Life-threatening hypokalaemia associated with ibuprofen-induced renal tubular acidosis.

Renal tubular acidosis is an underreported complication of ibuprofen misuse, and can result in life-threatening hypokalaemia. We describe four patients who presented with profound hypokalaemia and muscle weakness associated with excessive ibuprofen ingestion. Ibuprofen cessation and supportive management resulted in complete biochemical resolution within a few days. These cases remind practitioners about potential complications of unmonitored use of over-the-counter analgesics, including those with potential for misuse due to their codeine content.

Metabolic predictors of obesity. Contribution of resting energy expenditure, thermic effect of food, and fuel utilization to four-year weight gain of post-obese and never-obese women.

This prospective study was designed to identify abnormalities of energy expenditure and fuel utilization which distinguish post-obese women from never-obese controls. 24 moderately obese, postmenopausal, nondiabetic women with a familial predisposition to obesity underwent assessments of body composition, fasting and postprandial energy expenditure, and fuel utilization in the obese state and after weight loss (mean 12.9 kg) to a post-obese, normal-weight state. The post-obese women were compared with 24 never-obese women of comparable age and body composition. Four years later, without intervention, body weight was reassessed in both groups. Results indicated that all parameters measured in the post-obese women were similar to the never-obese controls: mean resting energy expenditure, thermic effect of food, and fasting and postprandial substrate oxidation and insulin-glucose patterns. Four years later, post-obese women regained a mean of 10.9 kg while control subjects remained lean (mean gain 1.7 kg) (P < 0.001 between groups). Neither energy expenditure nor fuel oxidation correlated with 4-yr weight changes, whereas self-reported physical inactivity was associated with greater weight regain. The data suggest that weight gain in obesity-prone women may be due to maladaptive responses to the environment, such as physical inactivity or excess energy intake, rather than to reduced energy requirements.

Prediction of resting energy expenditure from fat-free mass and fat mass.

On the basis of literature values, the relationship between fat-free mass (FFM), fat mass (FM), and resting energy expenditure [REE (kJ/24 h)] was determined for 213 adults (86 males, 127 females). The objectives were to develop a mathematical model to predict REE based on body composition and to evaluate the contribution of FFM and FM to REE. The following regression equations were derived: 1) REE = 1265 + (93.3 x FFM) (r2 = 0.727, P < 0.001); 2) REE = 1114 + (90.4 x FFM) + (13.2 x FM) (R2 = 0.743, P < 0.001); and 3) REE = (108 x FFM) + (16.9 x FM) (R2 = 0.986, P < 0.001). FM explained only a small part of the variation remaining after FFM was accounted for. The models that include both FFM and FM are useful in examination of the changes in REE that occur with a change in both the FFM and FM. To account for more of the variability in REE, FFM will have to be divided into organ mass and skeletal muscle mass in future analyses.

Role of fat oxidation in the long-term stabilization of body weight in obese women.

Two studies were performed to investigate the association between body fat mass and fat oxidation. The first, a cross-sectional study of 106 obese women maintaining stable body weight, showed that these two variables were significantly correlated (r = 0.56, P less than 0.001) and the regression coefficient indicated that a 10-kg change in fat mass corresponded to a change in fat oxidation of approximately 20 g/d. The second, a prospective study, validated this estimate and quantifies the long-term adaptations in fat oxidation resulting from body fat loss. Twenty-four moderately obese women were studied under controlled dietary conditions at stable weight before and after mean weight and fat losses of 12.7 and 9.8 kg, respectively. The reduction in fat oxidation was identical to that predicted by the above regression. We conclude that changes in fat mass significantly affect fat oxidation and that this process may contribute to the long-term regulation of fat and energy balance in obese individuals.

Effect of weight reduction on resting energy expenditure, substrate utilization, and the thermic effect of food in moderately obese women.

