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Objective: To determine folic acid dosage requirements for individuals across a broad range of BMI values, using dose per kilogram lean body weight (LBW) as a primary predictor of systemic exposure. Steady-state folate concentrations of ≥ 15.9 nmol/L were assumed to be sufficient for reducing the risk for neural tube defects in the general population., Methods: Data from a recent study of single-dose folic acid pharmacokinetics among 12 obese and 12 non-obese women of childbearing age were analyzed to determine expected steady-state concentrations. The mean folic acid dose per kilogram LBW that achieved serum folate concentrations of ≥ 15.9 nmol/L was applied to a broad range of BMI values to evaluate daily dose requirements., Results: Modest differences in folic acid requirements were noted for individuals among the non-obese, overweight, and obese categories. The current supplementation guidelines suggesting a daily dose of 0.4 mg appear to satisfy the needs of women at even the upper extremes of obesity. However, because even with appropriate folate supplementation obese women have an increased risk of neural tube defects, and they may benefit from higher intake and higher serum concentrations of folic acid., Conclusion: Current guidelines recommend an adequate folic acid dose for obese women of childbearing age. Thus, it is unlikely that folate deficiency is associated with the elevated risk for neural tube defects in this population.

Background: Although maternal folate deficiency during the periconceptional period represents a major risk factor for neural tube defects, obesity has been recognized as an additional risk factor. Studies have identified an increased risk for neural tube defect-affected births among obese mothers even after adjusting for folic acid supplementation. However, although folic acid intake may have been at the recommended dose in these samples, blood folate concentrations were not monitored to ensure that protective levels were reached. Hence, there is a need to compare folic acid pharmacokinetics in obese and nonobese women of childbearing age., Methods: Healthy obese (n=12) and nonobese (n=12) women of childbearing age volunteered to participate. Each obese participant was matched to a nonobese participant and assigned an equivalent dose of folic acid per kilogram body weight. Folic acid was orally administered after a 6-hour fast, and blood samples were taken over a 10-hour period to evaluate pharmacokinetic parameters., Results: Area under the time-concentration curve (AUC) was found to be significantly higher in the obese group (P=0.008). Defining AUC as a function of dose per kilogram lean body weight (LBW) was found to be a stronger predictor than dose per kilogram total body weight (r=0.90 and 0.76, respectively)., Conclusions: This indicates that the body tightly controls systemic exposure to folic acid, with 90% of the variability in AUC controlled by the dose per kilogram LBW. Periconceptional supplementation recommendations may need to be adjusted to account for LBW differences in the obese population.

Background: Synthetic folic acid (0.4-1.0 mg) consumed during the periconceptional period has been shown to reduce the risk of neural tube defects. Women with poor supplement adherence or a previous pregnancy affected by a neural tube defect may need to take higher doses of folic acid (4-5 mg). However, there are limited data on the pharmacokinetics of higher folic acid doses., Objective: Our aim was to compare steady state folate concentrations in women of childbearing age who took 5 or 1.1 mg folic acid daily for 30 wk., Design: Forty nonpregnant women aged between 18 and 45 y, who did not take folic acid supplements, were enrolled in the study. Subjects were randomly assigned to take either 5 or 1.1 mg folic acid daily for 30 wk. Plasma and red blood cell (RBC) folate concentrations were measured at baseline and at weeks 2, 4, 6, 12, and 30., Results: There was no significant difference in baseline RBC folate concentrations between the 2 groups (1121 +/- 410 and 1035 +/- 273 nmol/L for the 5- and 1.1-mg folic acid groups, respectively). Significant differences in RBC folate were detected between groups at weeks 4, 6, 12, and 30. RBC folate concentrations by week 30 were 2339 +/- 782 and 1625 +/- 339 nmol/L for the 5- and 1.1-mg folic acid groups, respectively., Conclusion: The use of 5 mg folic acid among women of childbearing age produced higher blood folate concentrations, with a faster rate of folate accumulation, compared with 1.1 mg folic acid.

Background: Severe exacerbation of chronic neuropathic pain often requires morphine in patients already treated with drugs such as tricyclic antidepressants, carbamazepine and gabapentin. However, it is unclear if a combination of these drugs intensifies the effects of morphine on the respiratory system and, if so, whether these effects are due to pharmacokinetic or pharmacodynamic interaction., Methods: We gave rabbits (n=6 per group) the following drugs daily for 4 days: subcutaneous normal saline 1 mL (control); amitriptyline subcutaneously 7 mg/kg; carbamazepine orally 100 mg/kg; gabapentin subcutaneously 25 mg/kg; and all three drugs concurrently (combination). On the fifth day, morphine 5 mg/kg was given IV, and Paco2, Pao2 and pH were measured. Morphine, morphine 3-glucoronide and morphine 6-glucoronide concentrations were measured in the plasma over the 4 h period after morphine injection., Results: Compared with controls, premorphine baseline Paco2 was significantly higher (P<0.05) in the amitriptyline group. Postmorphine Paco2 was significantly higher in the amitriptyline and combination groups at all time points over the 240 min, and in the gabapentin group at 10 and 30 min after morphine injection (P<0.05). Peak Paco2 was significantly higher in the amitriptyline group (58.4+/-1.6 mm Hg; mean SD, P<0.005) and in the combination group (57.4+/-1.0 mm Hg, P<0.02) than in the control group (50.2+/-5.2 mm Hg). Similarly, the area under the curve of Paco2 from zero to 240 min was significantly higher in the amitriptyline and combination groups than in the control (P<0.001). There were no significant differences among the groups in plasma concentrations of morphine and its metabolites., Conclusions: We conclude that pretreatment with amitriptyline increases morphine- induced hypercarbia through pharmacodynamic processes. The effects of carbamazepine or gabapentin were not obvious in this model.

