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Biomedical subjects

J Robert

Publications and source records attributed to J Robert.

At least 109 records · Page 6Linked to original sources
PubMed1999

Molecular characterisation and origin of the Coffea arabica L. genome.

Restriction fragment length polymorphism (RFLP) markers were used in combination with genomic in situ hybridisation (GISH) to investigate the origin of the allotetraploid species Coffea arabica (2n = 44). By comparing the RFLP patterns of potential diploid progenitor species with those of C. arabica, the sources of the two sets of chromosomes, or genomes, combined in C. arabica were identified. The genome organisation of C. arabica was confirmed by GISH using simultaneously labelled total genomic DNA from the two putative genome donor species as probes. These results clearly suggest that C. arabica is an amphidiploid formed by hybridisation between C. eugenioides and C. canephora, or ecotypes related to these diploid species. Our results also indicate low divergence between the two constituent genomes of C. arabica and those of its progenitor species, suggesting that the speciation of C. arabica took place relatively recently. Precise localisation in Central Africa of the site of the speciation of C. arabica, based on the present distribution of the coffee species, appears difficult, since the constitution and extent of tropical forest has varied considerably during the late Quaternary period.

Alleles↗
PubMed1999

Perioperative mortality and major cardio-pulmonary complications after lung surgery for non-small cell carcinoma.

OBJECTIVES: A database of patients operated of lung cancer was analyzed to evaluate the predictive risk factors of operative deaths and life-threatening cardiopulmonary complications. METHODS: From 1990 to 1997, data were collected concerning 634 consecutive patients undergoing lung resection for non-small cell carcinoma in an academic medical centre and a regional hospital. Operations were managed by a team of experienced surgeons, anaesthesiologists and chest physicians. Operative mortality was defined as death within 30 days of operation and/or intra-hospital death. Respiratory failure, myocardial infarct, heart failure, pulmonary embolism and stroke were considered as major non-fatal complications. Preoperative risk factors, extent of surgery, pTNM staging, perioperative mortality and major cardiopulmonary complications were recorded and evaluated using chi-square statistics and multivariate logistic regression. RESULTS: Complete data were obtained in 621 cases. The overall operative mortality was 3.2% (n = 19). Cardiovascular complications (n = 10), haemorrhage (n = 4) and sepsis or acute lung injury (n = 5) were incriminated as the main causative factors. In addition, there were 13 life-threatening complications (2.1%) consisting in strokes (n = 4), myocardial infarcts (n = 5), pulmonary embolisms (n = 1), acute lung injury (n = 1) and respiratory failure (n = 2). Four independent predictors of operative death were identified: pneumonectomy, evidence of coronary artery disease (CAD), ASA class 3 or 4 and period 1990-93. In addition, the risk of major complications was increased in hypertensive patients and in those belonging to ASA class 3 or 4. A trend towards improved outcome was observed during the second period, from 1994 to 97. CONCLUSION: Our data demonstrate that perioperative mortality is mainly dependent on the extent of surgery, the presence of CAD and provision of adequate medical and nursing care. Preoperative testing and interventions to reduce the cardiovascular risk factors may help to further improve perioperative outcome.

Adenocarcinoma↗
PubMed1999

Time trend in the surgical management of patients with lung carcinoma.

OBJECTIVE: The goal of the study was to analyze the histological and clinical trends in lung carcinoma and their influence upon the preoperative evaluation, surgical procedures and survival. METHODS: We retrospectively reviewed the charts of 1079 consecutive patients who underwent surgery for primary lung carcinoma between 1977 and 1996 in our institution. Patients were divided into five equal 4-year periods according to the year of surgery (1977-1980; 1981-1984; 1985-1988; 1989-1992; 1993-1996). RESULTS: Between 1977-1980 and 1993-1996, the incidence of squamous cell carcinoma significantly declined, whereas the incidence of adenocarcinoma and bronchioloalveolar carcinoma increased. During the same period, the proportion of squamous cell carcinoma visualized at bronchoscopy and the rate of preoperative histological diagnosis significantly decreased. An increasing proportion of lobectomy and less extended resection was associated with an increasing number of patients with stage I carcinoma. Meanwhile, the operative mortality significantly declined from 9 to 4% and the 5-year survival improved from 25 up to 40%. CONCLUSION: Over the last two decades, the shift in histological distribution was associated with an increasing proportion of patients with stage I disease, a lower operative mortality and a better 5-year survival.