It is not known whether the decrease in the thermic effect of food (TEF) in obesity is a consequence of obesity or a factor contributing to the development of obesity. The resting energy expenditure (REE) of 24 obese, nondiabetic, postmenopausal women was 5481 +/- 110 kJ/24 h (1310 +/- 26.4 kcal/24 h). After weight loss (12.7 +/- 0.45 kg) the REE was significantly decreased (4858 +/- 94 kJ/24 h, or 1161 +/- 22.4 kcal/24 h) and equivalent to the REE of 4866 +/- 119 kJ/24 h (1163 +/- 28.5 kcal/24 h) in 24 never-obese, postmenopausal women. The TEF, expressed as a percentage of the calories ingested, was 8.2 +/- 0.50% for obese subjects, 8.7 +/- 0.57% for postobese subjects, and 9.8 +/- 0.54% for never-obese subjects. Compared with never-obese subjects, the TEF was significantly reduced in obese subjects (P = 0.043) and remained unchanged after weight loss (P = 0.341). These findings indicate that the lower TEF in the obese subjects is uncorrected by weight loss, and thus it is a contributor to obesity rather than a consequence of obesity.

Time course of changes in gluconeogenesis from various precursors in chronically endotoxemic rats.

Rates of gluconeogenesis (GNG) from lactate and triosephosphate precursors were measured in hepatocytes isolated from rats that have received endotoxin or physiological saline by continuous infusion from an implanted pump. Six hours after the onset of infusion (day 2 postsurgery) GNG from lactate was significantly elevated in hepatocytes of endotoxemic (ET) animals. By 24 hours later, the gluconeogenic rate was depressed, compared to cells of NaCl-infused controls. However, providing ET cells with lactate at concentrations found in the in vivo milieu resulted in glucose production at rates not different from those of control cells incubated at their respective in vivo (lower) substrate levels. On day 2 postsurgery, ET rats were hyperglycemic and hyperlactacidemic; on day 3 the elevated blood lactate concentration was maintained, but the plasma glucose values were not different from those of NaCl controls. The glucagon-induced increment in glucose synthesis was depressed in cells of ET rats both on day 2 and day 3 postsurgery, although the total amount of glucose released was significantly less only on day 3. The pattern of norepinephrine stimulation was similar to that of glucagon, except for the increase above the basal rate of GNG on day 3 being the same for control and ET cells. GNG was also assessed from oxidized substrates (fructose (F) and dihydroxyacetone (DHA] and reduced substrates (sorbitol and glycerol) entering the pathway at the triosephosphate level. On day 2 both cell populations produced glucose from each of the four precursors at comparable basal rates.(ABSTRACT TRUNCATED AT 250 WORDS)

Protein turnover in advanced lung cancer patients.

Understanding the extent to which changes in whole-body protein kinetics contribute to the commonly observed weight loss and decrease in lean body mass (LBM) in patients with cancer is currently obscured by conflicting reports in the literature. While several studies have reported significant increases in whole-body protein turnover (WBPT), synthesis (WBPS), and catabolism (WBPC) in patients with cancer, others have failed to confirm these observations. We have measured whole-body protein kinetics using a primed constant infusion of 15N-glycine in a homogenous group of 32 newly diagnosed advanced lung cancer patients with comparable staging and before any antineoplastic treatment, and in 19 normal healthy volunteer controls. Urinary urea and ammonia 15N enrichment was determined in individually collected urine samples obtained during the 24-hour study period and averaged for the determination of protein kinetics. During the last 6 hours of urine collection, samples were obtained hourly for determination of 15N plateau enrichment. Twenty-four-hour urinary nitrogen and creatinine excretion was determined from 24-hour pooled urine samples. Resting metabolic expenditure (RME) was determined by indirect calorimetry and LBM was estimated from deuterium oxide dilution. Age body weight, LBM, RME, and 24-hour urinary nitrogen excretion did not differ between cancer and control subjects. WBPT, WBPC, and WBPS (g/kg/d) were significantly increased in lung cancer patients. However, when the same results were expressed either per kilogram LBM or per gram 24-hour urinary creatinine excretion, WBPT, WBPC, and WBPS rates were not statistically different from those of the controls.(ABSTRACT TRUNCATED AT 250 WORDS)

Protein and energy balance following femoral neck fracture in geriatric patients.

