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J H Newman

Publications and source records attributed to J H Newman.

At least 19 recordsLinked to original sources
PubMed1992

An imbalance between the excretion of thromboxane and prostacyclin metabolites in pulmonary hypertension.

BACKGROUND: Constriction of small pulmonary arteries and arterioles and focal vascular injury are features of pulmonary hypertension. Because thromboxane A2 is both a vasoconstrictor and a potent stimulus for platelet aggregation, it may be an important mediator of pulmonary hypertension. Its effects are antagonized by prostacyclin, which is released by vascular endothelial cells. We tested the hypothesis that there may be an imbalance between the release of thromboxane A2 and prostacyclin in pulmonary hypertension, reflecting platelet activation and an abnormal response of the pulmonary vascular endothelium. METHODS: We used radioimmunoassays to measure the 24-hour urinary excretion of two stable metabolites of thromboxane A2 and a metabolite of prostacyclin in 20 patients with primary pulmonary hypertension, 14 with secondary pulmonary hypertension, 9 with severe chronic obstructive pulmonary disease (COPD) but no clinical evidence of pulmonary hypertension, and 23 normal controls. RESULTS: The 24-hour excretion of 11-dehydro-thromboxane B2 (a stable metabolite of thromboxane A2) was increased in patients with primary pulmonary hypertension and patients with secondary pulmonary hypertension, as compared with normal controls (3224 +/- 482, 5392 +/- 1640, and 1145 +/- 221 pg per milligram of creatinine, respectively; P less than 0.05), whereas the 24-hour excretion of 2,3-dinor-6-keto-prostaglandin F1 alpha (a stable metabolite of prostacyclin) was decreased (369 +/- 106, 304 +/- 76, and 644 +/- 124 pg per milligram of creatinine, respectively; P less than 0.05). The rate of excretion of all metabolites in the patients with COPD but no clinical evidence of pulmonary hypertension was similar to that in the normal controls. CONCLUSIONS: An increase in the release of the vasoconstrictor thromboxane A2, suggesting the activation of platelets, occurs in both the primary and secondary forms of pulmonary hypertension. By contrast, the release of prostacyclin is depressed in these patients. Whether the imbalance in the release of these mediators is a cause or a result of pulmonary hypertension is unknown, but it may play a part in the development and maintenance of both forms of the disorder.

6-Ketoprostaglandin F1 alpha↗
PubMed1992

Effects of a novel prostaglandin, 8-epi-PGF2 alpha, in rabbit lung in situ.

We determined the effects of 8-epiprostaglandin (PG) F2 alpha, a noncyclooxygenase free radical-catalyzed product of arachidonic acid, on pulmonary vascular tone, its potency, and its mechanism of action. 8-Epi-PGF2 alpha (0.5-20 micrograms) was injected into the pulmonary artery (PA) catheter of 10 rabbits whose lungs were perfused in situ with Krebs-Henseleit buffer solution with 3% bovine serum albumin. PA pressure increased from a baseline of 13.5 +/- 0.6 to 25.6 +/- 2.0 cmH2O with 20 micrograms 8-epi-PGF2 alpha. 8-Epi-PGF2 alpha caused a rapid rise in PA pressure followed by a gradual decline over 40-60 min to baseline levels. Double vascular occlusion revealed a twofold increase in arterial resistance at peak rise in PA pressure. The rise in PA pressure with 20 micrograms 8-epi-PGF2 alpha was fivefold greater than with 20 micrograms of the cyclooxygenase-derived prostaglandin PGF2 alpha. The PA pressure response to 8-epi-PGF2 alpha was not altered by either cyclooxygenase block-ade with 150 microM meclofenamate or alpha-receptor blockade with 70 microM phentolamine, but was fully prevented by 40 microM SQ 29548, a thromboxane receptor antagonist. We conclude that in rabbits 8-epi-PGF2 alpha is a potent vasoconstrictor of the pulmonary vasculature, which appears to be due to the activation of SQ 29548-responsive thromboxane receptors.

Animals↗
PubMed1992

Differing effects of nitrogen mustard and hydroxyurea on lung O2 toxicity in adult sheep.

