Management of post-partum haemorrhage.

Management of post-partum haemorrhage (PPH) involves the treatment of uterine atony, evacuation of retained placenta or placental fragments, surgery due to uterine or birth canal trauma, balloon tamponade, effective volume replacement and transfusion therapy, and occasionally, selective arterial embolization. This article aims at introducing pregnancy- and haemorrhage-induced changes in coagulation and fibrinolysis and their relevant compensatory mechanisms, volume replacement therapy, optimal transfusion of blood products, and coagulation factor concentrates, and briefly cell salvage, management of uterine atony, surgical interventions, and selective arterial embolization. Special attention, respective management, and follow-up are required in women with bleeding disorders, such as von Willebrand disease, carriers of haemophilia A or B, and rare coagulation factor deficiencies. We also provide a proposal for practical instructions in the treatment of PPH.

Results at 3-year follow-up of totally extraperitoneal (TEP) hernia surgery with long-term resorbable mesh.

INTRODUCTION: Synthetic non-resorbable mesh is almost standard in hernia surgery. However, several studies have showed negative effects of permanent implants such as chronic inflammation and complications involving different organs bordering the mesh. Such complications can raise the risk of chronic post-operative pain (CPP). Recently promising results regarding CPP have been published in patients with Lateral Inguinal Hernia (LIH) using a slowly resorbable mesh in Lichtenstein technique. For this reason the aim of the present study was to find the effect of a slowly resorbable implant on the long-term rate of hernia recurrence and chronic post-operative pain in patients with LIH repaired with TEP procedure. METHODS: Prospective pilot study of TEP repair using TIGR® Matrix Surgical Mesh in 35 primary LIH. At 3-year follow-up the Visual Analogue Scale (VAS) and the Inguinal Pain Questionnaire were employed to assess pain. Recurrence was determined by ultrasound and clinical examination. RESULTS: All patients completed the pain questionnaires but one patient did not attend the planned clinical examination for the 3-year follow-up. No patients had CPP, as defined in the World Guidelines for Groin Hernia Management. Almost all patients had lower VAS score in any activity 3 years following surgery in comparison to the preoperative period. Three patients (8.8%) suffered symptomatic recurrence during the 3-year follow-up. CONCLUSION: TEP repair in patients with LIH using a synthetic long-term resorbable mesh was found to be encouraging respecting chronic post-operative pain at 3-year follow-up but at the cost of an increased risk of recurrence.

PET amyloid ligand [11C]PIB uptake shows predominantly striatal increase in variant Alzheimer's disease.

Variant Alzheimer's disease (VarAD) with spastic paraparesis and presenile dementia is associated with certain mutations of the presenilin 1 (PS-1) gene, particularly those leading to deletion of exon 9 (PS-1Delta E9). VarAD is neuropathologically characterized by the presence of unusually large, Abeta42 positive, non-cored 'cotton wool' plaques (CWPs), also devoid of dystrophic neurites. The aim of the present study was to find out whether [(11)C]PIB would show increased uptake and serve as an in vivo biomarker of amyloid accumulation in VarAD. A further aim was to assess the correspondence of the [(11)C]PIB binding to the amount and type of Abeta deposits in another group of deceased VarAD patients' brains. We studied four patients with VarAD and eight healthy controls with PET using [(11)C]PIB as tracer. Parametric images were computed by calculating the region-to-cerebellum and region-to-pons ratio in each voxel over 60-90 min. Group differences in [(11)C]PIB uptake were analysed with automated region-of-interest (ROI) analysis. [(11)C]PIB uptake was compared to the immunohistochemically demonstrated deposition of Abeta in the brains of another group of four deceased VarAD patients. Patients with VarAD had significantly higher [(11)C] PIB uptake than the control group in the striatum (caudate nucleus and putamen), anterior and posterior cingulate gyrus, occipital cortex and thalamus. In the caudate and putamen [(11)C]PIB uptake, expressed as region-to-cerebellum ratio, was on the average 43% greater than the mean of the control group. The increases in the anterior (28%) and posterior (27%) cingulate gyrus, occipital cortex (21%) and thalamus (14%) were smaller. All VarAD patients showed this similar topographical pattern of increased [(11)C]PIB uptake. The results were essentially similar when the uptake was expressed as region-to-pons ratios. [(11)C]PIB imaging shows increased uptake in patients with VarAD especially in the striatum, and it can be used to detect amyloid accumulation in vivo in these patients. The pattern of increased [(11)C]PIB uptake is different from that described in sporadic Alzheimer's disease and resembles that seen in Alzheimer's disease patients with certain presenilin-1 mutations or amyloid precursor protein gene duplication showing predominantly striatal increase in [(11)C]PIB uptake.