To elucidate the effect of total peripheral parenteral nutrition (TPPN) on protein kinetics following injury, we compared the whole-body leucine kinetic response using a primed-constant infusion of L-[1-14C]leucine in 33 elderly patients (aged 82 +/- 1.0 years) following hip fracture and 33 healthy elderly control subjects (aged 75 +/- 0.7 years). Following a 36-hour fast, leucine release from protein breakdown was 1.2 +/- 0.10 mumol.kg-1.min-1 and leucine incorporation into protein was 0.94 +/- 0.095 mumol.kg-1.min-1 in control subjects, and in injured subjects leucine release from protein breakdown was 1.3 +/- 0.14 mumol.kg-1.min-1 and leucine incorporation into protein was 0.97 +/- 0.092 mumol.kg-1.min-1. Control and injured subjects were then administered TPPN (protein, 1.5 g amino acids.kg-1; carbohydrate, 10.0 kcal.kg-1; lipid, 15.0 kcal.kg-1) for 24 hours, and leucine kinetics were redetermined. Compared with protein kinetics in the fasting state, leucine release from protein decreased to 1.0 +/- 0.14 mumol.kg-1.min-1 and leucine incorporation into protein increased to 1.16 +/- 0.097 mumol.kg-1.min-1 in control subjects. Injured patients also responded to TPPN with a decrease in leucine release from protein breakdown (1.12 +/- 0.156 mumol.kg-1.min-1) and an increase in leucine incorporation into protein (1.29 +/- 0.164 mumol.kg-1.min-1). These results indicate that in a geriatric population, whole-body leucine kinetics following hip fracture and the anabolic response to TPPN are not significantly altered from those of uninjured subjects.(ABSTRACT TRUNCATED AT 250 WORDS)

Regulation of glucose kinetics in trauma patients by insulin and glucagon.

The current study was undertaken to evaluate the contribution of insulin and glucagon to regulation of glucose metabolism in man following severe, traumatic injury by manipulating concentrations of insulin and glucagon with infusions of somatostatin. Glucose kinetics were assessed with [U-14C, 6-(3)H]glucose in severely injured patients and compared with data obtained from patients recovering from minor, elective operative procedures. Glucose production was significantly increased in subjects with traumatic injury compared with control subjects (13.0 +/- 0.63 mumol/kg/min v 8.6 +/- 0.27 mumol/kg/min). There was no impairment in glucose oxidation by the injured patients. Modulation of insulin and glucagon with somatostatin indicated that non-insulin-mediated glucose uptake (NIMGU) was significantly elevated in injured patients (12.2 +/- 0.94 mumol/kg/min v 7.4 +/- 0.61 mumol/kg/min). Hepatic glucose output (HGO) in the absence of glucagon was also significantly elevated in injured patients (12.2 +/- 1.20 mumol/kg/min v 5.8 +/- 1.08 mumol/kg/min). Indirect calorimetry showed a 27% increase in resting energy expenditure (REE). Increased protein oxidation accounted for 56% of the increase in REE. Changes in carbohydrate and lipid oxidation accounted for 28% and 15% of the increase in REE. There was no correlation between the injury severity score of the injured patient and the degree of metabolic abnormality. It is concluded from these studies that (1) injured patients have a high rate of glucose turnover in the absence of glucagon and insulin; (2) the reliance on glucose as a source of energy is not diminished in injured subjects; and (3) increases in protein oxidation account for the majority of the increased REE found in injured patients.

Enhanced lipolysis is not evident in adipocytes from exercise-trained SHR.

