A single-blind comparison of intravenous ondansetron, a selective serotonin antagonist, with intravenous metoclopramide in the prevention of nausea and vomiting associated with high-dose cisplatin chemotherapy.

Ondansetron (GR 38032F), a selective antagonist of serotonin subtype 3 receptors, is effective in the prevention of emesis associated with cisplatin as well as other chemotherapeutic agents. In this randomized, single-blind, multicenter, parallel group study, we compared the efficacy and safety of intravenous (IV) ondansetron with IV metoclopramide in the prevention of nausea and vomiting associated with high-dose (greater than or equal to 100 mg/m2) cisplatin chemotherapy. Three hundred seven patients receiving their first dose of cisplatin, either alone or in combination with other antineoplastic agents, were randomized to receive ondansetron 0.15 mg/kg IV every 4 hours for three doses or metoclopramide 2 mg/kg IV every 2 hours for three doses, then every 3 hours for three additional doses. The study prohibited the concurrent administration of other antiemetics or dexamethasone. Patients receiving ondansetron had a higher rate of complete protection from emesis (40% v 30%, P = .07), a higher complete plus major response rate (65% v 51%, P = .016), a lower rate of failure (21% v 36%, P = .007), and a lower median number of emetic episodes (one v two, P = .005) than did those receiving metoclopramide. The median time to the first emetic episode was longer on ondansetron (20.5 v 4.3 hours, P less than .001). Adverse events occurred in 48% of patients receiving ondansetron and 69% of those receiving metoclopramide (P less than .001). Akathisia and acute dystonic reactions occurred only on metoclopramide; headache (controlled with acetaminophen) was significantly more frequent with ondansetron. Ondansetron is more effective, produces fewer adverse events, and is easier to administer than metoclopramide for the prevention of emesis associated with high-dose cisplatin chemotherapy.

Delayed emesis following high-dose cisplatin: a double-blind randomised comparative trial of ondansetron (GR 38032F) versus placebo.

Despite recent advances in control of acute emesis, delayed nausea and vomiting following cisplatin-based chemotherapy remain a significant cause of treatment-related morbidity. Ondansetron, a selective 5HT3 receptor antagonist, is effective in preventing acute emesis in the initial 24-h period following high-dose cisplatin. The efficacy and safety of ondansetron in preventing the delayed emesis syndrome during days 2-5 after cisplatin (> or = 100 mg/m2) were evaluated in a double-blind, placebo-controlled multicentre trial. 50 patients having two or fewer emetic episodes during the first 24 h were randomised to receive ondansetron (16 mg) or placebo orally three times daily beginning 24 h after cisplatin. Rates of complete control of emesis were higher in ondansetron-treated patients during each study day, 59-78%, compared with 39-50% in placebo-treated patients, but the differences were statistically superior only on the third study day (P = 0.009). 40% of patients in the ondansetron treatment arm and 33% treated with placebo had complete control of emesis during the entire 4-day study period (P = 0.648). Withdrawal from study due to nausea and vomiting occurred in 13% of ondansetron-treated patients compared with 33% in the placebo arm (P = 0.102). Control of nausea was better with ondansetron, but differences were not statistically significant. Adverse effects of oral ondansetron given in this dose schedule were minimal. These data suggest that the delayed emesis syndrome may be partially mediated through the 5HT3 receptor, but that a serotonin antagonist alone provides inadequate control. Further investigation of ondansetron-based therapy in this clinical setting is warranted.

The delayed-emesis syndrome from cisplatin: phase III evaluation of ondansetron versus placebo.

Cisplatin may evoke both an acute emetic response during the first 24 hours following treatment and a less well-recognized syndrome of delayed emesis. While delayed emesis is usually less severe in terms of frequency of vomiting episodes, the problem continues to result in significant morbidity. In comparison with acute emesis, the exact pathogenesis of the delayed emesis syndrome remains unclear. Although a combination of oral metoclopramide and dexamethasone is effective in many patients in preventing delayed emesis, almost 50% continue to experience at least one emetic episode when treated with this regimen. A phase III multicenter study has evaluated oral ondansetron versus placebo in the prevention of the delayed-emesis syndrome in 50 patients during days 2 through 5 following high-dose cisplatin administration. Although the daily rates of complete emetic control, failure, and control of nausea favor ondansetron, this trial is statistically inconclusive in establishing efficacy of ondansetron as a single agent in the prevention of delayed emesis. Ondansetron was well tolerated in the dose and schedule used.