Background: A 2001 study suggested that supplementation with 5 mg folic acid, among women of childbearing age, is needed to render maximum protection against neural tube defects (NTD). No human study is presently available which examined the pharmacokinetics of 5 mg folic acid., Objective: To compare the pharmacokinetics of ingesting a single dose of 5 mg versus 1.1 mg folic acid contained in 2 prenatal multivitamins (PregVit and PregVit-Folic 5), and to estimate its contribution to steady-state folate levels., Method: The pharmacokinetics of 1.1 mg folic acid was determined in a previously published study. The method was replicated among 6 healthy, non-pregnant women who were given 5 mg folic acid to ingest. Blood samples were drawn and serum folate concentrations were measured at various time points during 10 hours post-ingestion. Standard pharmacokinetic parameters were determined and compared with Student's t-test, when appropriate., Results: The mean area under the curve (AUC) of 1.1 mg and 5 mg folic acid were 147.6 +/- 52.8 (ng/mL) x hr and 997.5 +/- 271.9 (ng/mL) x hr, respectively (p<0.0002). An approximate 5-fold difference was detected in the peak concentrations (Cmax) between the 2 groups (p<0.0005), alongside a slight difference in the times to peak (Tmax) (p=0.02). The estimated steady-state serum folate concentrations produced by 1.1 mg and 5 mg folic acid were 6.2 +/- 2.2 ng/mL and 41.6 +/- 11.3 ng/mL, respectively (p<0.0002), prior to its summation with initial (baseline) steady-state levels., Conclusion: Single dose administration between 1.1 mg and 5 mg folic acid demonstrated linear pharmacokinetics, with approximately a 5-fold difference between the 2 doses in serum folate contribution to steady-state levels, under ideal adherence.

Introduction: Although a variety of HPLC methods have been previously described for the quantification of glyburide, attempts to implement them clinically have been unsuccessful. Some are time consuming, expensive, or not directly applicable to human plasma. Others are outdated, as the necessary materials are no longer available., Objective: To describe a simple, rapid, and sensitive HPLC method for the analysis of human plasma and perfusate., Design and Method: Samples were extracted by liquid-liquid extraction with chloroform at neutral pH. Glyburide was detected at 254 nm, with a total run time of 7 min per sample., Results: Standard curves of 50 to 400 ng/mL of glyburide were linear (r(2)=0.998). Inter-day and intra-day sample coefficient of variations were 8% and 4%, respectively. Recoveries ranged from 71 to 75% in human plasma samples for the 20-400 ng/mL concentration range., Conclusion: Clinically, this method can be applied in the therapeutic drug monitoring of glyburide.

Aims: To compare the incorporation rate (ICR) of fatty acid ethyl esters (FAEE) in hair between guinea pigs and humans, and to assess the relationship between ethanol exposure and FAEE concentrations in hair., Methods: Published data from pregnant guinea pigs, including maximum blood ethanol concentration (BEC), dosage regimen, and total hair FAEE concentration, were compared with published data from alcoholic patients, where dose of ethanol consumed and total hair FAEE concentration were reported. Mean values of ethanol Vmax for pregnant guinea pigs and humans were obtained from published data (26.2 and 24 mg/dl/h, respectively)., Results: Total and individual FAEE ICRs, defined as the ratio of hair FAEE to the area under the BEC-time curve (total systemic ethanol exposure), were found to be on average an order of magnitude lower in the guinea pig than in the human. The profiles of ester incorporation also differed slightly between species, with ethyl stearate being highly incorporated in guinea pig hair and less so in human hair. The results may reflect in the human greater FAEE production, greater FAEE deposition in hair, slower FAEE catabolism, differential sebum production and composition, or a combination thereof. Also, ethyl oleate was found to correlate with total systemic ethanol exposure for both guinea pigs and humans, correlation coefficients equalling 0.67 (P < 0.05) and 0.49 (P < 0.05), respectively. No other ethyl esters, nor total FAEE, were found to correlate with systemic ethanol exposure., Conclusion: When extrapolating FAEE concentrations in hair from guinea pigs to humans, an order of magnitude difference should be considered, with humans incorporating more FAEE per unit of ethanol exposure. Also, the results suggest caution should be taken when interpreting values of single esters because of their differential incorporation among species. Lastly, our findings suggest ethyl oleate may be of keen interest in FAEE hair analysis, particularly across species.

A newborn infant whose mother had used venlafaxine, a selective inhibitor of both norepinephrine and serotonin reuptake, throughout pregnancy exhibited signs consistent with the norepinephrine and serotonin reuptake withdrawal syndrome. Is it possible that mother's milk can help mitigate the effects of norepinephrine and serotonin reuptake withdrawal? Pharmacokinetic analysis and review of the only published case with active treatment of a baby with venlafaxine suggest that breastfeeding may mitigate the neonatal withdrawal syndrome.