Adipocytes from spontaneously hypertensive rats (SHR) are not as responsive to isoproterenol or dibutyryl adenosine 3',5'-cyclic monophosphate (cAMP) stimulation compared with Sprague-Dawley or Wistar-Kyoto rats. Lipolytic activity in adipocytes from trained normotensive rats was enhanced in response to 1 microM isoproterenol and 0.5 mM dibutyryl cAMP but not in adipocytes from trained SHR. Decreases in isoproterenol-stimulated (1 microM) cAMP accumulation were evident in adipocytes from trained normotensive rats but not in adipocytes from trained SHR. Basal and agonist-induced lipolysis in fat cells isolated from both normotensive rats and SHR immediately following a 60-min run was increased in both sedentary and trained rats. Adenylate cyclase activity in fat cell membranes was blunted in sedentary and trained SHR both in the absence and presence of 100 microM 5'-guanylyl imidophosphate. No apparent differences existed in antagonist affinity of binding sites for the antagonist dihydroalprenolol in normal rats or SHR. Evidence for a change in affinity of agonist isoproterenol might be indicated based on the enhanced potency of isoproterenol to stimulate lipolysis in trained normal rats. beta-Adrenergic receptor density and antagonist affinity were not different in normotensive rats and SHR in response to training. However, displacement of [3H]dihydroalprenolol in adipocytes from SHR required greater concentrations of isoproterenol compared with adipocytes from normotensive rats, further suggestive of increased agonist affinity of binding sites in normal rats. These data suggest a postreceptor lesion of the lipolytic pathway in adipocytes from spontaneously hypertensive rats, possibly at the guanine nucleotide regulatory protein level.(ABSTRACT TRUNCATED AT 250 WORDS)

Drug-related hospital admissions.

To describe the frequency and pattern of drug-related morbidity that results in hospital admission and the extent to which these admissions are avoidable, we prospectively reviewed the charts of 452 consecutive patients admitted to the intensive care unit or internal medicine service of a university-affiliated, county hospital. Of these, 73 (16.2%) were admitted due to drug-related morbidity. Forty patients (54.8%) experienced drug therapy failure, 24 (32.9%) had an adverse reaction, and 9 (12.3%) had overdoses. Thirty-six (49.3%) of these admissions were definitely avoidable. Compared with patients admitted for other reasons, these patients were more likely to report noncompliance with drug therapy (65.8% vs 15.7%, p < 0.0001) and were taking more drugs (p = 0.0037). We conclude that approximately half of drug-related hospital admissions are avoidable. Targeting patients taking several drugs and with a history of noncompliance may reduce this problem.

How to develop and implement a program to continuously demonstrate the value of clinical pharmacy services.

This paper summarizes key elements that support the success of clinical pharmacy services to continuously improve the quality of drug therapy. Five drivers identify a successful model for continuously demonstrating the value of clinical pharmacy services: knowing the organizational culture; providing leadership; recruiting pharmacy sponsors; showing tenacity; and acting with management courage. Difficulties encountered when communicating the value of clinical pharmacy services within a health care organization usually arise because of failure to include one of these drivers.

Whole-body protein kinetics in elective surgical patients receiving peptide or amino acid solutions.

We compared the efficacy of two enteral solutions that were isonitrogenous and of identical amino acid composition but differed in that one solution contained only free amino acids whereas the other contained a mixture of free amino acids and peptides. Protein kinetics and nitrogen balance were evaluated in a group of six elective surgical patients. Primed-constant infusion with 15N-glycine was started 24h after gynecologic surgery and sustained over 3 days. During the first postoperative day, patients received enteral 0.45% saline. During postoperative days two and three, the patients received either the free amino acid solution or the mixture of peptides and free amino acids in a crossover design. There were no differences in protein kinetics or nitrogen balance with the two treatments.

Glucose metabolism in advanced lung cancer patients.

