摘要:

Peptides corresponding to linear sequences of HLA molecules have been synthesized and tested for immunomodulatory activity inin vitroassays using human T lymphocytes. Sequences from different parts of the HLA molecules have different effects. Peptides corresponding to residues 75–84 of an HLA class I supratypic specificity of limited heterogeneity (HLA-Bw4) had profound inhibitory effects in a variety ofin vitroassays of human T lymphocyte function. Furthermore, a 2-wk course of human HLA sequences and cyclosporine therapy induced enduring immunologic tolerance in a rat model of heterotopic heart transplantation. These studies prompted clinical trials which are currently in progress. The peptides appear to induce T cell anergy by causing a prolonged intracellular calcium flux and interrupting normal signal transduction pathways. Furthermore, these peptides bind to members of the heat-shock protein 70 family, implicating these ubiquitous proteins in the immunomodulatory pathway. Such peptides may be normal physiologic mediators. In any case, they represent potential new immunotherapeutics for a variety of immune-mediated diseases.

ISSN:0031-3998    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

We have previously found an age-dependent relaxing effect of furosemide in normal fetal, newborn, and adult guinea pig airways with fetal trachea exhibiting the greatest relaxation and adult tissue the least. This study was designed to expand upon this finding by determining ifin vivohyperoxic exposure would influencein vitroairway relaxation mediated by the loop diuretics, furosemide and ethacrynic acid, and the β2-adrenoceptor agonist, salbutamol. Newborn guinea pigs were raised in >95% Fi02until ill; controls in room air. Isometric relaxation to 3 × 10−5M furosemide, 3 × 10−6M ethacrynic acid, or 10−8−10−6M salbutamol was recorded in 3 × 10−6M histamine-constricted airway rings. Ethacrynic acid, like furosemide, relaxed newborn guinea pig airways. Hyperoxia did not alter the contractile effect of 3 × 10−6M histamine but did significantly decrease the relaxing effect of furosemide, ethacrynic acid, and salbutamol. Loop diuretic mediated airway relaxation was accentuated in HEPES buffer when compared with Krebs, whereas salbutamol-mediated relaxation was unaffected. These results suggest that hyperoxia nonspecifically decreases airway responsiveness to the relaxing agents studied.

ISSN:0031-3998    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

Support of preterm infants with ventilation and oxygen therapy frequently leads to the development of chronic lung disease. Oxidative stress, through the generation of excess oxygen free radicals, is thought to play a major role in this condition. At present the radical species responsible for oxidative lung injury is not known, and effective antioxidant based therapies are not available. The purpose of this study was to determine whether hydroxyl radicals, potent reactive oxygen species, are involved in chronic oxidative lung injury. To obtain this information we developed a animal model of chronic lung injury using the preterm guinea pig and analyzed lung tissue from these pups foro-tyrosine, a specific marker of hydroxyl radical attack. In normoxia control pups the pulmonary content ofo-tyrosine was low during the first 4 wk of life (range 0.11–0.12% tyrosine). Pups maintained in 85% oxygen were found to have increasing lungo-tyrosine over this period (d 7, 0.51%; d 14, 0.8%; d 21, 1.28%; d 28, 1.45% tyrosine). From d 21, the nonenzymatic glycosylation end product,N-&epsis;-carboxymethyllysine was also present in significantly increased amounts in hyperoxic-exposed pups. These results implicate hydroxyl radicals as a significant oxidizing species in hyperoxic lung injury and provide a basis for understanding collagen deposition in the neonatal lung.

ISSN:0031-3998    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

In full-term newborn rats, propylthiouracil (PTU) treatment has been previously shown to decrease susceptibility to 02-induced lung damage and improve survival during hyperoxic exposure. However, no differences were found in lung antioxidant enzyme (AOE) activity responses to hyperoxia compared with 02-exposed untreated (control) term rats. To further explore possible pulmonary protective effects of PTU treatment in prematurely delivered animals, we administered PTU (0.015%) in drinking water to timed-pregnant rats for the final 10 d of gestation prior to delivery 1 d before term, and during lactation; control pregnant/nursing rats received untreated water. Both groups of 21-d premature rat pups were randomized to either >95% 02or room air exposure after birth for up to 14 d. The left lungs of 7-d exposure pups were used to quantitate the concentrations of AOE mRNA by solution hybridization; the right lungs of the same pups were assayed for AOE activities. PTU treatment resulted in survival rates of 02-exposed preterm rat pups that were consistently higher at all time periods in hyperoxia including 7 d [PTU, 67 of 82 (82%)versuscontrol pups, 58 of 113 (51%);p< 0.001] and 14 d [PTU, 31 of 39 (79%)versuscontrol, 15 of 66 (23%);p< 0.001]. Further evidence of increased tolerance to >95% 02in PTU pups included a significant decrease in the incidence of microscopic intraalveolar edema and a significant increase in lung tissue surfactant-related phospholipids compared with 02-exposed control pups. At 7 d in high 02, the PTU-treated pups showed greater increases in the lung AOE mRNA levels and AOE activities of catalase and glutathione peroxidase in response to hyperoxia compared with the untreated control 02group. Thus, we conclude that PTU treatment protects premature rats against 02-induced lung injury and lethality during prolonged hyperoxic challenge. The protective action of PTU may be related, at least in part, to the enhanced pulmonary AOE gene expression in the treated rat pups with resultant increases in protective AOE activity levels in response to neonatal lung oxidant challenge.