Premedication with pregabalin 75 or 150 mg with ibuprofen to control pain after day-case gynaecological laparoscopic surgery.

BACKGROUND: Multimodal pain management has been suggested to improve postoperative analgesia. In this study, we evaluated the quality of analgesia in women undergoing day-case gynaecological laparoscopic surgery, after premedication with pregabalin 75 mg (P75) or 150 mg (P150), compared with diazepam 5 mg (D5). All patients were given ibuprofen 800 mg orally. METHODS: Altogether 90 consenting women were anaesthetized in a standardized fashion. Postoperative analgesia was provided by ibuprofen 800 mg twice a day with fentanyl i.v. on request in the recovery room (RR), and combination tablets with acetaminophen and codeine after the RR. The visual analogue scale (VAS) scores for pain and side-effects and the amounts of postoperative analgesics were recorded for 24 h after surgery. The areas under the curves (AUC) were calculated for the VAS scores for pain at rest, pain in motion, and pain at cough 1-8 and 1-24 h after surgery. RESULTS: The median AUC values for VAS scores for pain at rest (P=0.048) and in motion (P=0.046) 1-8 h after surgery were lower in the P150 group than that in the D5 group. The amounts of rescue analgesics or the degree of drowsiness did not differ in the three study groups. CONCLUSIONS: Analgesia was better after premedication with pregabalin 150 mg than after diazepam 5 mg, both with ibuprofen 800 mg, during the early recovery after day-case gynaecological laparoscopic surgery. Pregabalin 150 mg did not reduce the amount of postoperative analgesics required.

Midazolam and other benzodiazepines.

The actions of benzodiazepines are due to the potentiation of the neural inhibition that is mediated by gamma-aminobutyric acid (GABA). Practically all effects of the benzodiazepines result from their actions on the ionotropic GABA(A) receptors in the central nervous system. Benzodiazepines do not activate GABA(A) receptors directly but they require GABA. The main effects of benzodiazepines are sedation, hypnosis, decreased anxiety, anterograde amnesia, centrally mediated muscle relaxation and anti-convulsant activity. In addition to their action on the central nervous system, benzodiazepines have a dose-dependent ventilatory depressant effect and they also cause a modest reduction in arterial blood pressure and an increase in heart rate as a result of a decrease of systemic vascular resistance. The four benzodiazepines, widely used in clinical anaesthesia, are the agonists midazolam, diazepam and lorazepam and the antagonist flumazenil. Midazolam, diazepam and flumazenil are metabolized by cytochrome P450 (CYP) enzymes and by glucuronide conjugation whereas lorazepam directly undergoes glucuronide conjugation. CYP3A4 is important in the biotransformation of both midazolam and diazepam. CYP2C19 is important in the biotransformation of diazepam. Liver and renal dysfunction have only a minor effect on the pharmacokinetics of lorazepam but they slow down the elimination of the other benzodiazepines used in clinical anaesthesia. The duration of action of all benzodiazepines is strongly dependent on the duration of their administration. Based on clinical studies and computer simulations, midazolam has the shortest recovery profile followed by lorazepam and diazepam. Being metabolized by CYP enzymes, midazolam and diazepam have many clinically significant interactions with inhibitors and inducers of CYP3A4 and 2C19. In addition to pharmacokinetic interactions, benzodiazepines have synergistic interactions with other hypnotics and opioids. Midazolam, diazepam and lorazepam are widely used for sedation and to some extent also for induction and maintenance of anaesthesia. Flumazenil is very useful in reversing benzodiazepine-induced sedation as well as to diagnose or treat benzodiazepine overdose.