We measured the effects of leukocyte depletion on the pulmonary response to breathing 100% O2 in adult sheep, using two dissimilar agents. A group of eight sheep received 4.0 g/day of hydroxyurea for 4 to 6 days, and six sheep received two to four doses of 0.4 mg/kg of nitrogen mustard before exposure to 100% O2. A group of seven sheep breathed 100% O2 with no drug treatment. A group of five control sheep breathed compressed air for 96 h. Hydroxyurea selectively reduced circulating neutrophils (602 +/- 245 neutrophils, 2,537 +/- 394 lymphocytes per mm3), and nitrogen mustard decreased both circulating neutrophils (633 +/- 326) and lymphocytes (521 +/- 129). In untreated sheep breathing 100% O2, survival time was 92.6 +/- 3.4 h and postmortem blood-free lung water to dry lung ratio was 4.4 +/- 0.2. Hydroxyurea significantly delayed the onset of oxygen toxicity as measured by changes in lung lymph flow, PaO2, PaCO2, and time to respiratory failure (111.8 +/- 7.7 h), although the degree of final lung injury was unchanged and postmortem lung water was elevated (5.3 +/- 0.3). Nitrogen mustard shortened the time to hypoxemia, and CO2 retention and decreased time to respiratory failure (84.0 +/- 4.3 h). Neutrophils were markedly reduced but not absent in the lungs of both groups of leukocyte-depleted sheep. We conclude that neutrophils are not essential for the full expression of lung O2 toxicity in adult sheep. Secondary effects of hydroxyurea and nitrogen mustard appear to influence the rate of development, but not the outcome of oxygen toxicity, by effects independent of leukocyte depletion.

Animals↗
PubMed1991

Pulmonary vascular effects of prostaglandin D2, but not its systemic vascular or airway effects, are mediated through thromboxane receptor activation.

Prostaglandin D2 (PGD2) can cause pulmonary vasoconstriction or vasodilation depending on animal species and age. Because the constrictor effects of PGD2 in some vascular beds may be mediated through thromboxane receptors, the purpose of this study was to determine whether the vascular or bronchial effects of PGD2 are mediated through thromboxane/endoperoxide (TX/E) receptor activation. In chronically instrumented awake sheep, PGD2 (5-25 micrograms/kg i.v.) produced a dose-dependent increase in pulmonary arterial pressure and in systemic arterial blood pressure. These changes were due to increases in resistance, because cardiac output remained unchanged. PGD2 also decreased dynamic compliance at lower doses (0.1-5 micrograms/kg i.v.) than those required to produce pulmonary vasoconstriction, confirming that PGD2 is a potent bronchoconstrictor. The airway and systemic vascular effects of PGD2 were not altered by TX/E receptor antagonism. In contrast, PGD2-induced pulmonary vasoconstriction was blocked by two TX/E receptor antagonists, SQ-29,548 and AH-23848, implying that this effect is mediated through activation of TX/E receptors. The pulmonary vasoconstrictor effects of PGD2 could not be explained by thromboxane generation, because neither cyclooxygenase inhibition with ibuprofen nor thromboxane synthase inhibition with OKY-046 had any effect on PGD2 actions. In contrast, a mild but consistent pulmonary vasodilation produced by PGD2 could be uncovered if the pulmonary vascular bed was preconstricted by hypoxia with simultaneous TX/E receptor blockade. These results indicate that TX/E receptor antagonists, although still useful pharmacological probes to determine the role of TX/E receptor activation in pathophysiological processes, should not be used to infer a role of endogenous thromboxane A2. It is possible that PGD2 participates in pulmonary processes previously ascribed uniquely to thromboxane A2.

Animals↗
PubMed1991

Simultaneous exposure of sheep to endotoxin and 100% oxygen.

The purpose of this study was to determine the effect of endotoxin on the development of vascular and airway dysfunction during O2 toxicity. Sheep were prepared for chronic measurement of vascular pressures, cardiac output, gas exchange, and collection of lung lymph. Tracheostomies were made for accurate delivery of gas mixtures. Sheep were placed in one of three experimental groups: those receiving endotoxin (n = 9), those breathing 100% O2 and receiving endotoxin (n = 7), and those exposed to 100% O2 alone (n = 6). Sheep had daily measurements of hypoxic vasoconstriction (FIO2 = 0.12), gas exchange, circulating white blood cell counts, lymph flow, and lymph and plasma protein concentrations. Lung neutrophils were counted, and copper-zinc superoxide dismutase and manganous superoxide dismutase were measured in lung samples from some sheep biopsies taken at baseline surgery and postmortem. Endotoxin markedly prolonged survival time and partially protected against the increased lung vascular permeability in sheep breathing 100% oxygen, but impairment of gas exchange, loss of hypoxic pulmonary vasoconstriction, and ultimate progression of respiratory failure were not prevented. Induction of MnSOD occurred in sheep breathing 100% O2, in sheep receiving endotoxin alone, and in those exposed to 100% O2 plus endotoxin. We conclude that endotoxin markedly increases tolerance to O2 toxicity but that some of the pathophysiology of O2 toxicity is unaltered. The role of superoxide dismutase in the observed protection is unclear.