Background: In a new preparation of prenatal multivitamins, PregVit, two tablets a day (a.m. and p.m.) are given. Folic acid is separated from iron and zinc and is given in the p.m. tablet to overcome problems due to folic acid interactions with iron or zinc, and frequent presence of nausea and vomiting of pregnancy in the morning. The circadian variation of folate in humans has not been investigated. This is the first study attempting to determine whether circadian variation of folate pharmacokinetics exists in humans., Objectives: To determine whether circadian rhythm of folate pharmacokinetics exists in humans., Methods: In a crossover design, six healthy, non-pregnant women were randomized to receive 1 tablet of PregVit p.m., containing 1.1 mg of folic acid, in the morning or evening. Serum folate levels were measured over 10 hours. The area under the concentration-time curve (AUC) was used to compare the extent of absorption between the two time periods., Results: The mean AUC values for serum folate after administration of PregVit p.m. were 334.5+/-119.6 nM*h and 283.1+/-64.3 nM*h for morning and evening, respectively (P = 0.17). The morning and evening peak serum folate concentrations were also similar (135.3+/-41.7 nM and 130.3+/-14.2 nM, respectively) (P = 0.75). Similarly, the time to peak for the morning arm (1 0.5 hour) was similar to evening administration (1+/-0.4 hour)., Conclusions: There is no evidence of circadian variation in folate pharmacokinetics. Thus, the introduction of folate in PregVit p.m. will not affect its effectiveness as compared to its routine administration in the morning.

A youngster with long-standing renal failure changed from peritoneal to hemodialysis, which worsened psychiatric symptoms and tics. TDM analysis of potential causes is presented.

This case report involving a placebo-controlled nicotine patch trial illustrates the difficult issue of conducting placebo studies in pregnancy, when one of the two patients involved cannot be asked to consent.

Question: In the 1960s, Dr Cameron, a Montreal, Que, psychiatrist, experimented with drug-induced sleep and electroconvulsive therapy for psychiatric patients, believing that this method "wipes them clean of harmful memories." In 1992 the government of Canada settled lawsuits by former patients of Dr Cameron, awarding them large payments. The government rejected a similar claim by Lloyd Schrier, whose mother had been treated by Dr Cameron while she was carrying Lloyd, arguing that Lloyd was not Cameron's patient. Or was he?, Answer: The fetus was exposed to the medications taken by his mother, (eg, barbiturates) and thus qualifies as an unconsenting patient.

Objective: To compare iron absorption of a prenatal multivitamin supplement containing both iron and calcium (HICA) to that of another multivitamin containing a lower iron dose and no calcium (LI)., Methods: In a crossover study, serum iron was measured in 12 healthy women administered HICA and LI separately on 2 different occasions. Blood samples were taken at 0, 1, 2, 3, 4, 6, and 8 hours after administration of each supplement., Results: The values of the area under the concentration-time curve (AUC) were not significantly different between LI (79.1 +/- 36.0 micro M*h) and HICA (91.4 +/- 50.4 micro M*h) (P =.37). After standardizing the AUC for dose, the relative absorption over the 8-hour time period was significantly higher for LI (2.3 +/-.0 micro M*h/mg) than for HICA (1.5 +/- 0.8 micro M*h/mg) (P =.021)., Conclusion: The absorption of iron from a low-iron-containing supplement was similar to that from a supplement with almost twice the amount of iron, due possibly to the exclusion of calcium in the LI product. Thus, while offering similar amounts of iron, the LI supplement may be better tolerated by women who are sensitive to iron-induced adverse effects.

The detection of fatty acid ethyl esters (FAEE) in meconium may provide an objective estimate of prenatal alcohol exposure independent of maternal history. The authors report the results of the first population-based study conducted to investigate basal FAEE levels in the meconium of neonates not exposed to alcohol. Two hundred seven nondrinking women and their neonates were recruited from Toronto and Jerusalem. FAEE were extracted from meconium by solid-phase extraction and analyzed by GC/FID. Similar procedures were conducted in six neonates born to confirmed heavy drinkers. Low levels of meconium FAEE were detected from both cohorts (mean, 1.37 nmol/g vs. 2.08 nmol/g, Toronto vs. Jerusalem). Ethyl stearate, oleate, and linoleate were below the limit of detection in >80% of all samples, whereas ethyl laurate and palmitate were detected in >50% of the samples. Ethyl myristate was the FAEE most commonly detected (>80%). All six meconium samples with confirmed maternal drinking histories tested positive for FAEE at significantly higher levels (mean, 11.08 nmol/g). The use of 2 nmol total FAEE/g meconium as the positive cutoff, when lauric and myristic acid ethyl esters were excluded, yielded the greatest sensitivity (100%) and specificity (98.4%). The authors conclude that certain FAEE are present at measurable levels in the meconium of neonates not exposed to maternal drinking, and correction is needed to allow high specificity.

Background: Three quarters of neural tube defects (NTD) can be prevented by sufficient dietary folate supplementation. Despite this knowledge, most women do not supplement their diet effectively. Red cell folate concentrations correlate with the risk of NTD, and levels of less than 900 nM are associated with an increased risk of these serious congenital anomalies., Objective: Laboratory tests to assess anemia include testing for folate. This study was conducted to estimate the potential benefits of informing women of reproductive age who are unaware of their low folate levels, uncovered in their anemia tests., Methods: The number of Ontario women of reproductive age who undergo folate tests and are at an increased risk of NTD was calculated. In addition, the authors calculated the number of NTD cases that could have been prevented if these women were informed of the possible consequences of their low folate levels should they become pregnant., Results: In 1998, red cell folate concentrations were measured in 23,109 women of childbearing age (15-45 y). Approximately half of the women [n = 11,392 (49.3%)] had folate levels below 900 nM and thus were at an increased risk of giving birth to a child with NTD should they have become pregnant. Their overall mean relative risk (RR) of NTD was 1.95, or 1:512 births. If they would have been informed of this risk and subsequently increased their consumption of folate before becoming pregnant, 22.3 cases of NTD per year could have possibly been prevented at no extra cost, since the folic acid results were a part of investigational blood tests performed for another reason (anemia)., Conclusions: Women of reproductive age who are being evaluated for the cause of anemia and have low red cell folate results constitute a high-risk group for NTD in their children. These women should be informed of the increased risk and of methods of dietary folate supplementation.

