Prevalence of gestational diabetes mellitus among Swampy Cree women in Moose Factory, James Bay.

BACKGROUND: Although high rates of gestational diabetes mellitus have been documented in native populations, few studies have examined rates of the disease among native Indians in Canada. The authors conducted a study to estimate the prevalence of gestational diabetes among Swampy Cree women, to identify factors predictive of the occurrence of gestational diabetes, and to identify delivery and infant outcomes related to the presence of the disease. METHODS: Information on Swampy Cree women who gave birth at Weeneebayko Hospital, Moose Factory, James Bay, Ont., between 1987 and 1995 was obtained from medical charts. Patients with and without gestational diabetes were compared. Logistic regression analysis was used to identify independent predictors of gestational diabetes. Delivery and infant outcomes that occurred secondary to gestational diabetes were also identified by means of logistic regression. RESULTS: A total of 1401 deliveries occurred at Weeneebayko Hospital over the study period, of which 1298 were included in the study. Gestational diabetes was diagnosed in 110 (8.5% [95% confidence interval (CI) 6.9%-9.9%]) of the 1298 pregnancies. Factors predictive of gestational diabetes were age 35 years or more (relative risk [RR] 4.1, 95% CI 1.5-11.7), a history of gestational diabetes in a previous pregnancy (RR 6.4, 95% CI 3.5-11.7), diastolic blood pressure of 80 mm Hg or higher at the first prenatal visit (RR 1.7, 95% CI 1.1-2.8), weight greater than 80 kg at the first prenatal visit (RR 4.9, 95% CI 1.8-12.9) and having a first-degree relative with diabetes (RR 3.0, 95% CI 1.4-6.1). The only delivery outcome independently associated with the presence of gestational diabetes was an increased likelihood of needing assisted delivery (forceps or vacuum extraction) (RR 2.8, 95% CI 1.1-7.0). Shoulder dystocia was indirectly associated with gestational diabetes owing to increased infant birth weight. Infant outcomes associated with the presence of gestational diabetes were birth weight greater than 4500 g (RR 2.4, 95% CI 1.4-3.8), hyperbilirubinemia (RR 2.9, 95% CI 1.4-6.1), hypoglycemia (RR 7.3, 95% CI 3.7-14.4) and hypocalcemia (RR 8.9, 95% CI 2.3-33.7). INTERPRETATION: Gestational diabetes occurred in a significant minority of Swampy Cree women and was associated with a number of adverse outcomes.

Mode of chemotherapy does not affect complications with an implantable venous access device.

BACKGROUND: Few reports have been made regarding the long term safety of implantable venous access devices used for the delivery of chemotherapeutic agents. The authors' goals were to determine the frequency of complications in patients receiving chemotherapy with these devices; to determine whether complications were associated with the mode of chemotherapy delivery (push/bolus or infusional regimens); and to evaluate the influence of other risk factors, including home-based versus hospital-based administration. METHODS: A total of 152 oncology patients at the John L. McClellan Memorial Veterans Administration Medical Center in Little Rock, Arkansas (ages 26-81 years; mean age, 62 years), who underwent surgical placement of an Infus-a-Port (Strato, Inc., Beverly, MA) between May 1, 1992 and May 31, 1994, were evaluated retrospectively for postplacement device complications, such as infection, thrombosis, and mechanical failure. RESULTS: Twenty-seven patients experienced 1 complication each: 17 episodes of device-related sepsis, cellulitis, or fever of unknown origin; 8 episodes of thrombosis or catheter occlusion; 1 episode of drug extravasation; and 1 mechanical failure. Patient age, frequency of port accession, mode of chemotherapy delivery, tumor type, and neutropenia were evaluated as risk factors, but none was statistically significant. Complications were more frequent during the first 90 days after implantation, but they continued to occur throughout the observation period. CONCLUSIONS: Complications attributable to an implantable venous access device were infrequent in this patient population. No differences in complications for patients receiving home-based versus hospital-based chemotherapy administration were noted, opening the possibility of significant time and cost savings with home treatment.

