injury.
In the immunosuppressed burn patient serum levels of both IL-2 and a soluble form of IL-2 receptor alpha (sIL-2R alpha) are significantly elevated. Strikingly, the production of these markers by the in vitro activated patients' cells is decreased. This study examines the role of IL-2 in the decreased production of the sIL-2R alpha in vitro in patients with major burns (n = 18, 30 to greater than 70% total body surface area). Peripheral blood mononuclear cell (PBMC) cultures from patients with highly elevated serum sIL-2R alpha, and from healthy controls (n = 12) were activated with concanavalin A (Con A) at initiation. In patients' cultures mitogen-induced increments of sIL-2R alpha levels were significantly lower. There was a significant negative correlation (r = 0.64, P less than 0.001) between a high serum sIL-2R alpha level and a decreased lectin-induced sIL-2R alpha release in vitro. Low levels of sIL-2R alpha in patients' samples were not normalized by increasing the number of T lymphocytes. Also exogenous rIL-1 was without effect, whereas rIL-3 increased sIL-2R alpha release in some cultures. However, sIL-2R alpha levels were significantly increased in patients' cultures by (i) addition of exogenous IL-2; (ii) removal of adherent cells; (iii) addition of cyclooxygenase inhibitor, indomethacin; (iv) bypassing cell surface activation by the combination of the calcium ionophore A23187 and the phorbol ester 12-o-tetradecanoyl acetate. The cyclic AMP-elevating drug, forskolin, abrogated the ability of exogenous IL-2 to increase sIL-2R alpha production. Thus, in the burn patient, the reduced in vitro sIL-2R alpha release appears to relate to abnormalities in IL-2 production and action mediated through its functional surface receptor. Elevated levels of sIL-2R alpha in vivo may, therefore, reflect systemic activation of T lymphocytes in response to biologically active IL-2.
Adult↗
Diffuse and localized glaucomatous field loss in light-sense, flicker and resolution perimetry.
A total of 75 eyes in 75 patients with different types of glaucoma (21 eyes with low-tension glaucoma, 49 with primary open-angle glaucoma and 5 with pigmentary glaucoma) were examined by automated light-sense, flicker and resolution perimetry. All fields were classified in a masked fashion as being "normal" (N) or as having "diffuse loss" (D), "localized loss" (L) or "diffuse plus localized loss" (DL). The frequency distributions for the various field loss categories were plotted against the highest intraocular pressure ever reported in the patients' records. The frequency distribution for the purely localized defects showed a peak at 20 mmHg and were markedly skewed to low pressure values, whereas those for both diffuse plus localized damage and purely diffuse loss peaked at about 30 mmHg. The data suggest that diffuse field loss may be an indicator of pressure-induced damage.
Adult↗
[Diffuse and localized glaucomatous visual field changes in light sense, flicker and visual acuity perimetry. Evidence of pressure damage].
75 eyes of 75 patients with different types of glaucoma (21 eyes with normal-tension glaucoma, 49 eyes with primary open-angle glaucoma and 5 eyes with pigmentary glaucoma) were examined by automated light-sense, flicker and resolution perimetry. All fields were classified as being "normal" (N) or having "diffuse loss" (D), "localized loss" (L) and "diffuse plus localized loss" (DL) in masked fashion. The frequency distributions for the various field loss categories against the highest intraocular pressure ever reported in the patients' records were plotted. The frequency distributions for the purely localized defects show a peak at 20 mmHg and are markedly skewed to low pressure values, while the diffuse plus localized damage and the purely diffuse loss, however, show a peak at about 30 mmHg. The data support the hypothesis that diffuse field loss may be an indicator of pressure-induced damage.
Adult↗
Expression and secretion of IL-2 receptor in trauma patients.
The high-affinity cell-surface receptor for interleukin-2 (IL-2R) consists of the 75-kilodalton (kd) chain and a 55-kd glycoprotein known as Tac. This report examines the cellular expression of IL-2R and secretion of the soluble form of Tac in immunosuppressed blunt trauma (n = 20, injury severity score -20) and thermally injured (n = 20, Total body surface area greater than 35%) patients. The percentage of IL-2R-expressing peripheral blood mononuclear cells (PBMC) in mitogen-stimulated cultures from patients and age-matched normal donors was determined by direct immunofluorescence with a monoclonal anti-Tac followed by flow cytometry analysis. Levels of soluble Tac in patient sera were measured by a monoclonal antibody-based enzyme-linked immunosorbent assay. Expression of Tac antigen by mitogen-activated PBMC cultures from blunt trauma patients was transiently reduced (by as much as 40%) in 4 of 14 patients examined. Levels of serum Tac were significantly elevated (p less than 0.05) in 15 of 20 blunt trauma patients ranging from 750 to 3000 U/mL compared with 180 to 420 U/mL in control subjects. All burn patients studied 10 to 50 days after the injury demonstrated a significant reduction (by 50% to more than 90%) in the percentage of IL-2 receptor-bearing cells. Similarly serum levels of IL-2R increased significantly (p less than 0.001 to 0.05) in all burn patients studied, reaching concentrations as high as 5500 U/mL. These results suggest that major trauma, whether mechanical or thermal, induces alterations in the T-lymphocyte activation process. However the degree and duration of such changes may vary based on the nature of the injury.
Adolescent↗
Functional impairment in COPD patients: the impact of anxiety and depression.
The authors examined the relationship between functional status and comorbid anxiety and depression and the relationship between utilization of health care resources and psychopathology in elderly patients with chronic obstructive pulmonary disease (COPD). Elderly male veterans (N = 43) with COPD completed anxiety, depression, and functional status measures. The authors constructed regression models to explore the contribution of COPD severity, medical burden, depression, and anxiety to the dependent variables of functional impairment and health care utilization. Anxiety and depression contributed significantly to the overall variance in functional status of COPD patients, over and above medical burden and COPD severity, as measured by the 8 scales of the Medical Outcomes Study (MOS) 36-item Short Form Health Survey. Surprisingly, medical burden and COPD severity did not contribute significantly to overall variance in functional status. Few patients were receiving any treatment for anxiety or depression.
Activities of Daily Living↗
Modulation of biological responses of normal human mononuclear cells by antiestrogens.
The effect of three non-steroidal antiestrogens, Tamoxifen, Toremifene and ICI 164, 384, on various aspects of the immune response was studied in cultures of normal peripheral mononuclear blood cells. The drugs differ somewhat in their effect on the functions tested (pokeweed mitogen-induced immunoglobulin synthesis and cell proliferation, mixed lymphocyte reaction, Interleukin 2 (IL 2) synthesis, IL 2 receptor expression and Tumor Necrosis Factor (TNF alpha) synthesis). However, all three are immunosuppressive. On the other hand, ICI 164, 384 and Tamoxifen were stimulatory for TNF alpha production by adherent cells which may prove as an additional feature in antiestrogen treatment.
Adult↗