Fluctuation in spontaneous recovery of left visual neglect: a 1-year follow-up.

Spontaneous recovery and possible fluctuation in left visual neglect, and its relation to stroke severity, basic activities of daily living (ADL) and extended ADL were examined at 10 days, at 3, 6, and 12 months after onset. Twenty-one of 56 right hemisphere stroke patients had visual neglect. Three visual neglect recovery groups were identified: continuous, fluctuating and poor recovery. We concentrated on the comparison of the continuous and the fluctuating recovery groups. At the acute phase the fluctuating recovery group had larger infarcts, more severe neglect and stroke, and a lower level of basic ADL compared to the continuous recovery group. In the continuous recovery group stable recovery was detected up to 6 months, whereas in the fluctuating recovery group recovery was incoherent in neglect and in extended ADL. A minimum follow-up period of 6 months including the evaluation of extended ADL is recommended for neglect patients due to possible fluctuation in visual neglect.

De novo seropositive rheumatoid arthritis during immunosuppressive treatment after kidney transplantation.

We detected de novo seropositive erosive rheumatoid arthritis (RA) in a patient seven years after successful cadaveric kidney transplantation (RTx). RA developed in spite of treatment with cyclosporine A (CyA), methylprednisolon (MP) and azathioprine (Aza), compounds often also used for treatment of active RA. Renal failure was due to diabetes mellitus (DM) nephropathy. Besides a slight increase in C-reactive protein (CRP) concentration two years after RTx, the clinical symptoms of RA were observed seven years after RTx. RA was confirmed by X-ray examination, isotopic skeletal scan and positive serum RA factor. After switching Aza to methotrexate (Mtx) treatment, his symptoms disappeared and CRP concentration returned to normal. Our patient had HLA DRB1 *0101, *0401 alleles and DQB1 *0501, *0302 alleles which have strong genetic association with both DM and RA. To our best knowledge, this is the first case in which de novo seropositive erosive RA developed while on treatment with triple immunosuppression after RTx. The immunosuppressive treatment probably masked the inflammation and symptoms of RA.

Effects of dietary sodium and magnesium on cyclosporin A-induced hypertension and nephrotoxicity in spontaneously hypertensive rats.

Arterial hypertension, nephrotoxicity, and magnesium loss are common side effects of the immunosuppressive agent cyclosporin A (CsA). In the present study, the effects of dietary sodium and magnesium on CsA toxicity were examined in spontaneously hypertensive rats. A 6-week treatment with CsA during a moderately low-sodium diet (Na 0.3%, Mg 0.2% of the dry weight of the chow) raised blood pressure only slightly, without evidence of nephrotoxicity. By contrast, CsA during a high-sodium diet (Na 2.6%) produced a pronounced rise in blood pressure as well as marked nephrotoxicity, comprising decreased creatinine clearance, increased levels of serum creatinine and urea, and increased urinary protein excretion. During the high-sodium diet, CsA decreased myocardial and bone magnesium concentration and increased myocardial and renal calcium concentration. Magnesium supplementation (Mg 0.6%) protected against the CsA-induced hypertension and nephrotoxicity during the high-sodium diet. Magnesium supplementation also completely prevented the CsA-induced myocardial magnesium depletion and calcium accumulation in the heart and kidney during the high-sodium diet. Our findings indicate a detrimental interaction between increased sodium intake and CsA treatment and a marked protection by concomitant oral magnesium supplementation.

Effect of saquinavir on the pharmacokinetics and pharmacodynamics of oral and intravenous midazolam.