ISSN:0031-3998    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

Pathomechanisms involved in obstructive apneas remain obscure. Apnea arousal failure has been proposed as a cause for sudden death during sleep. The present study hypothesizes an interdependency between upper airway dilating submental muscle electromyogram (EMG) activity (EMGsub), diaphragmatic muscle activity (EMGdia), incidence of bradycardia, and transcutaneous measured Po2(tcp02) upon termination of apnea. Polygraphic recordings, including surface EMG (EMGsub, EMGdia), EEG, ECG, and transcutaneous Po2/Pco2(tcp02/ tcpC02) were performed on 10 preterm infants at 36, 40, 44, and 52 wk of conceptional age. EMGsub increased initially, then decreased in 28 of 33 non-rapid eye movement (N-REM) sleep apneas (REM: 35 of 69 events). This correlated with a decrease of tcp02during N-REM sleep (p< 0.05). A parallel decrease of EMGsub and EMGdia was correlated with the occurrence of bradycardia (REM and N-REM:p< 0.01). Concomitant termination of apnea and bradycardia (n= 22), occurred in the presence of a phasic, simultaneous activation of EMGsub and EMGdia in 64% of REM sleep and in 79% of N-REM sleep-related event, was characterized by a deep inspiration preceded by a short expiration, and correlated with the extent of tcp02-decline during REM sleep apneas (p< 0.05). In one apnea with bradycardia that progressed to asystolia, this mechanism was missing, but was evoked by a slight tactile stimulation, whereupon cardiorespiratory functions were immediately reestablished whereas N-REM sleep continued uninterrupted. Our data demonstrate an interdependency between changes of EMGsub and EMGdia activity, tcp02decline, and occurrence of bradycardia. A “cardiorespiratory arousal” terminated apneas and bradycardia without a change in sleep phase.

ISSN:0031-3998    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

Because of ontogenic influences on the pathophysiologic mechanisms of brain injury in the perinatal brain, and in particular, the incomplete development of adenosine receptor systems, we investigated the potential for adenosine to provide cerebro-protection in a well established newborn rat model of hypoxia-ischemia. Fifteen litters of postnatal d 7 animals were subjected to unilateral carotid ligation and exposure to hypoxia (8% oxygen) for 3 h. Immediately after hypoxia-ischemia, animals received either the adenosine deaminase inhibitor deoxycoformycin (DCF; 2.5 mg/kg intraperitoneally) or the adenosine uptake inhibitor propentofylline (PPF; 10 mg/kg intraperitoneally); paired littermates received an equivalent volume of normal saline. On postnatal d 14, injury or protection was assessed by differences in hemispheric weights, morphometric determinations of infarct area, and histopathologic analyses. DCF resulted in a 34% (p= 0.02) and 31% (p= 0.03) reduction in hemispheric weight disparities and infarct area, respectively; for PPF, these reductions were 46% (p= 0.03) and 32% (p= 0.04), respectively. Light microscopic examinations of striatum, thalamus, hippocampus, and cortex revealed that both drugs significantly improved histologic scores as well. Measurements in six separate litters indicated that neither drug significantly reduced core body temperature for at least 6 h postadministration. These findings indicate that potentiation of endogenous adenosine levels in the perinatal brain can significantly ameliorate brain injury. Each of these treatment strategies was effective even when administered after the hypoxic-ischemic insult. Thus, further investigations of adenosinergic therapies are warranted in this and other perinatal models of cerebral ischemia to elucidate in detail their potential for clinical application.