Although it is generally accepted that altered nutrient intake and metabolism are responsible for the progressive loss of body weight observed in most advanced cancer patients, there is still considerable controversy regarding the contributory role of changes in both resting energy expenditure (REE) and glucose metabolism. Several studies suggest increases in both REE and glucose appearance in advanced cancer patients compared with healthy control subjects, whereas others revealed no changes in either metabolic parameter. We measured REE with indirect calorimetry and glucose kinetics with a primed constant infusion of D-[U-14C]glucose and D-[6-3H]glucose over the last 4 h of a 24-h fast in 32 advanced lung cancer patients immediately after diagnosis and before any chemotherapy or radiotherapy and in 19 healthy volunteer subjects. REE for the lung cancer group was not significantly different from that in the control group (1535.8 +/- 78.0 vs. 1670.2 +/- 53.9 kcal/day, respectively, p = 0.151). When REE was expressed as a function of body weight, or lean body mass, no differences between the two groups were observed. The rate of glucose appearance was 9.88 +/- 0.36 mumol.kg-1.min-1 in the cancer patients and 10.15 +/- 0.53 mumol.kg-1.min-1 in control subjects (p = 0.667), of which 50.4 versus 58.2%, respectively, was oxidized. The amount of glucose recycled was 13.54 +/- 1.22% in cancer patients and 15.08 +/- 0.99% in control subjects (p = 0.394). The amount of VCO2 from direct oxidation of glucose was 23.39 +/- 0.74% in cancer patients and 27.45 +/- 1.36% in control subjects (p = 0.006).(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of insulin on glucose and amino acid uptake by skeletal muscle following burn injury. Studies with 2-deoxyglucose and alpha-aminoisobutyric acid.

Basal and insulin-stimulated uptake of 2-deoxyglucose (2-DG) and alpha-aminoisobutyric acid (AIB) by cells of the intact soleus muscle were studied 3 days after a 3-second scald on one hind limb of the rat. Soleus muscles from the burned and unburned limbs of burned rats, as well as from controls, were incubated with 1 mM [14C]2-DG or 50 micro M [14C] AIB and insulin (0, 1, 1.0, 10.0, or 100.0 mU/ml). Extracellular space was measured with [3H]inulin. Basal uptake of 2-DG and AIB by the cells of the burned limb muscles were 68% (p less than 0.001) and 40% (p less than 0.05), respectively, higher than those of controls. The intracellular concentrations of 2-DG and AIB of burned limb muscles were 112% (p less than 0.01) and 72% (p less than 0.01), respectively, higher than those in control muscles. Corresponding values in soleus muscles from the unburned limb of burned rats did not differ from controls. Addition of insulin increased both the rates of cellular uptake and intracellular concentrations of 2-DG and AIB in control and burned limb muscles but did not significantly affect those of burned limb muscles. It is concluded that thermal injury suppresses the insulin-induced augmentation of 2-DG and AIB uptake by skeletal muscle underlying the burn wound but does not alter the insulin sensitivity of skeletal muscle in the unburned region. Since glucose and amino acid uptakes are stimulated by insulin independently, the cellular mechanism of the burn-induced unresponsiveness to insulin may be located at a site which is common to both processes.

Glutamine supplementation of enteral nutrition: impact on whole body protein kinetics and glucose metabolism in critically ill patients.

BACKGROUND: Glutamine-supplemented parenteral nutrition has been reported to attenuate the early postoperative reduction in intracellular glutamine and improve protein synthesis and nitrogen balance. We investigated the effect of an enteral formula or protein and glucose kinetics and nitrogen balance in trauma patients. METHODS: The enteral formula (AlitraQ) provided a mean intake of 0.35 g of glutamine/kg body weight per day to 16 trauma patients and was compared with an isonitrogenous formula that provided a mean of 0.05 g of glutamine/kg body weight per day in 14 trauma patients. After 3 days of feeding, protein kinetics were measured using a 4-hour prime-continuous infusion of L-[1-13C]leucine. Glucose kinetics were measured during the same time interval using prime-continuous infusion of [U-14C]- and [6-3H]glucose. RESULTS: Nitrogen balance was not significantly different in the two groups. There were no significant differences in protein turnover, synthesis, and breakdown between the two groups. There were no significant differences in glucose turnover, oxidation, recycling, and percent of VCO2 from glucose oxidation between the two groups. CONCLUSIONS: Glutamine-enriched enteral formulas are well tolerated by the severely injured patient but provide no additional nutritional advantage compared with standard enteral formulas during the first 3 days of feeding immediately after trauma.