Objective: Folate deficiency in early pregnancy and maternal adiposity, independent of folate intake, lead to a greater risk of neural tube defects in infants. Atypical antipsychotics cause various degrees of weight gain. The authors assessed folate status and obesity among patients with schizophrenia receiving atypical antipsychotics., Method: A sample of 70 inpatients and outpatients (21 of them women) who were taking antipsychotics was randomly selected. Body weight, body mass index, daily folate intake, and folate serum concentrations were determined., Results: The majority of the patients were overweight. Only eight of 37 patients had folate intake above 400 microg/day, the level shown to be protective against neural tube defects. Mean serum folate was significantly lower than in a general hospital group of 810 patients., Conclusions: Women with schizophrenia who take atypical antipsychotics have a higher risk of neural tube defects in their infants because of the associated low intake of folate and obesity.

Background: Acetaminophen is a common cause of poisoning in children. Recent American studies suggest that acetaminophen poisonings pose serious risks in children, particularly in the case of chronic poisoning caused by therapeutic error., Objective: To evaluate whether chronic acetaminophen poisoning in children is a frequent occurrence in a large, Canadian, urban population., Patients and Methods: Retrospective study. Charts of all patients admitted to The Hospital for Sick Children, Toronto, Ontario from January 1, 1990 to June 31, 1996 with an acetaminophen overdose were reviewed., Results: A total of 110 patients were admitted within the study period; only four of whom were preschool children (younger than five years of age). Among the preschool children, three had an acute overdose and one had possible chronic poisoning by therapeutic error. All preschool children were treated with N-acetylcysteine; one developed hepatotoxicity (aspartate aminotransferase or alanine aminotransferase greater than 1000 U/L) after presenting 24 h after acute ingestion. Of the remaining patients, all were adolescents; 102 had acute intentional overdose and four had staggered intentional overdoses. Fifty-three adolescents were treated with N-acetyl cysteine. Hepatotoxicity was present in 13 of 63 adolescents (21%). No patients required liver transplantation or died., Conclusions: Contrary to American experience, chronic acetaminophen poisoning, including therapeutic error in children in Toronto, is a rare occurrence--most cases of acetaminophen poisonings are acute intentional ingestion in adolescents.

Fortification of flour with folic acid aims to prevent neural tube defects. In Canada, flour fortification began in 1997. The objective of this study was to quantify the changes in women's erythrocyte folic acid levels. Comparing these levels among normocytic women revealed an almost twofold increase (from 517+/-215 nmol/L in 1995 to 901+/-318 nmol/L in 1998) (P<0.00001). While the mean value increased substantially, even now, women at the low range of measured values (367 nmol/L) confer a relative risk of 3.2 for neural tube defects. For these women, higher intake of nutritional folic acid and perinatal supplementation of folic acid tablets continue to be crucial.

Summary: Smoking in pregnancy is associated with a well-characterized increase in perinatal risks. Despite their wish to discontinue smoking, some pregnant women cannot stop. To characterize nicotine and cotinine levels in women who could not quit smoking after the first trimester, the authors recruited 19 white women (age 17-41 years) between 14-23 weeks of gestation who could not quit smoking. They started smoking at ages 11-22 years (mean 14.5) and smoked for 17 +/- 6 years. They had their first cigarettes 5-60 minutes after waking up (mean 12). Nicotine levels were compared with those expected in white patients in the general population, and the cotinine levels per cigarette smoked were compared with the population-based values. Sixteen of the 19 women had nicotine levels substantially lower than those expected. The mean level of serum cotinine produced by one cigarette per day was 19.1 +/- 15.8 ng/mL (range 6.1-67). The expected levels in white patients in the general population are 13 +/- 7.7 ng/mL. The data suggest that pregnant women who cannot quit heavy smoking in the second trimester form a selective group with pharmacokinetic predisposition to a high rate of nicotine metabolism.

Objective: To create a nomogram that will guide lactating women who drink socially on how to avoid neonatal exposure to ethanol through breast milk., Design: Pharmacokinetic modeling of ethanol elimination from milk based on reference values. Calculation of the time to zero alcohol in breast milk for a range of doses and body weights., Results: The elimination of alcohol and time-to-zero levels in breast milk are described in a nomogram as a function of the amount of alcohol consumed and the body weight of the woman., Conclusions: Careful planning of a breast feeding schedule, by storing milk before drinking and/or waiting for complete alcohol elimination from the breast milk, can ensure women that their babies are not exposed to any alcohol., (Copyright 2001 S. Karger AG, Basel)

Methadone treatment programs commonly monitor patient compliance by screening urine samples for drugs of abuse. Our experience suggests that re-submission of urine samples (for example, providing a urine sample that is either not that of the patient or was previously submitted) is often used as a method of sample tampering. We have developed an algorithm that combines urine sodium, chloride, creatinine and pH values with urine drug screening results to effectively detect resubmitted samples. Given the widespread use of urine drug screening in drug and alcohol rehabilitation programs, we believe this technique has significant practical benefits. This technique may also have an application in forensic identification of duplicate samples.