Evaluation of cisplatin, carboplatin, and etoposide in metastatic nonsmall cell lung carcinoma. A phase II study of the Southwest Oncology Group.

BACKGROUND: The combined use of cisplatin and carboplatin chemotherapy offers a unique means of platinum dose intensification. Response rates using either of these agents in combination with etoposide are comparable. In a Phase II trial, the authors investigated the combination of cisplatin and carboplatin with etoposide for the treatment of patients with advanced nonsmall cell lung carcinoma. METHODS: Eligible patients were chemotherapy naive and had histologically confirmed, evaluable, or measurable selected Stage IIIB and Stage IV nonsmall cell lung carcinoma. Based upon the results of an earlier Phase I and II pilot study, patients received carboplatin, 225 mg/m2, on Day 1; cisplatin, 50 mg/m2, on Days 2 and 3; and etoposide, 75 mg/m2, on Days 1, 2, and 3 every-4-weeks. RESULTS: Eighty-three patients (75 eligible patients) received chemotherapy with cisplatin, carboplatin, and etoposide. Two patients refused therapy after registration and were not analyzable. Thirty-six of the remaining 75 patients had Grade 4 toxicities, mostly hematologic, and 6 patients died of toxicity. The confirmed response rate was 24% (95% confidence interval, 15-35%). Median progression-free survival was 4 months and the median survival was 8 months. CONCLUSIONS: Combination cisplatin, carboplatin, and etoposide chemotherapy appears to be no better than cisplatin/etoposide or carboplatin/etoposide for the treatment of patients with nonsmall cell lung carcinoma. The toxicity of this regimen may be higher, and therefore it cannot be recommended for general use.

Purification of class I medullipins from the venous effluent of isolated normal kidneys perfused under high pressure with saline.

Medullipin I (Med I) is a vasodepressor prohormone which is continuously elaborated into the renal venous effluent (RVE) of isolated rat kidneys perfused under high pressure. We have improved the yield of Med I by substituting saline for the albumin perfusate previously reported; and considerably improved refinement by directly fractionating the crude lipid extract of the RVE with high pressure liquid chromatography. The results show that Med I, as defined by previous physiologic and pharmacologic criteria, is not a single molecule. The 3 Class I medullipins described here are distinguished by subtle or overt differences in polarity and biologic activity.

Phase II study of edatrexate in advanced head and neck cancer. A Southwest Oncology Group study.

Fifty-two patients with persistent, recurrent and/or metastatic squamous cell cancer of the head and neck were treated with weekly edatrexate, 80 mg/m2. Nine patients had received previous adjuvant or neoadjuvant chemotherapy. Of the 46 eligible patients, two complete responses and one partial response were observed (6%, 95% confidence interval of 1-18%). The most common toxicities were myelosuppression and mucositis, but dermatologic toxicity was also observed in 25% of patients. Edatrexate appears to have limited activity in advanced head and neck cancer.

Use of a modified Transwell culture to quantitate the contribution of non-IL-7 substances to growth of an IL-7-dependent pre-B cell clone.

Clone 3 is a mouse pre-B cell line that cannot grow in standard tissue culture media but is immortalized by coculture with a bone marrow-derived feeder layer. In addition, clone 3 cells can be passaged indefinitely in recombinant interleukin-7 (IL-7) in the absence of a feeder layer if maintained at high cell density. Using monoclonal antibody to IL-7 and Transwells ligated to dialysis membranes, we have examined the relative contributions of IL-7, both endogenous and exogenous, and of "non-IL-7" feeder layer factors to growth promotion of clone 3 cells. There is synergy between feeder layers and exogenous IL-7 that is most marked when the latter is present in suboptimal concentrations. The synergizing activity is not neutralized by antibody to IL-7 and appears to be freely dialyzable. This "non-IL-7" effect is common to two different feeder layers, the one derived from bone marrow (3E) being an IL-7 producer, and the other, 3T3 fibroblasts, making no detectable IL-7. These experiments reveal a substantial contribution of the dialyzable moiety to the total feeder layer effect, and are the first to demonstrate cytokine-dependent low-molecular-weight synergy in a coculture. This demonstration is possible because the synergizing cofactor(s) can cross a semipermeable membrane whereas the cytokine and its neutralizing antibody cannot.