ISSN:0031-3998    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

There is considerable concern over the widespread use of caffeine during and after pregnancy. We have therefore examined the effect of perinatal caffeine use on the vulnerability of the immature brain to hypoxic ischemia (HI). Rat pups were exposed to caffeine during the first 7 d after birth by addition of a low or a high dose (0.3 or 0.8 g/L) of caffeine to the drinking water of their dams. At 7 d the pups were exposed to unilateral carotid occlusion + exposure to 7.70% oxygen for 100 min. The extent of HI brain damage was evaluated 2 wk after the insult. The effects of caffeine on A1and A2areceptors, A1mRNA and A2amRNA, were examined by receptor autoradiography andin situhybridization. Caffeine, theobromine, theophylline, and paraxanthine were analyzed in plasma of separate animals. Exposure to caffeine reduced HI brain damage from 40.3 ± 3.2% in controls to 29.8 ± 4.0% (p< 0.05) in low dose and 33.7 ± 3.9% (NS) in the high dose group. The A1receptor density measured as [3H]-l,3-dipropyl-8-cyclopentyl xanthine ([3H]-DPCPX) binding was not significantly affected after low dose caffeine but increased in the brain of rat pups in the high dose group. The A2areceptor density measured as [3H]-2[p-(2-carbonylethyl)-phenethylamino]-5′-N-ethylcarboxamidoadenosine ([3H]-CGS 21680) binding and the expression of A1mRNA and A2amRNA were not altered by caffeine treatment. In conclusion, low dose caffeine exposure (plasma levels corresponding to umbilical cord plasma in newborns of coffee-consuming mothers) reduced HI brain damage by 30% in 7-d-old rats. This ameliorating effect could not be accounted for by up-regulation of adenosine receptors.

ISSN:0031-3998    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

Changes in cerebral venous oxyhemoglobin saturation reflect changes in the balance between cerebral oxygen delivery and cerebral oxygen consumption. Invasive monitoring of cerebral venous saturation (CSvo2) has provided useful information in the management of critically ill adults at risk of cerebral hypoxia. This study describes the development and validation of a noninvasive method of measuring CSvo2suitable for use in sick neonates using near-infrared spectroscopy (NIRS) and partial jugular venous occlusion. This technique was validated by comparison with an invasive measurement of CSvo2, co-oximetry of jugular bulb blood obtained during cardiac catheterization. Agreement between the two methods was assessed using the method of J. M. Bland and D. G. Altman. Fifteen children were studied, aged 3 mo to 14 y (median 2 y). CSvo2by co-oximetry ranged from 36 to 80% (median 60%). The mean difference (Co-Oximeter—NIRS) was 1.5%. Limits of agreement were—12.8 to 15.9%. Three different methods of analyzing the NIRS signal were compared. The best agreement was obtained when the changes occurring during the first 5 s of partial jugular venous occlusion were studied. Greatest accuracy was seen in those subjects with least movement artifact, and we believe this technique will be reliable in sick neonates.

ISSN:0031-3998    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

Acylcarnitine profiling from blood or plasma samples by electrospray tandem mass spectrometry (ESI-MS/MS) has been recognized recently as a useful tool in the biochemical diagnosis of propionic acidemia, methylmalonic acidemia together with short-chain and medium-chain acyl-CoA dehydrogenase deficiencies. In the current study, we have investigated the diagnostic capabilities of ESI-MS/MS in other types of organic acidemias and amino acid catabolism disorders. Using multiple scanning functions, we examined the potential for the simultaneous profiling of both acylcarnitines and amino acids, in each of the samples. Our method was found to be specific and accurate; allowing quantification of acylcarnitines and amino acids well below, and significantly above, published normal levels. Complete automation of sample introduction has been achieved, allowing the analysis of up to 200 samples in one injection sequence, at a rate of one sample every 3 min, with excellent separation between successive injections. In our hands, this method permits screening for 20 organic acid and amino acid disorders, using a single sample injection. In our laboratory, more than 2000 blood samples have been analyzed, and 52 new cases were diagnosed by this method. We also confirmed the diagnosis of another 75 previously known cases.

ISSN:0031-3998    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

In term infants sucrose given by mouth has been reported to reduce duration of crying after a heel prick. This study was designed primarily to investigate the effect of sucrose administered orally immediately before heel lancing on the nociceptive reaction in preterm infants as assessed by change in heart rate and duration of crying. A secondary objective was to document changes in cerebral blood volume during acute pain. We used a randomized, masked, placebo-controlled, crossover trial in a neonatal intermediate care unit in a level 3 perinatal center. The patients studied were 16 preterm infants; birth weight, 900–1900 g; gestational wk, 27–34; corrected postmenstrual age at time of investigation, 33–36 wk. Each infant was assessed twice receiving 2 mL of sucrose 50% or 2 mL of distilled water in random order immediately before heel lance. Heart rate, thoracic movements, and transcutaneous blood gases were monitored continuously. Crying during the procedure was documented by a video-camera. A change in cerebral blood volume was assessed by near-infrared spectroscopy. We found the heart rate increased by a mean of 35 beats/min (bpm) after sucrose and 51 bpm after placebo (median difference 16 bpm, interquartile range 1–30 bpm,p= 0.005). Infants cried 67% of time after sucrose and 88% after placebo (median difference 10%, interquartile range 3–33%,p= 0.002). Cerebral blood volume decreased in 5 of 14 infants after sucrose and in 6 of 14 infants after placebo (difference not significant). We concluded that sucrose administered orally before a heel lance reduces the pain reaction in preterm infants. Response of cerebral blood volume to pain does not seem to be altered by sucrose.

ISSN:0031-3998    

出版商:OVID    

年代:1995

数据来源: OVID