Objective: To report an accidental contamination of antibiotic suspension by methadone that occurred in a retail Canadian pharmacy, leading to severe poisoning in a young child., Case Summary: A 4 1/2-year-old healthy Asian boy was prescribed amoxicillin suspension for cough and fever. Shortly after receiving the second dose of 5 mL he became drowsy and less responsive. On admission, he was arousable by deep pain, and pinpoint pupils were noted. A urine sample sent for a toxicology screen revealed the presence of methadone and its metabolite. Blood methadone concentrations were 0.23 and 0.14 mg/L, five and nine hours after the second dose of amoxicillin was given, respectively. The amoxicillin suspension was tested for methadone and was found to have a concentration of 2.4 g/L. The child gradually improved and was discharged on day 4 in good condition. The pharmacy in which the antibiotic was dispensed has been a dispensing center for a local methadone maintenance program, and methadone was accidentally mixed with the antibiotics., Discussion: In this case, a near fatal outcome occurred when methadone was inadvertently mixed with antibiotics in a community pharmacy. A literature search revealed two previous reports of opiate toxicity in children following ingestion of oral antibiotic preparations., Conclusions: Prompt action is needed in Canadian pharmacies that dispense methadone in order to minimize such errors in the future. General practitioners, pediatricians, and emergency department physicians should recognize and suspect this rare cause of opiate toxicity in a child. In a patient presenting with a decreased level of consciousness and miosis, with or without respiratory depression, naloxone administration should be considered, whether or not a history of opioid ingestion is obtained.

This study sought to determine whether saliva concentrations of morphine correlate with plasma levels of morphine in pediatric patients receiving morphine analgesia for severe pain, and to evaluate whether the measurement of saliva morphine concentrations would be a useful, noninvasive, clinical tool to diagnose systemic exposure to morphine. Fifteen pediatric patients were enrolled; for the control group, 18 adult volunteers were recruited. Patients received continuous morphine drips to ameliorate pain caused by a sickle cell vasoocclusive crisis (range, 10-40 micrograms/kg.h). Control subjects were randomized into those receiving acetaminophen with either 8 mg (n = 13) or 30 mg (n = 5) of codeine. All participants fasted at least 2 hours before sample collection. Blood and saliva samples were collected simultaneously. All samples were analyzed by radioimmunoassay for morphine. There was no correlation between saliva and plasma morphine concentrations in either the patients receiving intravenous morphine (r = 0.04, P = 0.89) or in the controls receiving codeine (r = 0.43, P = 0.08). There was no observed difference in the mean counts per minute (CPM) for saliva samples in the pH range 3.96 to 8.06. Saliva concentrations of morphine cannot be used to predict the plasma concentration of morphine in children or adults. However, the concentration of morphine in saliva may be used as a qualitative indicator of systemic exposure to morphine in a subject.

Gender differences in peak breath alcohol concentrations (BrACs) reached in alcohol administration studies can make the interpretation of study findings difficult. This study evaluated the CBAC computer program as a way of minimizing gender differences in the BrAC curve. After consuming a predrink meal that was adjusted by body mass, 31 female and 27 male subjects consumed an alcoholic beverage targeted for either 0.04% or 0.08%. Mean peak BrACs for women and men were not significantly different. Similarly, the four BrAC readings obtained over the first 2 hr postdrink showed no gender differences. A dose x gender interaction was observed on time to peak BrAC, with women reaching peak BrAC faster than men only in the high dose groups. By decreasing gender differences in BrAC curves, this dosing procedure can aid in reducing the potential confound of dose and gender.

A study of risk factors for wound infection among patients undergoing elective cholecystectomy was undertaken. Over a 2-Year period 177 patients who underwent elective cholecystectomy for symptomatic gall stone disease were randomized into groups, one receiving antibiotics (96 patients) and the other not receiving antibiotics (81 patients). Gall bladder bile and wound swab were cultured to detect bacterial growth. Duration of preoperative hospital stay, type of skin incision and operating time were noted for each patient. Postoperatively wound infection developed in 22/177 (12%) patients. The infection rate was lower in the antibiotic group 3/96 (3%) as compared to the non-antibiotic group 19/81 (23.5%). Wound sepsis occurred in 11/37 (23%) of patients with bactibilia as compared to 11/140 (7.8%) patients with sterile bile. Stepwise logistic regression analysis showed that bactibilia and use of prophylactic antibiotics were the most significant predictors of wound infection in low risk patients undergoing elective cholecystectomy.

Dietary intake and plasma lipids were estimated in 200 patients with gallstones and 98 control subjects from a hospital in Northern India and were matched for age, sex, and social class. The intake of total calories and carbohydrates and the plasma triglyceride values were higher in all gallstone patients as compared with controls (p < 0.05 and p < 0.01, respectively). The dietary intake of refined carbohydrates was higher than in controls, but only in the female patients with gallstones (35.6 +/- 32.9 g/day compared with 24.5 +/- 11.8 g/day; p < 0.001). By contrast, the male patients with gallstones had an increased intake of fat (patients 79.0 +/- 38.1 g/day vs. controls 60.2 +/- 24.3 g/day; p < 0.05) and had increased plasma cholesterol values (patients 166.4 +/- 54.2 mg/dl vs. controls 140.3 +/- 32.8 mg/dl; p < 0.01). Such sex differences in the dietary intake and plasma lipid values may form a special feature of gallstone disease in Northern India and should be studied further.

Of 171 patients who were followed-up prospectively for 2.8 years after cholecystectomy, 31 developed postcholecystectomy symptoms, 24 of them being mild to moderate and 7 severe. Symptomatic patients mostly had functioning gall bladders preoperatively and longer duration of symptoms prior to cholecystectomy. The causes of postcholecystectomy symptoms could be identified in all of them except 9 patients who were labelled as having "essential dyspepsia". The symptoms in the latter syndrome as well as in other conditions diagnosed in the symptomatic postcholecystectomy patients appeared unrelated to the absence of gallbladder. Hence, we feel the term postcholecystectomy syndrome is an anachronism and should be redefined.