The characteristics of respiratory ill health of wool textile workers.

The relations of lung function and chest radiographic appearances with exposure to inspirable dust were examined in 634 workers in five wool textile mills in west Yorkshire, randomly selected to represent fully the range of current exposures to wool mill dust. Most of these workers could be categorised into three large sex and ethnic groups; European men, Asian men, and Asian women. Exposures to inspirable dust had been measured at a previous survey and time spent in current job, and in the industry were used as surrogates for lifetime cumulative exposures. Chest radiographs were interpreted on the International Labour Office (ILO) scale by three medically qualified readers, and the results combined. Profusions of small opacities of 0/1 on the ILO scale, or greater, were present in only 6% of the population, and were not positively associated with current exposure to wool mill dust, or duration of exposure. In general, statistically significant relations between exposure and lung function indices were not found, with the exception of an inverse relation between the forced expiratory volume/forced vital capacity ratio and dust concentration in European women. A suggestive but not statistically significant inverse relation between FVC and current dust concentration was seen in Asian men. Substantial differences were found between mills in mean values of lung function variables after adjustment for other factors but these were not apparently related to the differences in dust concentrations between these mills. Dyeworkers and wool scourers (mostly European men in relatively dust free jobs) on average experienced an FEV1 251 ml lower than other workers when age, height, smoking habits, and occupational factors had been taken into account. Twenty four per cent of the workforce responded to intracutaneous application of one or more common allergens (weal diameter at least 4 mm), only 12 (7.9%) of these responding to wool extracts. Atopic subjects did not appear to have an increased susceptibility to the effects of inspirable wool dust on lung function. These studies suggest that exposure to wool mill dust may cause functional impairment in some workers but there is little indication from these data of frequent or severe dust related functional deficits. More detailed estimates of cumulative dust exposure by reconstruction of exposure histories might clarify associations between exposure to dust and lung function. These chest radiographic findings provide no evidence that exposure to wool mill dust is related to lung fibrosis.

Case-control study of leukaemia and non-Hodgkin's lymphoma in children in Caithness near the Dounreay nuclear installation.

OBJECTIVE: To examine whether the observed excess of childhood leukaemia and non-Hodgkin's lymphoma in the area around the Dounreay nuclear installation is associated with established risk factors, or with factors related to the plant, or with parental occupation in the nuclear industry. DESIGN: Case-control study. SETTING: Caithness local government district. SUBJECTS: 14 cases of leukaemia and non-Hodgkin's lymphoma occurring in children aged under 15 years diagnosed in the area between 1970 and 1986 and 55 controls matched for sex, date of birth, and area of residence within Caithness at time of birth. MAIN OUTCOME MEASURES: Antenatal abdominal x ray examination; drugs taken and viral infections during pregnancy; father's occupation; father's employment at Dounreay and radiation dose; distance of usual residence from the path of microwave beams, preconceptional exposure to non-ionising radiation in the father; and other lifestyle factors. RESULTS: No raised relative risks were found for prenatal exposure to x rays, social class of parents, employment at Dounreay before conception or diagnosis, father's dose of ionising radiation before conception, or child's residence within 50 m of the path of microwave transmission beams. Results also proved negative for all lifestyle factors except an apparent association with use of beaches within 25 km of Dounreay. However, this result was based on small numbers, arose in the context of multiple hypothesis testing, and is certainly vulnerable to possible systematic bias. CONCLUSION: The raised incidence of childhood leukaemia and non-Hodgkin's lymphoma around Dounreay cannot be explained by paternal occupation at Dounreay or by paternal exposure to external ionising radiation before conception. The observation of an apparent association between the use of beaches around Dounreay and the development of childhood leukaemia and non-Hodgkin's lymphoma might be an artefact of multiple testing and influenced by recall bias.

Effect of H2 antagonists on the differential secretion of triamterene and its sulfate conjugate metabolite by the isolated perfused rat kidney.