Animals↗
PubMed1991

Axial movement and tibial fractures. A controlled randomised trial of treatment.

Diaphyseal fractures of the tibia in 80 patients were treated by external skeletal fixation using a unilateral frame, either in a fixed mode or in a mode which allowed the application of a small amount of predominantly axial micromovement. Patients were allocated to each regime by random selection. Fracture healing was assessed clinically, radiologically and by measurement of the mechanical stiffness of the fracture. Both clinical and mechanical healing were enhanced in the group subjected to micromovement, compared to those treated with frames in a fixed mode possessing an overall stiffness similar to that of others in common clinical use. The differences in healing time were statistically significant and independently related to the treatment method. There was no difference in complication rates between treatment groups.

Adolescent↗
PubMed1991

Postoperative collection and reinfusion of autologous blood in total knee arthroplasty.

A series of 40 patients undergoing primary unilateral total knee arthroplasty were entered into a randomised controlled trial to assess the safety and efficacy of postoperative autologous blood salvage and reinfusion. The mean volume of autologous blood reinfused was 520 ml per patient (51% of the mean total drainage). Homologous blood transfusion was required in only 35% of patients in the study group compared with 95% of patients in the control group (P less than 0.001). The mean volume of homologous blood transfused was 0.9 units per patient in the study group compared with 2.5 units in the control group (P less than 0.001), a saving of 64%.

Aged↗
PubMed1991

Eosinophilic fasciitis is clinically distinguishable from the eosinophilia-myalgia syndrome and is not associated with L-tryptophan use.

Induration of the skin develops in a majority of patients with the eosinophilia-myalgia syndrome associated with L-tryptophan, and bears striking clinical and histopathological resemblance to eosinophilic fasciitis (EF). These similarities have led to the suggestion that eosinophilia-myalgia syndrome and EF are the same disease. To study the relationship of eosinophilia-myalgia syndrome and EF, we ascertained the prevalence of L-tryptophan use in a cohort of patients with EF, and compared their clinical and laboratory findings to those of patients with eosinophilia-myalgia syndrome associated cutaneous involvement. None of 11 patients who were diagnosed as having EF between 1970 and 1989 used L-tryptophan containing preparations prior to the onset of their illness. Marked clinical and laboratory test differences were observed between patients with EF and eosinophilia-myalgia syndrome. Patients with eosinophilia-myalgia syndrome had a more acute onset, more severe symptoms, higher frequency of rash and of pulmonary, cardiac, gastrointestinal, neurologic, myopathic and thyroid involvement compared to patients with EF. Corticosteroid therapy resulted in improvement of cutaneous involvement in 88% of patients with EF but it was only partially successful in patients with eosinophilia-myalgia syndrome. Hospitalization and fatalities occurred only among patients with eosinophilia-myalgia syndrome. These observations demonstrate that eosinophilia-myalgia syndrome is a more severe disease with multisystemic involvement that can be clinically distinguished from EF. In contrast to eosinophilia-myalgia syndrome, EF is not associated with L-tryptophan ingestion.

Adrenal Cortex Hormones↗
PubMed1990

Acute effects of atrial natriuretic peptide on lung mechanics and hemodynamics in awake sheep.

