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Biomedical subjects

G H Clowes

Publications and source records attributed to G H Clowes.

At least 19 recordsLinked to original sources
PubMed1989

Sequential determinations of urinary cytology and plasma and urinary lymphokines in the management of renal allograft recipients.

Urine cytology, plasma (P), and urinary (U) interleukin-2 (IL-2)* and IL-2 receptor (IL-2R) levels were evaluated as immunological monitoring techniques in 65 renal allograft recipients. Normal individuals showed normal urine cytology, IL-2(U) = 0, IL-2(P) = 0.4 +/- 0.1 ng/ml (mean +/- SEM) and IL-2R(P) = 318 +/- 26 U/ml. Stable transplants also showed normal urine cytology, no IL-2(U), IL-2(P) = 0.8 +/- 0.2 ng/ml, and IL-2R(P) = 326 +/- 29 U/ml. Rejection episodes (n = 21) were accompanied by cytologic changes, including lymphocyturia, exfoliation of immature tubular cells, platelet aggregates, and fibrin deposits. The corresponding lymphokine changes were IL-2(U) = 39.6 +/- 1.4 ng/ml, IL-2(P) = 79 +/- 21 ng/ml, and IL-2R = 1884 +/- 202 U/ml, all markedly increased. Successful treatment was associated with return of all parameters to normal; treatment failure was associated with continued abnormalities. Fourteen rejections unresponsive to Solumedrol (500 mg x 5 days) required OKT3 rescue (5 mg x 14 days). In the 11 that were reversed, onset of OKT3 therapy was characterized by markedly increased exfoliation of necrotic cellular debris, lymphocytes, and collecting duct cells. Interestingly, serum creatinine increases of 57.2 +/- 18.9% (range 25-90%) over pre-OKT3 levels were noted. Maximal changes occurred 48-72 hr after the first dose, followed by gradual return to normal. Rejections unresponsive to OKT3 (n = 3) showed no cytologic changes from the pretreatment mean creatinine increase of 13.2 +/- 2.7% (range 9-15%), and maximum change occurred 24 hr after the first dose. Rejections responsive to Solumedrol only (n = 4) showed gradual improvement of all parameters. Rejections treated with Solumedrol following failed OKT3 prophylaxis (n = 3) did not reverse and continued to show rejection associated cytologic changes and abnormal creatinines. Patients experiencing CsA toxicity (n = 12) showed mild creatinine elevations, normal or negative IL-2(P) and IL-2R(P) levels, and no IL-2(U). They showed distinctive cytologic changes consisting of swollen convoluted tubular cells with nuclear pyknosis and cytoplasmic vacuoles. Pretransplant IL-2(P) levels of patients who subsequently rejected were elevated, with 19/21 patients with preoperative IL-2 levels greater than 15 ng/ml having subsequent rejections. In contrast, pretransplant creatinine, urine cytology, and IL-2(U) levels showed no correlation to subsequent clinical course.(ABSTRACT TRUNCATED AT 400 WORDS)

Antibodies, Monoclonal↗
PubMed1988

Immunologic and metabolic effects of caval versus portal venous drainage in small-bowel transplantation.

We compared the immunologic and metabolic effects of systemic (i.e., caval) versus portal venous drainage of small-intestinal allografts in rats. Survival times in either unidirectional rejection or graft-versus-host disease models were not significantly altered by the route of venous drainage. Portoportal and portacaval isografts and controls were then pair-fed after transplantation. After 6 weeks of pair-feeding, weight gain, plasma amino acid concentration, and the histologic appearance of the liver were similar among the three groups. Hepatic protein synthesis was greater in pair-fed rats with portoportal isografts, although this difference disappeared in the fasted state. Our data suggest that there is little immunologic or metabolic advantage of portal versus systemic venous drainage of small-intestinal allografts in rats. Because the latter is technically simpler, it may be preferable in small-bowel transplantation.

Animals↗
PubMed1987

Amino acid clearance in cirrhosis. A predictor of postoperative morbidity and mortality.