Genetic defects of the UDP-glucuronosyltransferase-1 (UGT1) gene that cause familial non-haemolytic unconjugated hyperbilirubinaemias.

Congenital familial non-haemolytic hyperbilirubinaemias are potentially lethal syndromes caused by genetic lesions that reduce or abolish hepatic bilirubin UDP-glucuronosyltransferase activity. Here we describe genetic defects that occur in the UGT1 gene complex that cause three non-haemolytic unconjugated hyperbilirubinaemia syndromes. The most severe syndrome, termed Crigler-Najjar syndrome type I, is mainly associated with mutations in exons 2 to 5 that affect all UGT1 enzymes and many of the mutations result in termination codons and frameshifts. Crigler-Najjar type II syndrome which is treatable with phenobarbital therapy is associated with less dramatic missense mutations or heterozygous expression of mutant and normal alleles. Gilbert's syndrome, the most prevalent (2-19% in population studies) and mildest of the three syndromes is principally caused by a TA insertion at the TATA promoter region upstream of the UGT1A1 exon. Current methods used for the diagnosis and treatment of these diseases are discussed.

Drug-mediated toxicity caused by genetic deficiency of UDP-glucuronosyltransferases.

Human gene families encoding UDP-Glucuronosyltransferases (UGTs) have been identified and partially characterised. This family of enzymes catalysed the glucuronidation of drugs, xenobiotics and endobiotics. Genetic mutations and polymorphisms have been identified in several UGT genes and examples should be anticipated in all UGT genes. A common genetic defect in the TATA box promoter of the UGT1A1 gene is associated with Gilbert's Syndrome (GS) causing mild hyperbilirubinaemia. Recently, adverse effects of anticancer agents have been observed in Gilbert's patients due to reduced drug or bilirubin glucuronidation.

The market for nurses - we've come a long way.

The oldest and largest segment of nursing manpower is the diploma educated R.N. This year, several thousand R.N.'s across the country are actively seeking work and are unable to find it. Many of these unemployed nurses are in the province of Ontario. A look at the Ontario experience in the area of nursing manpower offers some interesting insights into developments in other provinces and territories.

Studies on cell lineage of metaphyseal bone in repleted scorbutic guinea pigs.

Young weanling guinea piglets were placed on a diet deficient only in vitamin C. When they reached a state of severe scorbutus, they were given vitamin C and the morphological differentiation of various mesenchymal cells in the proximal end of the tibia was followed over 7 days. The altering metaphyseal cellular pattern is recorded descriptively as well as quantitatively. Levels of mesenchymal cells, preosteoblasts, osteoblasts, and osteocytes remained relatively steady for 24 h. However, by 48 h there was a precipitous decline of mesenchymal cells with a concomitant rise in recognizable osteogenic cells; this change continued until the 7th day of repletion. At this time, with the exception of the preosteoblasts, the cellular population had returned to about the level in the control animals. Osteoclastic and endothelial cellular movements fluctuated widely during the period of repletion under examination. These results support the concept of separate lines of differentiation for osteoclasts and osteoblasts in the postnatal animal. Moreover, mesenchymal cells appear to be precursors of osteogenic cells.

Left ventricular hypertrophy in left bundle branch block.

The detection of left ventricular hypertrophy (LVH) in the presence of left bundle branch block (LBBB) remains a difficult clinical problem. Its prevalence and significance have not previously been studied in a group of living patients. M-mode echocardiography was utilized to determine the prevalence of anatomic LVH in 28 patients with LBBB. Various ECG and chest x-ray criteria as predictors of LVH were assessed. Anatomic LVH was present in 89% by echocardiography. A left atrial abnormality on ECG and a cardio-thoracic ratio greater than .50 were the best predictors of LVH. Hypertension and/or ischemic heart disease was present in 78.5% of the patients while only one patient was free of any evidence of cardiovascular disease.

Isolation of a human YAC contig encompassing a cluster of UGT2 genes and its regional localization to chromosome 4q13.