Adenocarcinoma↗
PubMed1999

Thoracic outlet syndrome: influence of personal history and surgical technique on long-term results.

OBJECTIVE: Long-term results after surgery for thoracic outlet syndrome (TOS) are reviewed in terms of personal histories and surgical techniques. METHODS: Forty-eight operations were performed in 37 patients. In 21 instances, the picture was one of ordinary TOS, in eight TOS was traumatic and in nine the picture was sub-acute. Cervical ribs were excised through a supraclavicular approach (in seven cases), and first ribs through transthoracic, transaxillary or supraclavicular approaches (in 25, 15 or one, respectively). Long-term follow-up was obtained in 41 cases and averaged 11.7 years. RESULTS: Surgical decompression was successful in 28 cases (68%), including all patients with traumatic TOS (8/8) and seven with sub-acute symptoms (7/9). Outcome was good in five of seven supraclavicular cervical rib resections, and in 23 of 34 first rib excisions. First rib resections performed transaxillary had shorter post-operative stays, fewer complications. CONCLUSION: Surgical decompression is more successful when TOS is traumatic or sub-acute. When involved, a cervical rib can be resected through a supraclavicular approach, since the procedure is easy and has little morbidity. The transaxillary approach should be preferred for first rib resections because of shorter post-operative stays and fewer complications than after the transthoracic approach.

Adolescent↗
PubMed1999

Influence of age on operative mortality and long-term survival after lung resection for bronchogenic carcinoma.

The proportion of elderly patients presenting with bronchogenic carcinoma is increasing. To study the impact of age on clinical presentation, management and outcome of patients, the authors have reviewed their clinical experience over the last 20 yrs. Between 1977 and 1996, 1,079 patients underwent thoracotomy for primary lung carcinoma in the authors' institution. Patients were grouped by age at the time of surgery as <60 yrs, 60-69 yrs and > or =70 yrs. Although the mode of clinical presentation was similar between all age groups, patients <60 yrs were more prone to have advanced stage carcinoma at the time of diagnosis. The rates of exploratory thoracotomy and pneumonectomy were higher in patients <70 yrs, whereas lobectomies and lesser resections largely predominated in patients > or =70 yrs. The mortality rate following lobectomy and lesser resection increased from 1.3% in patients <60 yrs to 5.5% in patients > or =60 yrs (p=0.04) and the mortality rate following pneumonectomy increased from 6.5% in patients <60 yrs to 13.7% in patients > or =70 yrs (p=0.24). The specific long-term survival, which included only the patients who died from primary lung carcinoma, was similar in all age groups. Operative mortality and survival rates are acceptable in patients > or =70 yrs. Therefore, age in itself should not constitute a contraindication to surgical lung resection for primary lung carcinoma as long as a careful preoperative assessment is performed to appropriately select surgical candidates.

Adult↗
PubMed1999

Preclinical evaluation of the cardiac toxicity of HMR-1826, a novel prodrug of doxorubicin.

Cardiotoxicity represents the major side-effect limiting the clinical use of anthracyclines, especially doxorubicin, in cancer chemotherapy. The use of non-toxic prodrugs, or of liposome-encapsulated drugs, allows a better targeting of the tumours and may, therefore, improve the tolerance to the treatment. Using the model of isolated perfused rat heart, we have evaluated the cardiotoxicity of a novel prodrug of doxorubicin, HMR-1826, which consists of the association of doxorubicin to glucuronic acid. We have compared the cardiac effects (developed pressure, contractility and relaxation of the left ventricle) induced by HMR-1826 to those induced by doxorubicin and Doxil, a liposomal form of doxorubicin. HMR-1826 was administered intravenously every other day for 11 days at doses of 50-200 mg kg(-1) per injection while doxorubicin was administered according to the same protocol at doses of 1-3 mg kg(-1) per injection. Doxorubicin strongly decreased the cardiac functional parameters at the doses of 2.5 and 3 mg kg(-1) per injection. Doxil (3 mg kg(-1) and HMR-1826 (50-150 mg kg(-1)) were largely devoid of cardiotoxicity. HMR-1826 only induced significant alterations of the cardiac function at the highest dose used (200 mg kg(-1) per injection). These alterations were much lower than those of doxorubicin at 2.5 mg kg(-1) per injection, despite similar general toxicity symptoms (weight loss, nose bleeding and diarrhoea) at these respective doses. Thus, HMR-1826 appeared about 100-fold less cardiotoxic than doxorubicin.