The isolated perfused rat kidney model was used to examine the effect of the histamine H2 antagonists cimetidine, ranitidine, and famotidine and the organic anion inhibitor probenecid on the differential renal handling of triamterene and its active metabolite p-hydroxytriamterene sulfate. The kidneys were perfused with a Krebs-Henseleit buffer containing albumin, glucose, and amino acids to pH 7.4, and drug concentrations were measured by HPLC. At an initial triamterene concentration of 0.5 mg/liter, the unbound renal clearance to glomerular filtration rate (GFR) ratio was 11.0 +/- 2.5 (mean +/- SD): 1, indicating substantial tubular secretion of the drug. Cimetidine and ranitidine reduced the tubular secretion by about 80% (p less than 0.01), famotidine by between 35 and 60% (p = 0.05), whereas probenecid had no inhibitory effect. For p-hydroxytriamterene sulfate, its unbound renal clearance to GFR ratio was 41 +/- 25:1; this was not affected by cimetidine, ranitidine, or famotidine, whereas probenecid significantly (p less than 0.01) reduced the rate of tubular secretion by 80%. These data indicate that the renal tubular secretion of triamterene is mediated by the organic cation system, whereas for p-hydroxytriamterene sulfate its tubular secretion is via the organic anion system. Famotidine is a weaker inhibitor of the organic cation system compared with cimetidine and ranitidine. These results have implications for drug-drug interaction studies involving renal elimination pathways.

Expression of the CD11/CD18, leukocyte adhesion molecule 1, and CD44 adhesion molecules during normal myeloid and erythroid differentiation in humans.

We have used three-color flow cytometry to investigate the pattern of expression of the CD11/CD18, CD44, and leukocyte adhesion molecule 1 (LAM-1) adhesion molecules during myeloid and erythroid differentiation in humans. The earliest myeloid cells, identified as CD33loCD15-, were exclusively CD44hi but contained both leukocyte function-associated antigen 1 (LFA-1hi) and LFA-1lo cells, as well as LAM-1+ and LAM-1- cells. This CD33loCD15- myeloid subpopulation expressed only low levels of CD11c and failed to express CD11b, CD14, or any lymphoid (CD3, CD16, CD19) antigens or glycophorin. Commitment to monocyte differentiation, suggested by the presence of an LFA-1hi CD11c+ subset within the CD33loCD15- subpopulation, was clearly signaled by upregulation of CD33; these monocyte-lineage committed cells were exclusively CD33hi, CD44hi, CD11ahi, CD11c+, and exhibited a broad range of intensity of CD15 expression. Later stages of monopoiesis were identified by acquisition of CD11b, and subsequently of CD14. Myeloid cells committed to granulopoiesis remained LFA-1lo, and underwent a sharp upregulation of CD15 along with downregulation of both CD33 and CD44. Successive stages of granulocyte development were marked by expression of CD11b and, subsequently, of CD16. The earliest cells capable of erythroid differentiation were CD44hi, LFA-1lo, and LAM-1+. Both LFA-1 and LAM-1 were lost before the onset of glycophorin (glyco) expression, whereas CD44 expression remained high on glyco+ cells, which also expressed CD45. CD44 expression was intermediate on glyco+ CD71+ cells, and low on glyco+ CD45- CD71- cells, similar to normal, circulating erythrocytes. Our results allow us to phenotypically define discrete stages in the normal development of monocytes, neutrophils, and erythrocytes. The expression of LFA-1, LAM-1, and high levels of CD44 on the most primitive hematopoietic cells detectable by flow cytometry suggests that at least some of these molecules are critically involved in leukocyte adhesion during development.

Several types of adherent cells elaborate a dialyzable lymphopoietic cofactor (Abelson Growth Promoter).