Previously we mapped the gene encoding a human bile acid UDP-glucuronosyltransferase (UGT2B4) to chromosome 4. Here we report the mapping of two additional human UGT2B genes to chromosome 4 utilizing the polymerase chain reaction (PCR) and a panel of human/rodent somatic cell hybrid cell lines. A yeast artificial chromosome contig containing the UGT2B4, UGT2B9, and UGT2B15 genes was isolated, and pulsed-field gel electrophoresis and PCR revealed that several members of the human UGT2B gene subfamily are clustered within a 195-kb region of the YAC contig. These data permitted a provisional ordering of the genes as UGT2B9-UGT2B4-UGT2B15. Fluorescence in situ hybridization analysis, using the YAC DNA, permitted the regional localization of this gene cluster to chromosome 4q13.

Endoluminal repair of atypical dissecting aneurysm of descending thoracic aorta and fusiform aneurysm of the abdominal aorta.

A 62-year-old male patient was admitted with acute dissociation of the descending thoracic aorta and an infrarenal abdominal aortic aneurysm (AAA). Investigation revealed that the thoracic dissection probably had arisen retrogradely in the posterior wall of the AAA and extended superiorly to the left subclavian artery as a blind sac. Implantation of an endoluminal graft device below the renal arteries enabled simultaneous treatment of the AAA and the thoracic aortic dissection. The patient had an uncomplicated recovery. Postoperative aortography and computed tomography demonstrated normal flow through the aorta and endograft without leak of contrast into the AAA sac or the false lumen of the dissection. Contrast computed tomography 6 months after operation demonstrated that the false lumen was no longer evident.

Genetic variation in bilirubin UPD-glucuronosyltransferase gene promoter and Gilbert's syndrome.

BACKGROUND: The genetic basis of Gilbert's syndrome is ill-defined. This common mild hyperbilirubinaemia sometimes presents as an intermittent jaundice. A reduced hepatic bilirubin UPD- glucuronosyltransferase (UGT) is associated with this syndrome. We have examined variation in the gene encoding the UGT1*1 enzyme and serum bilirubin levels in a Scottish population. METHODS: Blood was collected from 12 patients with confirmed or suspected Gilbert's syndrome, from 6 members of a family with 4 Gilbert members, and from 77 non-smoking, alcohol-free, drug-free volunteers recruited from the staff of a teaching hospital in Dundee. Polymerase chain reaction amplification was used to examine sequence variation of the promoter upstream of the UGT1*1 exon I. Genotypes were assigned as follows: 6/6 (homozygous for a common allele bearing the sequence [TA](6)TAA), 7/7 (homozygous for a rarer allele with the sequence [TA](7)TAA), and 6/7 (heterozygous with one of each allele). FINDINGS: Individuals in the population with the 7/7 genotype had significantly higher bilirubin concentrations than those who had the 6/7 or 6/6 genotype. 14 volunteers underwent a 24 h fasting test to see if they had Gilbert's syndrome, and all four positives had the 7/7 genotype. One confirmed Gilbert's patient, two recurrent jaundice patients (with suspected Gilbert's syndrome), and nine clinically diagnosed cases had the 7/7 genotype. Segregation of the 7/7 genotype with the Gilbert phenotype was also demonstrated in the family with four affected members. The frequency of the 7/7 genotype in this eastern Scottish population was 10-13%. INTERPRETATION: In a healthy population there was an association between variation in bilirubin concentration and a mutation within the gene encoding the enzyme bilirubin UGT. This and other findings suggest the existence of a mild and a more severe form of Gilbert's syndrome, depending on whether the gene defect lies in the promoter sequence upstream of UGT1*I exon I, as here (mild), or in the coding sequence (severe) of the gene.

Immunological and genetic analysis of 65 patients with a clinical suspicion of X linked hyper-IgM.