The central plasma clearance rate of amino acids (CPCR-AA), the ratio of peripheral amino acid entry rate into blood plasma to arterial amino acid concentration, was measured preoperatively in 149 noninfected cirrhotic patients. In 50 survivors of shunting or general surgical procedures, the mean (+/- SEM) CPCR-AA was 201 +/- 17 mL/m2/min; in 39 subsequent deaths, the mean ratio was 87 +/- 14 mL/m2/min. Comparing Child's classification with CPCR-AA reveals the following values: class A (mortality, two of ten patients) survivors, 152 +/- 23 mL/m2/min; class A deaths, 96 +/- 54 mL/m2/min; class C (mortality, 13 of 19 patients) survivors, 214 +/- 47 mL/m2/min; class C deaths, 101 +/- 13 mL/m2/min. The preoperative CPCR-AA of 46 patients receiving liver transplants was 91 +/- 9 mL/m2/min; 69% of these patients survived. Preoperative CPCR-AA values correlated significantly with rates of hepatic protein synthesis in incubated liver slices obtained by biopsy at operation in 22 patients. Thus, CPCR-AA determination is a true liver function test, valuable in predicting surgical mortality and selecting transplantation or other operations for cirrhotic patients.

Adult↗
PubMed1986

Augmentation of NK cell activity by a circulating peptide isolated from the plasma of trauma patients.

Natural killer cell (NK) activity was assessed in patients with nonthermal injury. NK activity was assessed employing a standard 4-hour 51Cr release. Peripheral mononuclear cells from healthy human donors and trauma ward patients served as effector cells at three effector/target ratios. Labeled K562 erythroleukemia cells were used as targets. Multiple dilutions of crude and purified proteolysis inducing factor (PIF), isolated from three septic patients, were evaluated in comparison with other adjuvants. Greater augmentation of anti-K562 activity was obtained in long-term pretreatment of effector cells with adjuvants present as opposed to immediate NK assay. Untreated effectors from trauma patients demonstrated the least amount of baseline NK activity; however, a combination of PIF and interferon showed the greatest cytotoxicity. Untreated healthy cells exhibited a significant (p less than 0.001), twofold greater amount of cytotoxicity than untreated trauma cells. PIF enhances NK activity and may be key to mobilization of host defense in trauma.

Blood Proteins↗
PubMed1986

Survival from hepatic transplantation. Relationship of protein synthesis to histological abnormalities in patient selection and postoperative management.

Forty-one patients, all in end stage hepatic failure, underwent 46 liver transplantations with a long-term survival rate of 63%. Six patients died of uncontrollable bleeding due to primary graft malfunction at or immediately after operation. Nine died early or late with overwhelming infection. In addition to clinical assessment, needle liver biopsy, central plasma clearance rate of amino acids (CPCR-AA), and routine "liver function tests" were employed to aid in selection of patients for transplantation and for guidance in postoperative management. Although liver biopsies usually afforded an exact diagnosis, neither they nor the routine liver function tests quantitated the extent to which hepatocyte function was impaired. CPCR-AA, which measures the rate of amino acid uptake by the liver and other central tissues for oxidation, gluconeogenesis, and protein synthesis was 91 +/- 9 ml/M2/min in the preoperative transplant group. This compares with a value of 97 +/- 16 in a previously studied series of cirrhotics who died following other forms of surgery and a CPCR-AA of 220 +/- 26 ml/m2/min in those who survived. In addition, the preoperative CPCR-AA was found to correlate with the in vitro hepatic protein synthetic rate of slices from the resected recipient liver (r = 0.72, p less than 0.02). After operation, serial hepatic needle biopsies were classified by histology into four grades of injury, ranging from normal liver transplant (Grade I) to mild hypoxic or rejection injury (Grade II), viral hepatitis (Grade III), and severe hypoxic or rejection injury (Grade IV). Significant relationships of the histological grades to ultimate mortality, CPCR-AA, and prothrombin times were found. CPCR-AA and prothrombin time correlate inversely (r = 0.57, p less than 0.001), further demonstrating the relationship of CPCR-AA to protein synthesis of clotting factors. These patterns of posttransplant response were delineated by serial CPCR-AA values. "Early" responders had values over 290 ml/M2/min and all survived. Twelve patients with delayed response were characterized by values of 150 +/- 12, rising to over 200 ml/M2/min after 2 weeks. Two who failed to increase CPCR-AA died. In six "poor" responders, CPCR-AA with Grade IV injury remained below 110 ml/M2/min. All died except for one whose CPCR-AA subsequently rose following retransplantation. It is concluded that percutaneous hepatic needle biopsies and CPCR-AA measurements in combination are of proven value, not only in understanding the nature of injury and functional impairment of the liver, but are also important as guides to selection of patients and for their posttransplant management.

Amino Acids↗
PubMed1986

Stimulation of muscle protein degradation by murine and human epidermal cytokines: relationship to thermal injury.