Animals↗
PubMed1999

A phase II trial of induction and consolidation therapy of acute myeloid leukemia with weekly oral idarubicin alone in poor risk elderly patients.

We have conducted a phase II outpatient trial testing weekly oral administration of idarubicin (ZAVEDOS-ZVD) alone to determine the rate of objective response and toxicity in poor risk acute myeloid leukemia (AML) patients over 60 years of age. The treatment consisted of three phases: induction, with 20 mg/m2 of ZVD on days 1, 8, 15 and 22; consolidation with 20 mg/m2 of ZVD for 4 weeks; and maintenance with six cycles lasting 3 months and consisting of oral 6 mercapto-purine 2 mg/kg/day, 4 days a week for 2 months; subcutaneous cytarabine 1 mg/kg, once a week for 2 months; and oral ZVD 20 mg/m2 on day 1 and day 8 of the third month. In case of failure after induction course, patients received salvage treatment with 4 weekly oral doses of 40 mg/m2 ZVD. Fifty-one patients with a median age of 76 years were enrolled and could receive induction course. Of these 51 patients, 37 could receive subsequent courses, which consisted either of consolidation, or salvage. Only 11 patients underwent maintenance treatment. Sixty-three percent of patients had to be hospitalized during induction, for a median duration of 14.5 days, and 87% required hospitalization during salvage for a median duration of 17.5 days. Only five patients (38%) required hospitalization during consolidation. There were three toxic deaths (6%), two from hemorrhage and one from pulmonary embolism. The overall response rate was 29%, with 12 patients in complete response (25%) and two in partial response (4%). The median overall survival rate is 4 months for the whole population, and the median DFS is 9.6 months among the 14 responding patients. The results of this trial show that this new weekly schedule of oral ZVD chemotherapy is feasible and effective in poor risk elderly patients with AML. This regimen may be helpful for patients unable to tolerate intensive intravenous regimens, and is a real alternative to palliative treatments.

Acute Disease↗
PubMed1999

Multidrug resistance in oncology: diagnostic and therapeutic approaches.

Resistance to anticancer drugs is often mediated by the overexpression of a membrane pump able to extrude many xenobiotics out of the tumour cells. The most frequently expressed of these pumps is called P-glycoprotein and is encoded by a gene called MDR1 (for multidrug resistance). There could be great clinical interest for investigating the expression of this gene or of its product in patients' tumours, as well as in developing ways of circumventing this mechanism of resistance. Multidrug resistance can be diagnosed in tumours by molecular biology techniques (gene expression at the mRNA level), by immunological techniques (quantification of P-glycoprotein itself) or by functional approaches (measuring dye exclusion). Numerous studies have tried to use the MDR status of tumours as a predictor of response to treatment, but they have not yet reached definitive conclusions to allow the use of this approach in routine determinations. This is because no consensus has emerged concerning the optimal technique and the best conditions for MDR determination. Continuous efforts are still required for defining appropriate standardization of the techniques. The development of MDR modulators for the treatment of resistant tumours is a promising approach requiring rigorous clinical trials with successive phase I, phase II and phase III studies. Phase I can be omitted when the reverter is already being used in therapeutics; phase II should be performed using a sequential design, in order to prove the inefficacy of the anticancer therapy before combining it to a modulator; and phase III must only be undertaken after the demonstration that responders can be recruited by the combination. However, the effect of some reverters on anticancer drug pharmacokinetics may hamper rapid evaluation. Several drugs are good candidates for MDR modulation, but definitive results are still lacking for the introduction of such combinations in standard therapeutic protocols.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1999

Incidence, risk factors and management of bronchopleural fistulae after pneumonectomy.