OBJECTIVE: To assess the effect of human immunodeficiency virus protease inhibitor saquinavir on the pharmacokinetics and pharmacodynamics of oral and intravenous midazolam. METHODS: In a double-blind, randomized, two-phase crossover study, 12 healthy volunteers (six men and six women; age range, 21 to 32 years) received oral doses of either 1200 mg saquinavir (Fortovase soft-gel capsule formulation) or placebo three times a day for 5 days. On day 3, six subjects were given 7.5 mg oral midazolam and the other six subjects received 0.05 mg/kg intravenous midazolam. On day 5, the subjects who had received oral midazolam on day 3 received intravenously midazolam and vice versa. Plasma concentrations of midazolam, alpha-hydroxymidazolam, and saquinavir were determined for 18 hours after midazolam administration, and midazolam effects were measured up to 7 hours by six psychomotor tests. RESULTS: Saquinavir increased the bioavailability of oral midazolam from 41% to 90% (P < .005), the peak midazolam plasma concentration more than twofold, and the area under plasma concentration-time curve more than fivefold (P < .001). During saquinavir treatment, five of the six psychomotor tests revealed impaired skills and increased sedative effects after midazolam ingestion (P < .05). Saquinavir decreased the clearance of intravenous midazolam by 56% (P < .001) and increased its elimination half-life from 4.1 to 9.5 hours (P < .01). After intravenous midazolam, only the subjective feeling of drug effect was increased significantly (P < .05) by saquinavir. CONCLUSION: The dose of oral midazolam should be greatly reduced or avoided with saquinavir, but bolus doses of intravenous midazolam can probably be used quite safely. During a prolonged midazolam infusion, an initial dose reduction of 50% followed by careful titration is recommended to counteract the reduced clearance caused by saquinavir.

Effect of rifampin and tobacco smoking on the pharmacokinetics of ropivacaine.

OBJECTIVE: Our objective was to assess the effect of rifampin (INN, rifampicin) and tobacco smoking on the pharmacokinetics of ropivacaine. METHODS: A randomized, 2-phase, crossover study was performed in both a group of 10 healthy nonsmokers and a group of 8 healthy smokers. In both groups each subject ingested daily for 5 days either placebo or 600 mg rifampin. On day 6 each subject received intravenously over 30 minutes a single dose of 0.6 mg/kg ropivacaine. Ropivacaine, 3-hydroxyropivacaine (3-OH-ropivacaine), and (S) -2',6'-pipecoloxylidide (PPX) in venous plasma and urine were measured for up to 12 hours and 24 hours, respectively. Pharmacokinetic parameters were calculated with noncompartmental methods, and t tests were used for comparisons between the phases and between the smokers and nonsmokers. The electrocardiogram was monitored for 3 hours. RESULTS: There were no statistically significant differences in the area under the plasma concentration-time curve (AUC), plasma clearance (CL), or half-life (t(1/2)) of ropivacaine between the smokers and nonsmokers. However, smokers excreted in urine 31% more 3-OH-ropivacaine and 62% less PPX than nonsmokers did. Rifampin decreased the AUC of ropivacaine in nonsmokers by 52% and in smokers by 38%. In nonsmokers rifampin increased the CL of ropivacaine by 93% and shortened its t(1/2) by 25%. In smokers rifampin increased the CL of ropivacaine by 47% and shortened its t(1/2) by 20%. Rifampin decreased the urinary excretion of 3-OH-ropivacaine in nonsmokers by 74% and in smokers by 68%, and it increased the excretion of PPX by 97% and 158%, respectively. No clinically significant differences in the QTc times were found between the groups or treatments. CONCLUSIONS: Tobacco smoking increases the excretion of 3-OH-ropivacaine in urine, probably because of the increased cytochrome P450 (CYP) 1A2-mediated metabolism of ropivacaine, and decreases the excretion of CYP3A4-formed PPX in urine. Rifampin considerably increases the metabolism of ropivacaine to PPX and decreases the metabolism to 3-OH-ropivacaine in both nonsmokers and smokers.