BACKGROUND: X linked hyper-IgM (XHIM) is a primary immunodeficiency caused by mutations in the tumour necrosis factor superfamily 5 gene, TNFSF5, also known as the CD40 ligand (CD40L) gene. Patients often present with recurrent infections, and confirmation of a diagnosis of XHIM enables appropriate therapeutic interventions, including replacement immunoglobulin, antibiotics, and bone marrow transplantation. AIM: To review and optimise the institution's diagnostic strategy for XHIM. METHOD: Samples from 65 boys were referred to this centre for further investigation of suspected XHIM. The results, which included a flow cytometric whole blood assay for CD40L expression followed by mutation analysis in selected patients, were reviewed. RESULTS: Twenty one patients failed to express CD40L and TNFSF5 mutations were found in 20 of these patients. In contrast, no TNFSF5 mutations were found in 16 patients with weak expression of CD40L. Interestingly, one quarter of patients with confirmed XHIM who had TNFSF5 mutations had low concentrations of IgG, IgA, and IgM. Most of the remaining patients with XHIM had the classic pattern of normal or raised IgM with low concentrations of IgA and IgG. CONCLUSIONS: This study demonstrates the usefulness of the whole blood staining method as a rapid screen to select patients for subsequent TNFSF5 mutation analysis, and shows the benefits of a unified protein/genetic diagnostic strategy.

Video-assisted thoracoscopy.

Recent advances in video-imaging and minimally invasive surgical instrumentation have expanded the role of thoracoscopy in the diagnosis and treatment of intrathoracic conditions. This prospective study describes the use of video-assisted thoracoscopy (VAT) in 100 consecutive patients. There were 70 males and 30 females with a mean age of 54.6. They underwent 103 VAT procedures with 41 thoracoscopic biopsies of lung, pleural, chest wall and mediastinal abnormalities, 32 for treatment of recurrent or persistent pneumothorax, 18 for thoracoscopic assessment of pulmonary and pleural tumours and 12 for thoracoscopic resection of peripheral lung lesions, chest wall, mediastinal and pleural tumours. Eighty-one patients had VAT procedures alone while the remaining 19 had VAT proceeding to thoracotomy. The mean operating time for VAT alone was 51 min (range 30-135 min). There were no operative deaths. There were 8 significant complications from which patients recovered fully. Patients who underwent VAT alone were shown to have earlier postoperative mobilization, reduction in parenteral analgesic requirement and reduced length of hospital stay compared to patients undergoing additional thoracotomy. A telephone survey of patients on returning home showed that patients undergoing VAT alone returned to full activity earlier than those who had thoracotomy (mean 9.0 vs mean 19.4 days). This study confirms that VAT is a safe and effective procedure in the management of pulmonary, mediastinal and pleural disease and the treatment of persistent and recurrent pneumothorax. Its role in the resection of pulmonary malignancy remains to be defined.

Gilbert's syndrome is a contributory factor in prolonged unconjugated hyperbilirubinemia of the newborn.

OBJECTIVE: Prolonged neonatal jaundice, beyond day 14 of life, is very common and of concern to the clinician. The aim of this study was to investigate whether a genetic mutation in the bilirubin UGT1A1 gene, which has been associated with Gilbert's syndrome in adults, is a contributory factor in prolonged neonatal jaundice. STUDY DESIGN: Blood was collected from 85 term newborns with unexplained hyperbilirubinemia, and DNA was prepared. The neonates were divided into 6 groups depending on whether they were breast-fed or bottle-fed and whether they had acute, prolonged, or very prolonged jaundice. UGT1A1 TATA promoter genotyping (DNA test for Gilbert's syndrome) was performed on all samples, and analysis of the entire UGT1A1 coding sequence was performed in a representative sample (11 of 26) of very prolonged cases. RESULTS: In addition to the known common UGT1A1 TATA alleles (TA6 and TA7), a novel TATA allele (TA5) in a neonate with very prolonged jaundice was identified. Statistical analysis of the TATA genotype distributions within the group of breast-fed neonates revealed significant differences among the acute, prolonged, and very prolonged subgroups (.05 > P >.01): the incidence of familial hyperbilirubinemia genotypes (7/7 and 5/7) is 5 times greater in very prolonged cases (31%) relative to acute cases (6%). Neonates with prolonged jaundice from family pedigrees were observed to demonstrate the Gilbert's phenotype as children or young adults. CONCLUSIONS: A genetic predisposition to develop prolonged neonatal hyperbilirubinemia in breast-fed infants is associated with TATA box polymorphism of the UGT1A1 gene and will be recognized as Gilbert's syndrome in adulthood.