The purpose of this study was to measure airway and hemodynamic effects of atrial natriuretic peptide (ANP) and its efficacy in counteracting the changes in lung mechanics that occur with aerosol histamine and carbachol. Synthetic human alpha-ANP was injected into the pulmonary arteries of awake sheep chronically instrumented for measurement of lung mechanics and hemodynamics (n = 7). Base-line dynamic lung compliance (Cdyn) and pulmonary resistance (RL) did not change after ANP injection. On separate days, the dose required to reduce Cdyn to 65% of base line (ED65Cdyn) to progressive doses of aerosol histamine and the dose required to increase RL by 100% of the base-line values (ED200RL) to progressive doses of aerosol carbachol were determined. ANP was given as bolus injections of 1, 5, and 10 micrograms/kg 3 min after either the ED65Cdyn or ED200RL doses of histamine and carbachol, respectively, and the airway response was monitored for 10 min. ANP significantly reversed the rise in RL after carbachol administration (n = 10). This action of ANP was not altered by cyclooxygenase inhibition with ibuprofen. ANP did not reverse the reduction in Cdyn caused by either histamine (n = 7) or carbachol. The bronchodilating effect of ANP appears to be more prominent in the larger central airways than in the peripheral airways. The hemodynamic effects of ANP were similar to those reported by others. Heart rate and cardiac output had a biphasic response, with an initial rise followed by a drop below the base line. Systemic arterial and left atrial pressures decreased significantly. Pulmonary arterial pressure did not change significantly.(ABSTRACT TRUNCATED AT 250 WORDS)

Airway Resistance↗
PubMed1990

Lung mechanics and airway reactivity in sheep during development of oxygen toxicity.

The causes of respiratory distress in O2 toxicity are not well understood. The purpose of this study was to better define the airway abnormalities caused by breathing 100% O2. Sheep were instrumented for measurements of dynamic compliance (Cdyn), functional residual capacity by body plethysmography (FRC), hemodynamics, and lung lymph flow. Each day Cdyn and FRC were measured before, during, and after the application of 45 min continuous positive airway pressure (CPAP) at 15 cmH2O. The amount of aerosol histamine necessary to reduce Cdyn 35% from baseline (ED35) was measured each day as was the response to aerosol metaproterenol. Cdyn decreased progressively from 0.083 +/- 0.005 (SE) 1/cmH2O at baseline to 0.032 +/- 0.004 l/cm H2O at 96 h of O2. Surprisingly, FRC did not decrease (1,397 +/- 153 ml at baseline vs. 1,523 +/- 139 ml at 96 h). The ED35 to histamine did not vary among days or from air controls. Metaproterenol produced a variable inconsistent increase in Cdyn. We also measured changes in Cdyn during changes in respiratory rate and static pressure-volume relationships in five other sheep. We found a small but significant frequency dependence of compliance and an increase in lung stiffness with O2 toxicity. We conclude that in adult sheep O2 toxicity reduces Cdyn but does not increase airway reactivity. The large reduction in Cdyn in O2 toxicity results from processes other than increased airway reactivity or reduced lung volume, and Cdyn decreases before the development of lung edema.

Animals↗
PubMed1990

The fixation and prognosis of trochanteric fractures. A randomized prospective controlled trial.

A randomized prospective controlled trial of 155 patients with trochanteric fractures compared the AO dynamic hip screw and the Jewett nail plate. The dynamic hip screw showed significantly less evidence of mechanical failure and a lower incidence of reoperation. The implant had no effect on mortality or success of rehabilitation. Mortality was significantly associated with social dependence before fracture and the hospital attended. Capacity to return home and walk again were associated with mobility before fracture and age. While the fate of the majority of patients appeared to be determined by their state before fracture, hospital differences appear to offer the greatest potential for influencing the outcome of this condition.

Activities of Daily Living↗
PubMed1989

Human recombinant interleukin 2-activated sheep lymphocytes lyse sheep pulmonary microvascular endothelial cells.

Administration of lymphokine-activated killer (LAK) cells in combination with interleukin 2 (IL-2) has been effective in reducing tumor mass in humans, but has been accompanied by significant toxicity. We used a chronic awake sheep model to investigate the cause of the vascular leak syndrome associated with IL-2 administration. Sheep repeatedly infused with human recombinant IL-2 (hrIL-2) developed mild pulmonary hypertension, systemic hypotension, acidemia, hypoxemia, and increased flow of protein rich lung lymph. We hypothesized that LAK cells may damage lung endothelium in vivo and cause increased lung vascular permeability. Sheep peripheral blood and lung lymph lymphocytes incubated in vitro with hrIL-2 generated cytotoxic activity for human K-562 cells and sheep pulmonary microvascular endothelial cells. In addition, cytotoxic effector cells were isolated from the peripheral blood of a sheep which had received hrIL-2. These observations suggest that LAK cells possess the ability to damage endothelial cells and may contribute to an increased pulmonary vascular permeability observed following hrIL-2 infusion in sheep.

Animals↗