The effect of ascorbate and ubiquinone supplementation on plasma and CSF total antioxidant capacity.

Free radicals are thought to be involved in the onset of neuronal disturbances such as Alzheimer's disease, Parkinson's disease, and neuronal ceroid lipofuscinosis. It is also assumed that they play a role in cerebral injury caused by ischemia or trauma. Plasma and cerebrospinal fluid (CSF), Total (peroxyl) Radical-trapping Antioxidant Parameter (TRAP), and the known antioxidant components of TRAP, for instance, ascorbic acid, uric acid, protein sulfhydryl groups, tocopherol, and ubiquinol were analyzed and the remaining unidentified fragment was calculated in five healthy volunteers before and after 4 weeks of ascorbate and ubiquinone (Q-10) supplementation. In CSF, TRAP was significantly lower than in plasma. The major contributor to plasma's antioxidant capacity was uric acid (UA), whereas in CSF it was ascorbic acid (AA). In CSF, AA concentrations were four times higher than in plasma. Oral supplementation of AA (500 mg/d first 2 weeks, 1,000 mg/d following 2 weeks) and Q-10 (100 mg/d first 2 weeks, 300 mg/d following 2 weeks) induced a significant increase in plasma AA and Q-10. Surprisingly, in spite of the high lipophilicity of Q-10, its concentration did not change in CSF. The supplementation of AA increased its concentration in CSF by 28% (p < .05). However, the increase in AA did not result in an increase in CSF TRAP. This indicates that AA had lost one-third of its radical trapping capacity as compared to that in plasma. The facts that AA is the highest contributor to CSF TRAP and its effect on TRAP is concentration dependent could indicate that the peroxyl radical-trapping capacity of CSF is buffered by AA.

Renal transplantation in 45 patients with amyloidosis.

The results of renal transplantation in patients with amyloidosis were studied in 45 patients receiving primary cadaver grafts at a single center between March 1973 and October 1981. A control group of 45 patients with glomerulonephritis receiving primary cadaver grafts during the same period was also studied. These were matched according to the number of A and B locus incompatibilities and the date of transplantation. The 3-year survival of the patients with amyloidosis was statistically significantly inferior (51%) to that of the controls (79%). Age over 40 years was the major factor determining low survival in these patients. Mortality was concentrated in the early posttransplantation period. The 3-year graft survival rate was the same in amyloidotics (38%) and controls (45%); with death of patients not included in graft loss, the corresponding figures were 53% and 49%. Appearance of amyloid in the transplant was established by biopsy in four patients at 11-37 months of follow-up. Renal transplants functioning for more than one year were calculated to incur a minimum risk of 20% of acquiring amyloid.

Serum amyloid A protein: a sensitive indicator of renal allograft rejection in humans.

Acute human renal allograft rejection induces a dramatic elevation of serum amyloid A protein (SAA). To evaluate the clinical significance of this finding we monitored 31 consecutive recipients of cadaveric renal allografts by daily SAA measurements. SAA increased significantly during 37/38 rejection episodes. Mean peak SAA level during the reversible rejections was 271 +/- 31 mg/L (SE, median 220 mg/L, n = 35) and during the irreversible rejections 680 +/- 29 mg/L (median 705 mg/L, n = 3). Excluding the predictable operation-induced SAA elevations that peaked on the second post-operative day, there were seven out of 42 SAA elevations (greater than or equal to 100 mg/L) not due to rejection. They were all caused by severe infections, and in one instance by a surgical complication. In 17 of the 35 SAA-positive rejections the SAA elevation (greater than or equal to 100 mg/L) preceded the clinical diagnosis by 1-5 days; in 11 it occurred on the same day; and in 7 one day later. Rejection episodes in recipients with initially nonfunctioning grafts were all also characterized by significant SAA elevations. We conclude that daily monitoring of SAA concentrations offers a valuable aid in the early diagnosis of acute allograft rejection. The SAA test is not a renal function test, so it can also be carried out in transplant patients who are anuric or oliguric in the postgrafting stage.