Postpneumonectomy bronchopleural fistula (BPF) remains a serious and often life-threatening complication. Over a seven-year period, seven cases of BPF occurred in a series of 100 consecutive pneumonectomies performed for lung carcinoma by the same surgical team. The incidence increased from 3% (1/33) prior to 1993 to 9% (6/67) thereafter. The presence of tumour within the main stem bronchus and the need for postoperative mechanical ventilation correlated significantly with the occurrence of BPF. However, it is likely that other risk factors, such as the introduction of systematic mediastinal lymph nodes dissection since 1992 and bronchial stapling since 1993, were involved. In four patients, closure of BPF was achieved by transposition of pedicled latissimus dorsi (LD) muscle flap and closed-chest irrigaiton of the pleural cavity. Patients were discharged after a median stay of 19 d; fistula recurred in one case and was successfully treated with an omental flap. No complications related to the LD division were observed. In conclusion, mediastinal lymph node dissection may increase the risk of post-pneumonectomy BPF. Systematic bronchial stapling should be used cautiously, especially if the tumour is present within the main stem bronchus. Treatment with predicted LD muscle flap or omental flap associated with closed-chest irrigation proved to be simple, time-saving and efficient.

Adult↗
PubMed1999

Primary pulmonary meningioma presenting as lung metastasis.

A benign primary pulmonary meningioma, an extremely rare tumour, was incidentally detected in a 57-year-old woman in association with a contralateral pulmonary adenocarcinoma. The meningioma was initially suspected to be a metastasis. Both tumours were excised, with excellent outcome. Anatomic features of primary pulmonary meningioma and differential diagnosis are discussed.

Adenocarcinoma↗
PubMed1999

In vitro differentiation of a CD4/CD8 double-positive equivalent thymocyte subset in adult Xenopus.

The thymus is the major site of selection and differentiation of T cells in mammals and birds. To begin to study the evolution of thymocyte differentiation, we have developed, in the frog Xenopus, an in vitro system that takes advantage of cortical thymocyte antigen (CTX), a recently discovered T cell antigen whose expression is restricted to Xenopus cortical thymocytes. Upon transient stimulation with suboptimal mitogenic concentrations of the phorbol ester phorbol myristate acetate (PMA) plus ionomycin, Xenopus thymocytes are induced to differentiate into cycling T lymphoblasts that actively synthesize and express high levels of surface MHC class I and class II molecules. This appearance of T lymphoblasts correlates with a rapid down-regulation of both surface CTX protein and CTX mRNA. A thymocyte subset with an immature phenotype (CTX+, CD8+, class II- or class II low and class I-) was characterized by depleting class II+ cells or by panning with anti-CTX mAb. This immature CTX+ thymocyte subset displays a limited proliferative capacity compared to total, class II+ or to CTX- thymocytes, and can be induced, by PMA/ionomycin, to differentiate into more mature T lymphoblasts expressing surface class II and class I molecules. These results provide the first in vitro evidence in an ectothermic vertebrate of a conserved intrathymic pathway of thymocyte differentiation. In addition, our data reveal that CTX can serve as a differentiation surface marker of a population of immature thymocytes that appears to be the equivalent of the mammalian CD4/CD8 double-positive subset.

Animals↗
PubMed1999

Comparative cardiotoxicity of idarubicin and doxorubicin using the isolated perfused rat heart model.

Attempts to reduce the incidence of congestive heart failure following anthracycline therapy include the replacement of the parent compounds (especially doxorubicin) by less cardiotoxic analogs. Among these analogs, idarubicin (4-demethoxy-daunorubicin) was shown to be less cardiotoxic than doxorubicin in phase II clinical trials, but its actual cardiotoxicity has never been evaluated in large series and has never been compared to that of doxorubicin in relevant experimental models. Using the isolated perfused rat heart model, we compared the cardiac effects (developed pressure, contractility and relaxation of the left ventricle) induced by idarubicin to those induced by doxorubicin. Drugs were administered i.v. every other day for 11 days at doses of 1, 2, 2.5 and 3 mg/kg per injection for doxorubicin and 0.5, 0.75 and 1 mg/kg per injection for idarubicin. We confirmed that similar general toxicity symptoms were obtained for a dose ratio of 1:4 (idarubicin:doxorubicin). However, at the maximum tolerated doses of both drugs (3 mg/kg per injection for doxorubicin and 0.75 mg/kg per injection for idarubicin), the cardiac toxicity of idarubicin remained significantly lower than that of doxorubicin. Anthracycline cardiac accumulation was evaluated in parallel and revealed a lower cardiac accumulation of idarubicin, which could explain the reduced cardiac toxicity of this analog. Direct perfusion of the drugs in the isolated hearts of untreated animals revealed that idarubicin was taken up more readily than doxorubicin in the cardiac tissue, despite the fact that it had less deleterious effects on cardiac function. This indicates that idarubicin also had less intrinsic cardiotoxicity than doxorubicin in this model.