Relationship of standardized mitotic indices to other prognostic factors in breast cancer.

OBJECTIVE: To examine the relationship between mitotic index (MI), calculated from direct microscopic counts, and other prognostic features in breast cancer. DESIGN: Mitotic index was based on direct microscopic observations of mitotic figures in 10 consecutive microscopic fields, and the average cell number was determined by counts of population density in three of those fields. Tumor grade and type were established from tissue sections, whereas metastases were detected in lymph node biopsy, chest roentgenograms, and bone scan. Estrogen receptor (ER) and progesterone receptor (PgR) levels were determined by flow cytometry. RESULTS: The MI for 242 patients ranged from 0.2 to 37.6, with a mean of 5.8 mitoses per 1000 cells. More than 85% of the tumors with an MI below 1.0 were diploid and contained an S-phase fraction of 6.7% or less. In contrast, more than 75% of tumors with an MI above 5.0 were aneuploid with more than 6.7% of cells in S-phase. There was an inverse relationship between ER and PgR status and MI. Eighty percent of tumors with an MI less than 1.0 were both ER and PgR positive while only 25% of those with an MI above 10.0 were both ER and PgR positive. Receptor-positive tumors with high S-phase and MI values had ER and PgR levels below 100 fmol/mg. CONCLUSIONS: Lower MI values calculated from direct cell counts are correlated with negative node status, diploid DNA content, low S-phase fraction, and positive receptor status. Thus, there is a significant relationship between objective MI values and several other factors that predict the probability of breast tumor recurrence.

A comparison of methods for self-adaptation in evolutionary algorithms.

Evolutionary algorithms, including evolutionary programming and evolution strategies, have often been applied to real-valued function optimization problems. These algorithms generally operate directly on the real values to be optimized, in contrast with genetic algorithms which usually operate on a separately coded transformation of the objective variables. Evolutionary algorithms often rely on a second-level optimization of strategy parameters, tunable variables that in part determine how each parent will generate offspring. Two alternative methods for performing this second-level optimization have been proposed and are compared across a series of function optimization tasks. The results appear to favor the approach offered originally in evolution strategies, although the applicability of the findings may be limited to the case where each parameter of a parent solution is perturbed independently of all others.

Combined tubal and cornual pregnancy in a patient without risk factors. A case report.

BACKGROUND: Ectopic pregnancy is the leading cause of pregnancy-related death during the first trimester. Bilateral ectopic pregnancy is a rare phenomenon, varying in frequency between 1 per 725 and 1 per 1,580 ectopic pregnancies. We report the case of a bilateral ectopic pregnancy (ruptured right cornual and intact left ampullary) in a patient with no known risk factors for extrauterine gestation. CASE: A 33-year-old, black woman, gravida 2, para 1001, presented at approximately 7 weeks' gestation with the acute onset of abdominal pain. She had a rigid surgical abdomen but was hemodynamically stable. Her beta-human chorionic gonadotropin level was 6,398 mIU/mL, and transvaginal ultrasound failed to reveal an intrauterine gestation, adnexal mass or cul-de-sac fluid. Findings at laparotomy included a 500-mL hemoperitoneum and a ruptured right cornual and intact left ampullary pregnancy. Pathology of both specimens confirmed the presence of chorionic villi. CONCLUSION: Although rare, heterotopic pregnancies can occur even in patients without risk factors.

Nosocomial transmission of Cryptosporidium in a veterinary hospital.

An outbreak of cryptosporidiosis occurred at a veterinary hospital, involving multiple species, including humans. The index case was an infected dairy calf that presented with diarrhea. Several other cases of cryptosporidial diarrhea subsequently developed during a 1-month period. The key features of this outbreak were the multiple species affected, the increased morbidity in immunocompromised neonates, and the failure of implemented control measures to contain the disease.