Changes of urinary alpha1-microglobulin in the assessment of prognosis in renal transplant recipients.

BACKGROUND: After transplantation, even if the graft starts functioning immediately, there are morphological and functional changes in tubular structures. In addition, acute allograft rejection causes damage in the tubular epithelium, tubular basement membrane, and intertubular connective tissue. It also affects the functional capacity of proximal tubular cells resulting in impaired reabsorption and thus increased urinary excretion of low molecular weight proteins. METHODS: We present a double-antibody radioimmunoassay for determination of the concentration of alpha1-microglobulin (alpha1 M) in urine. It was used to measure urinary excretion of alpha1 M approximately once a week during the first 1-6 posttransplant weeks in 136 consecutive patients: 30 patients developing acute rejection (75 24-hr urine samples) and 106 patients with stable graft function (223 24-hr urine samples). The results are expressed as alpha1 M/creatinine ratios. RESULTS: Approximately 8 days after transplantation the mean (+/-SD) urinary alpha1 M/creatinine ratio of all patients was 17.0+/-14.8 mg/mmol, being about the same both in patients with uncomplicated posttransplantation course (16.3+/-14.0 mg/mmol) and in those who later developed rejection (19.3+/-15.1 mg/mmol), but about 60-fold higher than in healthy controls (0.27+/-0.15 mg/mmol). At that time, when all patients were included there was a correlation (r=0.3465, P<0.001) between alpha1 M/creatinine ratio and duration of cold ischemia. Thereafter, during the second week alpha1 M/creatinine ratio decreased in 89% of patients with stable graft function, but only in 14% of patients who later developed rejection (P<0.001). On the contrary, a significant increase (P<0.01) of alpha1 M/creatinine ratio was observed 4 to 1 day before rejection in all 15 patients, who had urines collected at that time. At the end of the follow-up period, alpha1 M/creatinine ratio in patients with rejection was 3-fold compared with the nonrejecting patients, and 100-fold compared with the healthy controls. CONCLUSION: These results show that cadaveric transplantation results in impaired low molecular weight protein reabsorption, the degree of dysfunction relating to the duration of cold ischemia, and suggest that during the posttransplant weeks decreasing alpha1 M/creatinine ratio in consecutively collected urine samples indicates improved tubular function and in most cases rules out development of acute rejection.

An experimental model of chronic renal allograft rejection in the rat using triple drug immunosuppression.

BACKGROUND: Chronic rejection is a major problem in renal transplantation. Various experimental models have been developed to study vasculopathy of chronic rejection. However, animal models resembling the clinical situation of renal transplantation with combination therapy of basic immunosuppression are not available. The aim of this study was to find an experimental model of a donor-recipient rat strain combination that, under triple drug immunosuppressive treatment (methylprednisolone, cyclosporine, and azathioprine), would develop chronic rejection within a few weeks. METHODS: Renal transplantations were performed in strain combinations of DA-->AO, PVG-->BN, and DA-->BN. In each group, 5-8 animals received triple drug treatment of methylprednisolone (2 mg/kg), azathioprine (2 mg/kg), and cyclosporine (5 mg/kg) daily, 5-10 animals were left without treatment, and 6 syngenic transplantations were performed. The grafts were monitored with ultrasound-guided fine needle aspiration biopsies to quantify the inflammation in the graft. Graft histology was performed in parallel and quantified by using the chronic allograft damage index (CADI). RESULTS: In nonimmunosuppressed animals, irreversible acute rejection with a high peak of inflammation appeared in every strain combination within 5-8 days. In triple drug-treated rats, the DA-->AO combination demonstrated a prolonged acute rejection but no characteristic chronic changes, and the PVG-->BN combination showed practically no inflammation and did not develop any signs of chronic rejection within 60 days (CADI: 2.7+/-2.1), but the DA-->BN combination showed an early, mild inflammatory response 5-7 days after transplantation and developed chronic rejection within 40-60 days after transplantation (CADI: 7.9+/-3.1). Syngenic animals showed no inflammation or histological alterations (CADI: 1.7+/-2.0). CONCLUSIONS: In conclusion, in the DA-->BN combination with triple drug treatment, early mild inflammation was followed by the development of chronic rejection and can be used as an experimental model that resembles the clinical situation in renal transplantation.