We present herein two unusual cases of multicentric liposarcoma which highlight the problems associated with the management of this disease entity. When the surgeon is confronted with multicentric liposarcomas, it is necessary to define whether they are secondary tumors or independently arising multicentric liposarcomas, since the latter situation merits a more aggressive approach. Guidelines for this differentiation are suggested in the discussion following the case reports. Surgery, which is often multiple, remains the mainstay of treatment, although adjuvant chemotherapy and radiotherapy are also usually required.

In a double-blind, prospective study, 30 consecutive treatment-naive adult men with first-onset psychosis and DSM-IIIR provisional schizophreniform disorder (without good prognostic features) were randomized into true electroconvulsive therapy (ECT) and sham ECT groups. Both groups received haloperidol in a fixed dose of 15 mg at night. The ECT schedule comprised six bilateral, sinusoidal wave treatments administered on alternate days, thrice a week. Weekly ratings for the first 6 weeks showed an absence of significant difference between the groups in the number of patients responding and in the rate of attenuation of psychosis; severity of depression, while less in the true ECT group after the first 3 weeks, did not differ between the groups at any subsequent time point. Clinical ratings were repeated at 6 months, and social functioning was assessed; again, no group differences emerged. It is concluded that ECT does not meaningfully improve response in unselected schizophreniform disorder that is treated with an adequate dose of neuroleptic.

The first case of synchronous double malignant tumors of the gall bladder having squamous cell carcinoma and an angiosarcoma at different sites is being reported in the world literature. The etiologic, diagnostic and therapeutic aspects of these malignancies and the significance of their concurrence are discussed.

The nutritional status of 24 patients of carcinoma oesophagus was assessed before and after central hyperalimentation with a liquid blenderized diet containing 3000-3500 cal and 100-120 g protein. The overall prevalence of malnutrition was found to be 70.8 per cent before the initiation of therapy. Of the various parameters used for assessment of nutritional status weight loss was the most common finding (91.6%) followed by alteration in midarm circumference, haemoglobin, triceps skin fold thickness, midarm muscle circumference and serum albumin. Enteral hyperalimentation for 10 days improved nutritional status by inducing significant gain in body weight (74.1%), triceps skin fold thickness (50%), midarm circumference (58%), midarm muscle circumference (62.5%) and serum albumin levels (91.6%). There was no significant change in haemoglobin levels.

A 31 year old male presented with high grade fever and abdominal pain of 20 days duration. At the age of 9 he had been operated on for a solitary retroperitoneal hydatid cyst and had been asymptomatic until the age of 21 when he sustained a blunt injury to the abdomen. An exploratory laparotomy for splenic rupture revealed multiple intra-abdominal hydatid cysts, which were removed. The patient remained well until the present episode. An ultrasound examination revealed multiple intra-abdominal hydatid cysts. Seven days after admission, the patient developed hydatidemesis (hydatid cysts and membranes in the vomitus) and hydatidenteria (passage of hydatid membranes in the stools), and his pain and fever subsided. A Gastrografin study and a computerized tomography (CT) scan revealed hydatid cysts communicating with the stomach and duodenum. In view of his disseminated recurrent abdominal hydatidosis, he was treated with high dose, long-term albendazole along with regular follow up. This is the first documented case of disseminated abdominal hydatidosis presenting with a cystogastric fistula and hydatidemesis.

Surgery in patients with surgical obstructive jaundice is known to be associated with increased risk of post-operative acute renal failure. A prospective study was carried out to evaluate the renal function in patients with obstructive jaundice. Renal functions of thirty two patients with jaundice secondary to mechanical obstruction of the biliary tract were evaluated pre-operatively and 7 days after surgical biliary decompression. Although no significant difference was seen in the mean values of pre and post operative renal function variables, two patients had overt renal failure, one with pre-operative cholangitis and acute tubular necrosis and another with carcinoma of the pancreas and postoperative acute renal failure. The overall satisfactory outcome in our obstructive jaundice patients may be related to pre-operative and intraoperative preparation with intravenous fluids and mannitol. It is concluded that patients with obstructive jaundice can be satisfactorily treated with special preoperative care including good hydration and mannitol therapy during anaesthesia and surgery.

In the present paper, major issues related to drug testing are discussed. For example, drug-testing techniques measure the presence of a drug or drugs but are not sophisticated enough to measure impairment from drug use. Moreover, it is difficult to determine the route of drug administration, quantity or frequency, as well as when the drug was taken, on the basis of the laboratory results. Selection of the drug to be tested should depend on the local availability of the drug, its abuse potential and clinical effects, as well as on the availability of analytical technology and expertise in testing and in interpreting laboratory results. The most sophisticated drug-testing approach is gas chromatography coupled with mass spectrometry (GC/MS), which is regarded as a "gold standard"; it is used in confirmatory testing. Typically, GC/MS is preceded by a rapid immunoassay method to eliminate the majority of the "negative" samples. Despite the existence of sophisticated drug-testing methods, it is still possible to obtain incorrect test results. Such results may be caused by the presence of interfering substances or adulteration of the urine sample. A number of techniques can be employed to reduce the likelihood of obtaining erroneous results and to detect adulterated urine samples. A "positive" drug finding can have a serious impact on the livelihood of an individual, therefore, persons conducting such tests should adhere to the strictest standards of laboratory performance. Only qualified and experienced individuals with proper laboratory equipment should perform these analyses. The standards of laboratory performance must meet local legal and forensic requirements. Access to patient samples and laboratory records must be restricted in order to prevent the tampering of samples and results. In order to maintain confidentiality, the results must be communicated only to the medical review officer. Chain-of-custody documents and all file so that they can be examined in case of a legal challenge. The laboratory must have a complete record on quality control. Finally, specific initial and confirmatory testing requirements should be met.