Accelerated muscle proteolysis is a characteristic of systemic reaction following trauma, sepsis, or extensive thermal injury. The factors involved in this accelerated muscle breakdown have not been fully described. However, recently leukocytic pyrogen or interleukin 1 (IL-1) have been implicated in the induction of muscle protein degradation in septicemia or trauma. The epidermal cytokine epidermal cell-derived thymocyte activating factor (ETAF) is biochemically and functionally similar to IL-1. Injury to skin can augment ETAF activity. Using a murine model, we found that thermal injury can significantly enhance ETAF/IL-1 activity in a dose-dependent fashion. In addition, ETAF can cause net muscle protein breakdown in vitro. Thus, increased amounts of ETAF produced by thermally injured skin may contribute to the accelerated muscle breakdown in extensive thermal injury.

Animals↗
PubMed1985

Tumor-associated metabolism in the rat is a unique physiologic entity.

The metabolic responses associated with the tumor-bearing state, as compared to states of sepsis and prolonged starvation, were examined. Tumor-bearing rats manifested significant elevation of triglycerides, significant reduction of glucose and insulin levels, significantly increased plasma skeletal muscle proteolysis-inducing activity, and an unchanged hepatic protein synthetic activity compared to control rats. Prolonged starvation produced an adaptation characterized by significant hypoglycemia and hypoinsulinemia, reduced hepatic protein synthesis, and increased peripheral protolysis compared to controls. Septic animals had glucose, insulin, and lipid levels similar to control animals but had increased hepatic protein synthesis. Each state manifested its own unique metabolic response compared to controls. It appears that the metabolic consequences of cancer in this sarcoma rat model is different than septic and prolonged starvation states.

Animals↗
PubMed1985

Survival from sepsis. The significance of altered protein metabolism regulated by proteolysis inducing factor, the circulating cleavage product of interleukin-1.

Amino acid (AA) arterial blood plasma concentrations, K1 (peripheral production + infusion rates), and central plasma clearance rates (K1 divided by arterial concentration) (CPCR-AA) were measured in 70 seriously septic patients. All of these people were in the "hyperdynamic" state at the time of observation. Thirty-seven recovered and 33 died. In addition, 10 noninfected, nontraumatized patients about to undergo laparotomy were studied. In 31 patients receiving parenteral alimentation, CPCR-AA was 326 +/- 38 in survivors and 160 +/- 17 ml/M2/min in the deaths (p less than 0.005). In 58 patients studied, while fasted with no intravenous amino acid infusion, values for CPCR-AA were: survivors 202 +/- 22 (28) and deaths 112 +/- 16 (30) ml/M2/min (p less than 0.002). The CPCR-AA in 10 noninfected patients was only 68 +/- 11 ml/M2/min. CPCR-AA in 19 patients correlated with hepatic protein synthetic rates in liver biopsies obtained simultaneously (r = 0.658, p less than 0.01), which shows that CPCR-AA is an indicator of visceral protein synthesis. To study the regulation of amino acid metabolism by synthesis. To study the regulation of amino acid metabolism by proteolysis inducing factor (PIF), the proteolysis inducing activity (PIA) of the plasma fraction (0-50,000 D) was measured 55 times in conjunction with metabolic studies. No significant differences existed in PIA between survivors and deaths. However, in those patients who recovered, PIA was significantly correlated to both peripheral amino acid production (r = 0.773, p less than 0.001) and to CPCR-AA (r = 0.721, p less than 0.001). This observation demonstrates the presence of one or more circulating agents affecting amino acid flux. PIA measured simultaneously in vivo correlated with in vitro protein synthetic rate in incubated liver biopsies (r = 0.653, p less than 0.01). PIF (4,000 D), isolated by chromatography, in patients without amino acid infusion was 35 +/- 3% in survivors and 33 +/- 6% in deaths (N.S.) and only 9 +/- 3% over control in noninfected patients. In patients who recovered, PIF titre was strongly correlated with peripheral amino acid production (r = 0.798, p less than 0.001) and with CPCR-AA (r = 0.835, p less than 0.001). However, values for patients who later died were significantly less for a given PIF titre. Thus, it is concluded that survival from sepsis is, in part, dependent on a significantly elevated CPCR-AA and hepatic protein synthesis, both of which appear to be related to the blood plasma PIF titre.

Amino Acids↗
PubMed1985

Prognosis and survival as determined by visceral amino acid clearance in severe trauma.