Cytotoxic T cells recognizing minor transplantation antigens, and possibly a variant of the HLA-B8 molecule. Cause of rejection of an HLA-identical sibling kidney transplant?

A male uremic patient was first transplanted with a kidney from a female cadaveric donor. The kidney was rejected after two weeks. He was retransplanted approximately one year later with a kidney from his HLA-identical sister. This graft was also irreversibly rejected after one week. No serum antibodies could be detected against the sibling donor before or after transplantation, but the recipient had formed donor-specific cytotoxic T lymphocytes (CTLs). The CTLs were cloned, and clones with two different specificities were obtained. One clone lysed target cells from the donor, from some other family members, and from 50% of a panel sharing HLA-B15 with the recipient. It may recognize a minor transplantation antigen, that is restricted by HLA-B15. The other clone lysed target cells from the donor, from all HLA-B8-positive family members (except the recipient), and from third-party cell donors sharing HLA-B8 with the recipient. When CTLs from third-party individuals were induced toward HLA-B8, target cells from all HLA-B8-positive family members were lysed, except those from the recipient. This indicates that the recipient may have inherited a variant of HLA-B8 that is not detectable by antibodies but by CTLs. These donor-specific CTLs may have contributed to the rejection of the HLA-identical sibling transplant.

Does increased urinary interleukin-1 receptor antagonist/interleukin-1beta ratio indicate good prognosis in renal transplant recipients?

BACKGROUND: Interleukin-1 (IL-1) is produced by activated monocytes/macrophages; highly increased amounts of IL-1 have been found in renal tissue in acute rejection of renal grafts. The endogenous inhibitor of IL-1, interleukin-1 receptor antagonist (IL-1ra), is produced in many cells in response to the same stimulus as IL-1. There is some evidence that the balance between IL-1 and IL-1ra is important in the regulation of inflammatory responses. In many inflammatory diseases in both humans and animals, a high concentration of endogenous IL-1ra or administration of exogenous IL-1ra has been shown to relate to shorter recovery time or to reduced mortality. METHODS: We measured the urinary excretion of IL-1ra and IL-1beta during the first 3-6 posttransplant weeks in 23 patients with acute rejection (69 24-hr urine samples) and in 17 patients with stable graft function (51 24-hr urine samples) and expressed the results as cytokine/creatinine ratios. RESULTS: Within the follow-up time, patients with rejection had higher urinary IL-1beta/creatinine (ng/mmol) ratios (median 5.0 vs. 2.7; P<0.005), lower IL-1ra/creatinine (ng/mmol) ratios (median 18.1 vs. 34.2; P<0.1), and consequently lower IL-1ra/IL-1beta ratios (median 3.6 vs. 20.3, P<0.005), compared with patients without rejection. In rejecting patients, IL-1ra/creatinine was constantly low and decreased even further during acute rejection, whereas IL-1beta/creatinine ratios increased from a median prerejection value of 3.5 (range not measurable to 9.0) to a median value of 8.1 (P<0.0005) (range 1.6 to 18.3) during rejection. CONCLUSION: These results suggest that patients who produce high amounts of IL-1ra in relation to IL-1beta are less prone to acute allograft rejection than patients with low IL-1ra/IL-1beta ratios.

Mechanisms of insulin resistance after kidney transplantation.