We have cloned a stromal cell from mouse bone marrow selected on the basis of its ability to promote the growth of an Abelson virus-transformed pre-B cell line. These stromal cells have smooth muscle features, and the ultrafiltrate of stromal cell-conditioned medium has proliferative effects on all feeder layer-responsive mouse pre-B cell lines tested, as well as on normal pre-B cells. One of these low MW substances is a protease-resistant factor with an MW of approximately 450 Da which we designate Abelson Growth Promoter (AGP). AGP was initially characterized as an activity which promotes the growth of Abelson virus-transformed mouse pre-B cells, but it also promotes the growth of a ras-transformed pre-B cell line as a single agent and in synergistic fashion with recombinant interleukin (IL) 7. AGP as a single agent has no effect on normal pre-B cells, which have a brisk response to IL-7. In contrast, transformed pre-B cells display a blunted response to IL-7. We propose that AGP plays a role in normal lymphopoiesis by expanding clones of pre-B cells which have been activated by other stromal cell-derived signals, such as IL-7, and directly promotes the growth of nascently transformed pre-B cells.

Amiloride disposition in geriatric patients: importance of renal function.

1. The absorption and disposition of the potassium sparing diuretic amiloride were determined in nine elderly patients aged 71 to 87 years and in eight young (25 to 38 years) subjects following oral administration of 5 mg amiloride HCl daily to steady-state. 2. The maximum and steady-state plasma amiloride concentrations were significantly (P less than 0.05 and P less than 0.001) higher in the elderly patients. The renal clearance of amiloride was lower in the elderly than in young subjects (102 +/- 36 ml min -1 vs 300 +/- 64 ml min-1, P less than 0.001) as was the urinary excretion of amiloride (36 +/- 13 vs 62 +/- 18% of the dose, P less than 0.01). 3. The steady-state plasma amiloride concentration correlated significantly (r2 = 0.61, P less than 0.001) with amiloride renal clearance and with creatinine clearance (r2 = 0.59, P less than 0.001). There was a very strong positive correlation between renal amiloride clearance and creatinine clearance (r2 = 0.76, P less than 0.001). The slope of the regression line was 2.5 indicating substantial proximal tubular secretion of amiloride. 4. Sodium and potassium excretion, along with urine volume were significantly (P less than 0.05) lower in the elderly (by 39, 45 and 34% respectively). 5. The disposition of amiloride was highly dependent on renal function, with higher plasma amiloride concentrations in the elderly reflecting diminished renal function. The dose of amiloride should be titrated to individual response, and the lower potassium excretion in the elderly patients suggests that the dose of amiloride could be reduced in this group of patients.

Deconjugation of p-hydroxytriamterene sulphate in the rat.

1. The extent of deconjugation of p-hydroxytriamterene sulphate was studied in rats, by h.p.l.c., after i.v., i.p., and oral administration. 2. After i.v. administration, deconjugation accounted for 29-54% of the recovered dose as free p-hydroxytriamterene in urine and faeces. Following i.p. administration, 70-88% was deconjugated and 72-96% was deconjugated after oral administration. Most of the p-hydroxytriamterene was recovered in faeces.

Renal tubular secretion of amiloride and its inhibition by cimetidine in humans and in an animal model.

The histamine H2 antagonist cimetidine has been shown to reduce the renal tubular secretion of other organic cations through competition for the specific transport system with organic cations in the renal proximal tubule. The potential interaction between cimetidine and the potassium-sparing diuretic amiloride was investigated in humans and in the isolated perfused rat kidney. A chronic dosing study was conducted in eight healthy subjects who received, in random order, amiloride (5 mg daily), cimetidine (400 mg twice daily), both drugs together, and a control phase in which no drug was present. Cimetidine reduced the renal clearance of amiloride by a mean of 17%, from 358 +/- 134 to 299 +/- 118 ml/min (p less than 0.05), and the urinary excretion of amiloride from 65 +/- 11 to 53 +/- 13% of the dose (p less than 0.05). Amiloride reduced the excretion of cimetidine from 43 +/- 7 to 32 +/- 9% of the dose (p less than 0.05) and the area under the plasma concentration-time curve for cimetidine by a mean of 14% (p less than 0.05) but had no effect on the renal clearance of cimetidine. In the perfused rat kidney, cimetidine reduced the amiloride unbound renal clearance to glomerular filtration rate ratio from 5-7:1 to 1-2:1 (p less than 0.05). These studies demonstrate that cimetidine inhibits the renal tubular secretion of amiloride in humans and in rats to a similar extent. In addition, in humans the gastrointestinal absorption of both amiloride and cimetidine appear to be reduced by each other, by an as yet unknown mechanism.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacokinetic drug interactions between triamterene and ranitidine in humans: alterations in renal and hepatic clearances and gastrointestinal absorption.