Animals↗
PubMed1999

Serum profiles of interleukin-6, interleukin-8, and interleukin-10 in patients with severe and mild acute pancreatitis.

Excessive leukocyte activation has been proposed as a key mechanism in the onset of acute pancreatitis. In this study, we assessed the systemic release of various inflammatory mediators and tried to identify differences between patients with mild and severe disease. In a prospective study, 19 patients admitted for severe acute pancreatitis were compared with 24 patients with mild pancreatitis. Serum levels of interleukin-6 (IL-6), IL-8, and IL-10 were determined at the time of admission, and on days 1, 2, and 5 after hospitalization. Severity of pancreatitis was determined according to the Atlanta criteria. IL-6 levels peaked on admission in both groups with significant differences (p < 0.05) from days 0-2. IL-8 levels increased from day 0 in severe cases, and from day 1 in mild cases, to reach a plateau between days 2 and 5; significant differences were observed on days 0 and 1. IL-10 was highest on day 0; it decreased rapidly in mild cases but stayed significantly higher from days 1 to 5 in severe cases. These findings provide new evidence on the role of mediators of the inflammatory/antiinflammatory balance in acute pancreatitis. These molecules appear to be valuable early markers of severity.

Acute Disease↗
PubMed1999

Type II topoisomerase mutations in ciprofloxacin-resistant strains of Pseudomonas aeruginosa.

We determined the sequences of the quinolone resistance-determining regions of gyrA, gyrB, and parC genes for 30 clinical strains of Pseudomonas aeruginosa resistant to ciprofloxacin that were previously complemented by wild-type gyrA and gyrB plasmid-borne alleles and studied for their coresistance to imipenem (E. Cambau, E. Perani, C. Dib, C. Petinon, J. Trias, and V. Jarlier, Antimicrob. Agents Chemother. 39:2248-2252, 1995). In the present study, we found mutations in type II topoisomerase genes for all strains. Twenty-eight strains had a missense mutation in gyrA (codon 83 or 87). Ten of them had an additional mutation in parC (codon 80 or 84), including a novel mutation of Ser-80 to Trp, but all were fully complemented by a plasmid-borne wild-type gyrA allele. The remaining two strains harbored the first gyrB mutation described in P. aeruginosa, leading to the substitution of phenylalanine for serine 464. The strains which had two mutations in type II topoisomerase genes (i.e., gyrA and parC) were significantly more resistant to fluoroquinolones than those with a single mutation in gyrA or gyrB (geometric mean MICs of ciprofloxacin, 39.4 versus 10.9 microg/ml, P < 0.01; geometric mean MICs of sparfloxacin, 64.0 versus 22.6, P < 0. 01). No mutant with a parC mutation alone was observed, which favors DNA gyrase being the primary target for fluoroquinolones. These results demonstrate that gyrA mutations are the major mechanism of resistance to fluoroquinolones for clinical strains of P. aeruginosa and that additional mutations in parC lead to a higher level of quinolone resistance.

Amino Acid Sequence↗
PubMed1999

Beneficial effects of leukocyte-depleted blood and low-potassium dextran solutions on microvascular permeability in preserved porcine lung.