Sepsis, the commonest cause of late death following severe trauma, is related in part to inadequate uptake of amino acids (AA) and synthesis by the liver and other central tissues of proteins essential to immunological defense. Since 'central plasma clearance rate' of amino acids (CPCR-AA) has been found to reflect these functions, serial measurements of CPCR-AA were made in 32 seriously injured patients of whom ten died (31%), nine of sepsis. The mean Index Severity Score on admission for survivors was 31 +/- 1.8 and in deaths 34 +/- 3.9 (N.S.). The blood plasma AA concentrations were not significantly different. However, early in the course before the onset of infection, CPCR-AA in surviving patients was 227 +/- 30 and in those who ultimately died 83 +/- 24 ml/M2/min (p less than 0.001). Later during sepsis the values of CPCR-AA were 176 +/- 28 and 85 +/- 14 ml/M2/min, respectively (p less than 0.01). Thus CPCR-AA appears to be of value as an indicator of amino acid utilization by central tissues and as a predictor of survival or death following severe trauma.

Adult↗
PubMed1984

Encephalopathy, oxygen consumption, visceral amino acid clearance, and mortality in cirrhotic surgical patients.

To assess the relationship of the high mortality of coma in cirrhotic surgical patients to defects in energy metabolism, reduced utilization of amino acids by the liver and other visceral tissues, oxygen consumption, central plasma clearance rate of amino acids (CPCR of amino acids), and the plasma concentrations of plasma inducing factors were measured in a series of 59 cirrhotic patients. They were classed as alert, encephalopathic, and comatose (Groups A, E, and C, respectively). The comatose group was set apart from the other two by a significantly higher mortality of 83 percent (p less than 0.005) combined with a lower whole body oxygen consumption of 103 +/- 6.8 ml/min per m2 compared with 135 +/- 10 ml/min per m2 in alert patients and 159 +/- 12 ml/min per m2 in the encephalopathic patients (p less than 0.01) and CPCR of amino acids of only 120 +/- 20 ml of plasma/min per m2 compared with 240 +/- 30 ml of plasma/min per m2 in the alert patients and 300 +/- 50 in the encephalopathic patients (p less than 0.01). An inverse correlation of tyrosine and phenylalanine concentrations existed with both whole body oxygen consumption (r = -0.56, p less than 0.01) and also with total amino acid clearance (r = -0.61, p less than 0.01). Tyrosine and phenylalanine concentrations also correlated directly with the octopamine concentration (r = 0.64, p less than 0.01). Thus, we conclude that coma is a symptom of hyperaminoacidemia, but that death is the result of impaired oxidative energy production and a deficiency of amino acid clearance for synthesis of proteins required for survival.

Adult↗
PubMed1984

Amino acid clearance and prognosis in surgical patients with cirrhosis.

To measure the effects of cirrhosis on amino acid (AA) flux and to assess the value of the central plasma clearance rate of amino acids (CPCR-AA) as a hepatocyte function test, 35 patients with cirrhosis were studied before and after operation. Fourteen of these patients died after the operation. CPCR-AA measures the number of milliliters of plasma cleared of AA per minute by the liver and other visceral tissues. It is the ratio of AA entry rate into plasma (from peripheral tissues plus infusion) to the arterial AA plasma concentration. Preoperative CPCR-AA measurements in 21 fasted patients with cirrhosis who were not infected revealed a pattern of AA plasma concentration and exchange similar to that previously observed in patients with sepsis with normal liver function. Whereas the concentration of AA in both groups was slightly lower than normal, the CPCR-AA of each was more than four times that of normal postabsorptive people (p less than 0.01). However, preoperative values of CPCR-AA in patients with cirrhosis who survived was 220 +/- 26 ml/M2/min while that in those who died was 97 +/- 16 ml/M2/min (p less than 0.001). Postoperative measurements remained relatively unchanged: survivors 212 +/- 24 ml/M2/min and those who died 89 ml/M2/min (p less than 0.0005). Measurements in vitro of the hepatic protein synthetic rate in liver biopsy specimens taken at operation correlated well with CPCR-AA values obtained immediately before operation in 10 patients (r = 0.73; p less than 0.01). Thus in patients with cirrhosis visceral amino acid uptake and hepatic protein synthesis are maximally stimulated. Nevertheless, if the preoperative CPCR-AA does not approach the value of 284 +/- 76 ml/M2/min previously observed in patients with sepsis who recover, the patient with cirrhosis is prone postoperatively to die of overwhelming infection and multisystem failure.

Amino Acids↗
PubMed1984

Cleavage of human interleukin 1: isolation of a peptide fragment from plasma of febrile humans and activated monocytes.