One hundred and fifty patients were prospectively randomised into 3 groups (50 in each group); to receive a passive drain, closed suction drain or no drain after elective cholecystectomy. The drain was removed within 24 hours in 84% of patients and was continued longer only if the amount of drainage was excessive or bilious. On the 3rd post-operative day, an ultrasound examination was performed in all patients for detection of subhepatic/subphrenic collection. Collections were more frequently encountered in the patients without any drain (42%) followed by passive drain (26%) and suction drain group (20%). Chest complications were frequently noted (passive drain; 6% suction drain, 12%, and no drain, 8%), however, occurrence of this complication in various groups was similar (p > 0.1). Two patients (4%) without drain required ultrasound guided aspiration of subhepatic collection. Mean post-operative hospital stay was nearly equal for all the groups (passive drain: 4.22 +/- 1 days, suction drain: 4.26 +/- 1.4 days and no drain: 4.62 +/- 2.3 days). Drainage reduced the incidence of post-cholecystectomy collections and need for invasive intervention for collection related complications. However, the type of drainage (active or passive) did not influence the incidence of collection, frequency of complications and duration of post-operative hospital stay.

Seven teenaged patients with primary oesophageal carcinoma, treated at our hospital in the last 6 years are presented and their management discussed. Five patients had localised disease. Three of them underwent total oesophagectomy, one was given radical radiotherapy, and one was lost to follow-up. Two patients had metastatic disease at presentation. The primary oesophageal carcinoma in this age group may not be so rare as reported in the literature and must be considered in the differential diagnosis of dysphagia. Like their older counterparts, the outcome depends on the stage of the disease and is not influenced by age per se.

Fifty-three patients with suspected gallbladder carcinoma underwent ultrasonography and laparoscopy. Laparoscopy correctly excluded malignancy in five patients when ultrasonography had suggested gallbladder neoplasia. Of 48 patients with gallbladder carcinoma, laparoscopy identified 46 (95.8%) as compared with 30 (62.5%) by ultrasonography (p less than 0.001). Distant metastases in the liver, parietal peritoneum, or omentum were present in 41 patients (85.4%) and were detected by laparoscopy in 39 (sensitivity 95%) and by ultrasonography in 21 (sensitivity 51.2%) (p less than 0.001). Combination of ultrasonography and laparoscopy improved the overall diagnostic accuracy to 100%. Laparoscopy provided histological diagnosis of the disease in 36 patients (75%) and circumvented unnecessary laparotomy in 40 (83.3%) patients by revealing advanced or associated disease. When laparoscopy suggested that the disease was localized, the diagnosis was correct in 83.3% (5 of 6) patients. Laparoscopy under local anesthesia is useful in the diagnosis and staging of gallbladder carcinoma, and therefore helpful in planning management.

We have tested an ethanol reagent strip developed at the Addiction Research Foundation of Ontario. Alcohol dehydrogenase and nicotinamide adenine dinucleotide, in the presence of pyrazole, react with ethanol to yield acetaldehyde plus reduced nicotinamide adenine dinucleotide. The latter reduces iodonitrotetrazolium chloride in the presence of diaphorase, generating an intense red color. The rate of color development is proportional to the concentration of ethanol. Color is compared at a specific time against a calibrated color scale ranging from green (negative) to red, representing alcohol concentrations of 0, 25, 50, 100, 200, and 400 mg/dl (0-0.4%; 0-87 mmol/liter). We were able to interpolate the color observed between the calibrated blocks. When tested on urine, serum/plasma, and saliva, ethanol concentration determined by the reagent strip correlates well with ethanol concentration as determined by gas chromatography or by automated enzymatic analysis (r = 0.92-0.98, p less than 0.001; slope 0.83-1.16). The reagent strip was shown to be used appropriately by nonexperienced individuals following a 1-min explanation (reagent strip values, r = 0.92; p less than 0.001, slope = 0.97, versus gas chromatography). The reagent strip does not react with methanol (wood alcohol), isopropanol (rubbing alcohol), and ethylene glycol (antifreeze) often found in accidental poisonings. In 379 clinical samples obtained without exclusion criteria from 12 hospital emergency rooms and a liver clinic, the sensitivity of the reagent strip in detecting ethanol was 98%. Specificity was 99%. The reagent strip was found to have virtually unlimited stability under refrigeration (4 degrees C) and to be stable for 3 to 4 months at room temperature (22-23 degrees C).(ABSTRACT TRUNCATED AT 250 WORDS)

The present study was carried out at a single surgical unit of AIIMS, to evaluate the risk and benefit of short post-operative stay in adult population after inpatient surgery under general anaesthesia for various intra-abdominal, Genitourinary, breast and thyroid disorders including emergency procedures. The age of the patients ranged from 17-71 years. Patients with minor surgical procedures were excluded from the study. A total number of 138 patients were included in the study comprising of Test group. The patients were discharged within 5 days of the operative procedure. There was no major morbidity or mortality related to early discharge. The mean duration of postoperative length of hospital stay was 5.25 days in test group of patients as compared to 10.20 in control group of patients. In conclusion therefore, short hospitals stay following major procedures is safe and effective in reducing the cost of hospital care to the patient and hospital both.