Modified Euro-Collins (EC) solution, a crystalloid intracellular-type solution, has been commonly used for pulmonary preservation. Several experimental studies have shown the advantages of using extracellular colloid-based solutions. The aim of this study was to compare the quality of preservation of two extracellular colloid solutions, leukocyte-depleted blood (BL) and low-potassium dextran (LPD) solutions, with that of EC solution. Lungs of 22 domestic pigs were flushed and preserved with EC (n = 8), BL (n = 7), or LPD (n = 7) solution. After harvesting, one of the lungs was reperfused immediately in an ex vivo circuit (control lungs), whereas the contralateral lung was reperfused after 8 h of cold (4 degrees C) storage (preserved lungs). Besides the lung function parameters (gas exchange, pulmonary hemodynamics and mechanics), the permeability of the endothelial-epithelial barrier was assessed by determining the transferrin leak index (TLI) using a double radioisotopic method, by measuring the alveolar/arterial protein concentration ratio, and by analyzing histopathologic changes. The functional quality (oxygenation, airway resistance, dynamic compliance [CL, dyn]) of both BL and LPD lungs was slightly but significantly superior to that of EC lungs. However, pulmonary vascular resistance was lower in BL-preserved than in EC- or LPD-preserved lungs. The TLI was increased in EC control and preserved lungs, whereas it was low in BL and LPD control lungs and did not increase after preservation. The alveolar/arterial protein concentration ratio was not different between control groups, but was increased fourfold in EC-preserved compared with BL- or LPD-preserved lungs. Finally, EC-preserved lungs presented a weight gain about twice that of BL- and LPD-preserved lungs. Morphologic analysis confirmed these results, because in the EC-preserved lungs, rupture of alveolar septa and severe alveolar edema and hemorrhage were observed, whereas BL- and LPD-preserved lungs showed a relatively well-preserved structure. The results demonstrate that both BL and LPD flush solutions preserve the endothelial-epithelial barrier better than does EC solution. Although the quality of preservation is similar, pulmonary vascular resistance is higher in LPD-preserved than in BL-preserved lungs.

Animals↗
PubMed1999

Outcome of multi-drug-resistant tuberculosis in France: a nationwide case-control study.

The factors related to the outcome of 51 cases of multi-drug-resistant tuberculosis (MDR-TB) reported in 1994 to the French National Reference Center were retrospectively analyzed. The patients (median age, 45 yr) were mainly male (75%), foreign-born (63%), and had pulmonary involvement (95%). Sixteen percent were human immunodeficiency virus (HIV)-coinfected. The number of drugs to which the Mycobacterium tuberculosis isolates were susceptible was four. Only 82% of the patients have been hospitalized at any time (median duration, 33 d). Five patients (9%) received no antituberculosis drugs, although three had drug susceptibility results, indicating that two or more active drugs were available; 46 (91%) received drugs, including 37 who received two or more active drugs. Among the nine cases who received only one active drug, three had drug susceptibility results, indicating that two or more active drugs were available. By December 1996, 10 patients were lost before treatment completion, 24 had treatment failure, and 17 had a favorable outcome. The median survival time was 31 mo. Factors related to a poorer outcome were HIV-coinfection (hazard ratio [HR] = 41), treatment with less than two active drugs (HR = 9.9), and MDR status knowledge at the time of diagnosis (HR = 3.3). The country of birth was not associated with a poorer outcome. The management and outcome of MDR-TB in France has to be improved. A solution would be to develop a specialized unit or team for the treatment of MDR-TB, as recommended by the World Health Organization (WHO).

AIDS-Related Opportunistic Infections↗
PubMed1999

Correlation between uracil and dihydrouracil plasma ratio, fluorouracil (5-FU) pharmacokinetic parameters, and tolerance in patients with advanced colorectal cancer: A potential interest for predicting 5-FU toxicity and determining optimal 5-FU dosage.

PURPOSE: Patients with genetic fluorouracil (5-FU) catabolic deficiencies are at high risk for severe toxicity. To predict 5-FU catabolic deficiencies and toxic side effects, we conducted a prospective study of patients treated for advanced colorectal cancer by high-dose 5-FU. PATIENTS AND METHODS: Eighty-one patients were treated with weekly infusions of 5-FU and folinic acid. The initial 5-FU dose of 1,300 mg/m(2) was individually adjusted according to a dose-adjustment chart. Plasma concentrations of uracil (U) and its dihydrogenated metabolite, dihydrouracil (UH(2)), were measured before treatment, and the ratio of UH(2) to U was calculated. Pharmacokinetic and pharmacodynamic studies were conducted to look for a relationship between the ratio of UH(2) to U and 5-FU metabolic outcome and tolerance. RESULTS: The UH(2)-U ratios were normally distributed (mean value, 2.82; range, 0.35 to 7.13) and were highly correlated to (1) 5-FU plasma levels after the first course of treatment (r =.58), (2) 5-FU plasma clearance (r =.639), and (3) individual optimal therapeutic 5-FU dose (r =.65). Toxic side effects were observed only in patients with initial UH(2)-U ratios of less than 1.8. No adverse effects were noted in patients with UH(2)-U ratios of greater than 2.25. CONCLUSION: The UH(2)-U ratio, easily determined before treatment, could help to identify patients with metabolic deficiency and, therefore, a risk of toxicity.

Adult↗