Ranitidine reduces the renal tubular secretion of the organic cations procainamide and N-acetylprocainamide in humans through competition for transport via the organic cation transport system. Ranitidine is thought to spare phase I hepatic metabolism mediated by cytochrome P-450, unlike its counterpart H2-receptor antagonist cimetidine. The aim of the present study was to determine, in eight human subjects, the effect of ranitidine on the disposition of the potassium-sparing diuretic triamterene, which undergoes renal tubular secretion, hepatic hydroxylation and subsequent sulphate conjugation to a pharmacologically active metabolite. Multiple blood and urine samples were collected throughout a dosing interval after chronic administration of triamterene alone, ranitidine alone or the two in combination. Ranitidine significantly (P less than .05) reduced the renal clearances of triamterene (51%) and p-hydroxytriamterene sulphate conjugate (47%), the clearance by hydroxylation of triamterene (30%) and the apparent absorption of triamterene (52%). In turn, triamterene reduced the renal clearance of ranitidine (14%). The interaction resulted in a small attenuation of the pharmacodynamic response to triamterene. These results necessitate consideration of the underlying mechanisms of the interactions and fall outside of our present understanding of the renal clearance of sulphate conjugates and the metabolic inhibitory effects of ranitidine. Competition for translocation across membranes is postulated as a common mechanism for the observed renal and hepatic interactions.

Pharmacokinetic interactions of cimetidine 1987.

The number of studies on drug interactions with cimetidine has increased at a rapid rate over the past 5 years, with many of the interactions being solely pharmacokinetic in origin. Very few studies have investigated the clinical relevance of such pharmacokinetic interactions by measuring pharmacodynamic responses or clinical endpoints. Apart from pharmacokinetic studies, invariably conducted in young, healthy subjects, there have been a large number of in vitro and in vivo animal studies, case reports, clinical observations and general reviews on the subject, which is tending to develop an industry of its own accord. Nevertheless, where specific mechanisms have been considered, these have undoubtedly increased our knowledge on the way in which humans eliminate xenobiotics. There is now sufficient information to predict the likelihood of a pharmacokinetic drug-drug interaction with cimetidine and to make specific clinical recommendations. Pharmacokinetic drug interactions with cimetidine occur at the sites of gastrointestinal absorption and elimination including metabolism and excretion. Cimetidine has been found to reduce the plasma concentrations of ketoconazole, indomethacin and chlorpromazine by reducing their absorption. In the case of ketoconazole the interaction was clinically important. Cimetidine does not inhibit conjugation mechanisms including glucuronidation, sulphation and acetylation, or deacetylation or ethanol dehydrogenation. It binds to the haem portion of cytochrome P-450 and is thus an inhibitor of phase I drug metabolism (i.e. hydroxylation, dealkylation). Although generally recognised as a nonspecific inhibitor of this type of metabolism, cimetidine does demonstrate some degree of specificity. To date, theophylline 8-oxidation, tolbutamide hydroxylation, ibuprofen hydroxylation, misonidazole demethylation, carbamazepine epoxidation, mexiletine oxidation and steroid hydroxylation have not been shown to be inhibited by cimetidine in humans but the metabolism of at least 30 other drugs is affected. Recent evidence indicates negligible effects of cimetidine on liver blood flow. Cimetidine reduces the renal clearance of drugs which are organic cations, by competing for active tubular secretion in the proximal tubule of the kidney, reducing the renal clearances of procainamide, ranitidine, triamterene, metformin, flecainide and the active metabolite N-acetylprocainamide. This previously unrecognised form of drug interaction with cimetidine may be clinically important for both parent drug, and metabolites which may be active.(ABSTRACT TRUNCATED AT 400 WORDS)