The nuclear DNA content of 98 operable breast cancers was determined by flow cytometric analysis using paraffin-embedded tissue. All patients were on follow-up and failure of treatment or recurrences were identified. DNA ploidy data in the form of ploidy status and DNA index (DI) has been correlated with various clinical and histopathologic factors. The only significant correlation using univariate analysis exists between the histologic grade and DI (P less than 0.025), recurrence of the disease and ploidy status (P less than 0.005), and recurrence of the disease and DI (P less than 0.005). The absence of correlation of ploidy status with other tumor derived factors indicates the independent nature of ploidy as a prognostic factor. Multivariate analysis showed that in the whole-group ploidy (P less than 0.01), tumor margin (P less than 0.01), and menopausal status (P less than 0.01) were significant factors in the order mentioned. DI with a cut of at 1.29 is not found to be a significant factor in the multivariate analysis. The maximum prognostic value of ploidy status was observed in the postmenopausal group (P less than 0.0005). In the node-negative group ploidy status (P less than 0.05) is the only independent significant factor predicting for early relapse. It is concluded that ploidy status is an independent prognostic factor predicting for recurrence of the disease. In the node-negative subgroup this could be used to identify the subset of patients who may benefit from adjuvant treatment.

Sixty nine patients with a median age of 45 years, 62.3 per cent of whom were premenopausal, with locally advanced breast cancer (T 4, N 0-3, M 0; Stage IIIb) were treated with 3 cycles of either neoadjuvant cyclophosphamide, doxorubicin and 5-fluorouracil, being the CAF group: 36 patients, or cyclophosphamide, methotrexate and 5-fluorouracil, being the CMF group: 33 patients. Patients achieving complete response or with residual disease of less than 2 cm in diameter received radical radiotherapy while those with more residual disease underwent radical mastectomy. Nine cycles of adjuvant chemotherapy were administered. Complete responses and disease control by radiotherapy with complete breast preservation were more frequently observed after CAF than CMF, being 25 per cent vs 3 per cent (p = 0.025) and 48.5 per cent vs 12 per cent (p = 0.002), respectively. Overall response rates, adverse effects, disease control following radiotherapy/surgery, local relapses and metastases were similar for both regimes. Relapsing patients were young, with a median age of 38 years, 68.4 per cent of relapses occurred at metastatic sites and 42 per cent of relapses occurred during adjuvant chemotherapy. This study suggests that in locally advanced breast cancer, a greater proportion of patients can be rendered disease free after neoadjuvant CAF and radiotherapy compared to neoadjuvant CMF and radiotherapy.

Primary breast lymphoma (PBL) is a rare tumor of the breast. Three cases of PBL are being described. All three cases achieved remission following biopsy, chemotherapy, and/or radiotherapy. The literature is extensively reviewed with emphasis on true incidence of PBL and survival rates.

Laparoscopy was performed in 40 patients with gastric carcinoma, whose lesions were otherwise considered amenable to operation, in order to more accurately stage the disease and ascertain the prospect of resectability. Laparoscopy disclosed hitherto unrecognized distant metastases in 5 cases (12.5%) and locally advanced, unresectable neoplasia in 11 cases (27.5%). Thus, laparoscopy served as a basis for avoiding the burden of futile laparotomy in 16 patients (40%). Laparoscopy confirmed the feasibility of resection in 24 patients, and this finding was borne out in 20 of 23 patients surgically explored (87%). The overall diagnostic accuracy of laparoscopy was 91.6%. Laparoscopy was performed in these patients with no mortality or morbidity. We conclude that laparoscopy is an effective means of evaluating resectability of gastric carcinomas and can provide valuable help in planning surgical approach.

Duodenoscopic sphincterotomy (DS) is a well established treatment for common bile duct (CBD) stones in post-cholecystectomy patients, but not in patients with gallbladder in situ. The main argument against the procedure in the latter set of patients has been that by performing it, one is leaving behind the diseased gallbladder which may require further treatment. We have, however, performed 60 DS in 49 patients with gallbladder in situ. The clinical picture of these patients was characterized by abdominal pain in 79.6%, jaundice in 91.8%, history of cholangitis in 46.9%, severe acute cholangitis at the time of DS in 28.6% and a major associated illness in 10.2% of them. Adequate sphincterotomy was performed in 91.8% of the patients with successful stone extractions in 93.3% and an overall CBD clearance in 85.7%. One patient (2%) with severe acute cholangitis, who had presented in a moribund state, died despite adequate DS. Three patients (6%) experienced an exacerbation of acute cholangitis after DS, two of them requiring emergency surgery. During subsequent follow-up, elective cholecystectomy was performed in 26 (54%) patients. Five additional patients are awaiting surgery. Seventeen (36%) patients continue to have their gallbladders in situ and over a mean follow-up period of 12.8 months (range, 4-32 mos) they have remained asymptomatic except for brief episodes of biliary pain in 2 patients. It is concluded that DS relieves the symptoms of CBD stones even in patients with gallbladders in situ and may suffice for patients who are frail, elderly and who have major associated illnesses.

Superior vena cava syndrome, an uncommon manifestation of carcinoma of the thyroid, is usually due to retrosternal extension of the growth. Rarely, however, there may be direct tumour extension into the great veins of the neck, which may cause sudden death. Only eight such cases have been reported in the English literature. The case reported by us is the first to be documented by computed tomography. Patients with carcinoma of the thyroid with the superior vena cava syndrome should undergo computed tomography to differentiate external compression due to goitre from intraluminal tumour.