Interleukin 1 (IL 1) is a product(s) of mononuclear phagocytes, and has multiple biologic activities that mediate several host responses to infection and inflammation. Highly purified IL 1 activates lymphocytes, induces fever, increases hepatic acute phase protein synthesis, and increases muscle protein degradation. A 4.2 kd peptide has been purified from plasma of febrile humans which also induces muscle proteolysis in vitro (termed proteolysis-inducing factor, PIF). Because IL 1 purified from activated human monocytes induces muscle proteolysis in vitro, studies were performed to determine the relationship of human monocyte-derived IL 1 to plasma-derived PIF. Purified PIF was highly active in the IL 1 thymocyte assay. After gel filtration of plasma from febrile patients, fractions with PIF activity also induced thymocyte proliferation and fever in mice. Thus, it seems likely that the plasma peptide PIF has IL 1 properties and probably represents a small m.w. cleavage product of IL 1. Further studies confirmed this finding. Highly purified 15 kd IL 1, rechromatographed over different gel filtration media, consistently fragmented into a 4 kd peptide with both muscle proteolysis-inducing and lymphocyte-activating properties. The breakdown of the 15 kd IL 1 into biologically active smaller fragments increased with time, and could be accelerated by trypsinization. The monocyte-derived IL 1 fragments were partially destroyed by heat. Highly purified 125I-labeled 15 kd IL 1 also fragmented into subunits, and these radioactive subunits produced fever in mice and were active in the thymocyte assay. Fragmentation of 125I-labeled 15 kd IL 1 was reduced by agents that inhibit proteases. These results indicate that some of the biologic activities of human IL 1 are conserved in small m.w. fragments. These studies also provide evidence that IL 1 may circulate in humans as a 4.2 kd peptide, and that this cleavage product can function as an active mediator of IL 1 effects in the host.

Animals↗
PubMed1984

Induction of hepatic protein synthesis by a peptide in blood plasma of patients with sepsis and trauma.

Accelerated release of amino acids from muscle and their uptake for protein synthesis by liver and other visceral tissues are characteristic of trauma or sepsis. Experimentally, this response is induced by interleukin-1 (IL-1) generated by activated macrophages in vitro. However, IL-1 has not been demonstrated in human blood. A small 4000-dalton peptide recently isolated from plasma of patients with sepsis and trauma induces muscle proteolysis and is called "proteolysis-inducing factor" (PIF). To test whether this agent has the ability also to induce hepatic protein synthesis, a series of animal experiments and clinical observations were undertaken. The structural and secretory (acute-phase reactants) in vitro protein synthesis in livers of normal rats injected intraperitoneally with IL-1 or PIF was significantly greater than that of normal rats or those injected with Ringer's lactate (p less than 0.01). In patients with sepsis and trauma the central plasma clearance rate of amino acids, a measure of visceral (principally hepatic) amino acid uptake, was elevated and correlated with the rates of protein synthesis in incubated liver slices obtained by biopsy at operation from the same patients (p less than 0.05). Both in vivo measured central plasma clearance rate of amino acids and in vitro measured hepatic protein synthesis correlated with plasma levels of PIF in the same patients (p less than 0.01 and p less than 0.05, respectively). We conclude that since PIF, and not IL-1, is present in human plasma and both are produced by activated macrophages, PIF seems to be the stable circulating cleavage product of IL-1, which induces not only muscle proteolysis but also hepatic protein synthesis, principally in the form of acute-phase reactants during infection and other states in which inflammation is present.

Amino Acids↗
PubMed1983

Muscle proteolysis induced by a circulating peptide in patients with sepsis or trauma.

Accelerated proteolysis of muscle is characteristic in patients with trauma or sepsis, but its cause is not well understood. Using rat muscle in vitro, we developed a bioassay to compare the proteolytic activity of plasma from 50 patients with trauma or sepsis with that of plasma from 14 normal volunteers and from 15 patients who had undergone "clean" elective surgical procedures. The mean proteolytic activity in the plasma of patients with trauma or sepsis was found to be 190 +/- 8.0 per cent of the control value (rat muscle incubated in medium alone), whereas the activity in normal plasma was 124 +/- 4.5 per cent (P less than 0.001). The activity in the plasma of patients who had undergone elective surgery was slightly elevated at 142 +/- 2.5 per cent (P less than 0.005). In 25 of the patients with trauma or sepsis the rate of amino acid release from one leg was measured by subtracting the concentration of tyrosine plus phenylalanine in the femoral artery plasma from that in the femoral vein; this rate correlated well with the bioactivity of the plasma in the bioassay system (r = 0.67, P less than 0.001). By means of ultrafiltration and chromatography, the plasma factor inducing proteolysis was isolated and found to be a peptide, probably containing sialic acid, with a chain of 33 amino acids and a molecular weight of approximately 4274 daltons.

Amino Acids↗