In order to study the effect of corticosteroids on energy metabolism in immunosuppressed patients after kidney transplantation, we have examined glucose utilization, energy expenditure, and lean body mass in 10 kidney-transplanted patients receiving steroids (methylprednisolone 8.2 +/- 1.5 mg/day) and in 10 healthy age- and weight-matched control subjects. Glucose utilization was measured during euglycemic insulin clamp in combination with indirect calorimetry and infusion of [3H-3]-glucose, while beta-cell function was measured during a hyperglycemic clamp. The kidney-transplanted patients were resistant to the glucoregulatory effect of insulin, as demonstrated by a 25% reduction in total glucose disposal compared to control subjects. This defect was almost completely accounted for by a defect in storage of glucose as glycogen (3.3 +/- 0.5 vs. 5.0 +/- 0.5 mg/kg LBM min; P less than 0.05). The reduction in nonoxidative glucose disposal was associated with reduced lean body mass and incapacity to release energy as heat after infusion of insulin, i.e. thermogenic defect. In contrast, oxidation of glucose and lipids was not influenced by steroid therapy. Furthermore, suppression of hepatic glucose production was normal, and insulin secretion was normally enhanced in relation to the degree of insulin resistance in the steroid-treated patients. In conclusion, steroid-induced insulin resistance in kidney-transplanted patients is due to alterations in the nonoxidative pathway of glucose metabolism. These findings raise the question of whether steroid therapy directly influences glycogen synthase in man.

CMV infection, class II antigen expression, and human kidney allograft rejection.

After successful transplantation, the major histocompatibility complex (MHC) antigens of kidney parenchymal cells are lost and no longer detectable in the graft, presumably due to administration of glucocorticosteroids. During rejection, the MHC antigens reappear in the graft parenchymal cells. The upregulation is possibly due to gamma-interferon released in situ by the allograft activated T (blast) cells. In this communication we demonstrate that cytomegalovirus (CMV) infection is invariably associated with an upregulation of the antigen display in the graft. In 12 of 14 (86%) cases with proved CMV disease, the display of class II antigens was associated with a cytological and/or clinical episode of rejection. In 223 transplant recipients without proved CMV disease transplanted during the same period, the frequency of late rejections was 17% (P less than 0.001). The results suggest that the display of class II antigens on the graft, mediated presumably by gamma-interferon as a consequence of CMV infection, is the reason for graft rejection in context of CMV disease.

Effect of cyclosporine on wound healing.

Two prophylactic immunosuppressive drugs, cyclosporine and methylprednisolone (MP), were compared for their effect on the in situ inflammatory reaction of granulation tissue formation and on wound healing. Granulation tissue was generated via implantation of viscous cellulose sponges in Sprague-Dawley rats. The rats were divided into six groups: One group received 40 mg/kg/day of cyclosporine, the second 10 mg/kg/day of cyclosporine, the third 2.5 mg/kg/day of cyclosporine, the fourth 12 mg/kg/day of MP, the fifth received the cyclosporine solvent, and the sixth group was given only saline. All drugs were given i.p. No reduction in the number of inflammatory cells was observed in the cyclosporine-treated sponges compared with the controls, whereas MP suppressed the inflammation strongly. Differential counts demonstrated a relative enrichment of macrophages in the cyclosporine-treated versus the MP-treated or control sponges. Chemical analyses of the sponge extracts agreed well with the cytological data: MP suppressed the total DNA content of the sponges, a marker of total cellularity, as well as the content of acid phosphatase and beta-glucuronidase, both markers of macrophages, but no such suppression was seen in the cyclosporine-treated sponges. The alkaline phosphatase content, a marker for granulocytes, was similar in all groups. A remarkable suppression in the contents of hydroxyproline, reflecting the amount of collagen, and in that of hemoglobin, reflecting the amount of neovascularization, was observed in the MP-treated sponges, whereas no such suppression--but possibly a slight enhancement of the second parameter--was observed in the cyclosporine-treated sponges. We conclude that, in contrast to MP, cyclosporine does not inhibit the inflammatory reaction of granulation tissue formation or the regenerative process of wound healing.